Cystic Fibrosis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

CYSTIC FIBROSIS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

J AM ES N. P ARK ER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2003 by ICON Group International, Inc. Copyright ©2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Cystic Fibrosis: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83617-5 1. Cystic Fibrosis-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on cystic fibrosis. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes & Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON CYSTIC FIBROSIS ........................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Cystic Fibrosis............................................................................... 9 E-Journals: PubMed Central ..................................................................................................... 122 The National Library of Medicine: PubMed .............................................................................. 140 CHAPTER 2. NUTRITION AND CYSTIC FIBROSIS ............................................................................ 273 Overview.................................................................................................................................... 273 Finding Nutrition Studies on Cystic Fibrosis ........................................................................... 273 Federal Resources on Nutrition ................................................................................................. 280 Additional Web Resources ......................................................................................................... 281 CHAPTER 3. ALTERNATIVE MEDICINE AND CYSTIC FIBROSIS...................................................... 283 Overview.................................................................................................................................... 283 The Combined Health Information Database............................................................................. 283 National Center for Complementary and Alternative Medicine................................................ 284 Additional Web Resources ......................................................................................................... 315 General References ..................................................................................................................... 317 CHAPTER 4. DISSERTATIONS ON CYSTIC FIBROSIS ....................................................................... 319 Overview.................................................................................................................................... 319 Dissertations on Cystic Fibrosis ................................................................................................ 319 Keeping Current ........................................................................................................................ 323 CHAPTER 5. CLINICAL TRIALS AND CYSTIC FIBROSIS .................................................................. 325 Overview.................................................................................................................................... 325 Recent Trials on Cystic Fibrosis ................................................................................................ 325 Keeping Current on Clinical Trials ........................................................................................... 342 CHAPTER 6. PATENTS ON CYSTIC FIBROSIS .................................................................................. 345 Overview.................................................................................................................................... 345 Patents on Cystic Fibrosis.......................................................................................................... 345 Patent Applications on Cystic Fibrosis...................................................................................... 376 Keeping Current ........................................................................................................................ 383 CHAPTER 7. BOOKS ON CYSTIC FIBROSIS ...................................................................................... 385 Overview.................................................................................................................................... 385 Book Summaries: Federal Agencies............................................................................................ 385 Book Summaries: Online Booksellers......................................................................................... 390 The National Library of Medicine Book Index ........................................................................... 396 Chapters on Cystic Fibrosis ....................................................................................................... 397 Directories.................................................................................................................................. 399 CHAPTER 8. MULTIMEDIA ON CYSTIC FIBROSIS ........................................................................... 401 Overview.................................................................................................................................... 401 Video Recordings ....................................................................................................................... 401 Bibliography: Multimedia on Cystic Fibrosis ............................................................................ 403 CHAPTER 9. PERIODICALS AND NEWS ON CYSTIC FIBROSIS ........................................................ 405 Overview.................................................................................................................................... 405 News Services and Press Releases.............................................................................................. 405 Newsletter Articles .................................................................................................................... 411 Academic Periodicals covering Cystic Fibrosis.......................................................................... 411 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 413 Overview.................................................................................................................................... 413 U.S. Pharmacopeia..................................................................................................................... 413 Commercial Databases ............................................................................................................... 416

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Contents Researching Orphan Drugs ....................................................................................................... 417 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 423 Overview.................................................................................................................................... 423 NIH Guidelines.......................................................................................................................... 423 NIH Databases........................................................................................................................... 425 Other Commercial Databases..................................................................................................... 428 The Genome Project and Cystic Fibrosis ................................................................................... 428 APPENDIX B. PATIENT RESOURCES ............................................................................................... 433 Overview.................................................................................................................................... 433 Patient Guideline Sources.......................................................................................................... 433 Associations and Cystic Fibrosis................................................................................................ 439 Finding Associations.................................................................................................................. 444 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 447 Overview.................................................................................................................................... 447 Preparation................................................................................................................................. 447 Finding a Local Medical Library................................................................................................ 447 Medical Libraries in the U.S. and Canada ................................................................................. 447

ONLINE GLOSSARIES................................................................................................................ 453 Online Dictionary Directories ................................................................................................... 457 CYSTIC FIBROSIS DICTIONARY ............................................................................................ 459 INDEX .............................................................................................................................................. 539

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with cystic fibrosis is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about cystic fibrosis, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to cystic fibrosis, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on cystic fibrosis. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to cystic fibrosis, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on cystic fibrosis. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON CYSTIC FIBROSIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on cystic fibrosis.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and cystic fibrosis, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “cystic fibrosis” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Liver Disease in Pediatric Patients with Cystic Fibrosis is Associated with Glutathione S-Transferase P1 Polymorphism Source: Hepatology. 36(4 Part 1): 913-917. October 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Liver disease in patients with cystic fibrosis (CF) is inconstant and has not yet been clearly related to any specific risk factor. Among liver detoxifying enzymes, the glutathione S-transferases (GSTs) play a key role in the protection against oxidative stress. This article reports on a study that provides the first demonstration of a significant association between GST gene polymorphism and the development of liver disease in patients with CF. The authors hypothesize that the major role of GSTs as

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detoxifying enzymes is probably emphasized in CF disease by the frequent use of antibiotics and other drugs in these patients. Identification of GSTP1 polymorphism may have prognostic significant in pediatric patients with CF and may direct more targeted therapy toward children with an increased risk of liver disease. 3 tables. 25 references. •

Liver Disease in Cystic Fibrosis: A Prospective Study on Incidence, Risk Factors, and Outcome Source: Hepatology. 36(6): 1374-1382. December 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Incidence of liver disease (LD) associated with cystic fibrosis (CF) and its clinical characterization still is unsettled. The authors of this article assessed prospectively the incidence and risk factors of this complication, and its impact of the clinical course of CF. Between 1980 and 1990, the authors enrolled 177 CF patients without LD in a systematic clinical, laboratory, ultrasonography screening program of at least a 10 year duration. During a 14 year median follow (2,432 patient-years), 48 patients developed LD, with cirrhosis already present in 5 patients. Incidence rate (number of cases per 100 patient-years) was 1.8 percent, with sharp decline after the age of 10 years and higher risk in patients with a history of meconium ileus, male sex, or severe mutations. Incidence of cirrhosis (liver scarring) was 4.5 percent during a median period of 5 years from diagnosis of liver disease. Among the 17 cirrhotic patients, 13 developed portal hypertension, 4 developed esophageal varices, and 1 developed liver decompensation requiring liver transplantation. Development of LD did not condition different mortality or higher incidence of other clinically relevant outcomes. The authors conclude that LD is a relatively frequent and early complication of CF, whose detection should be focused at the first life decade in patients with history of meconium ileus, male sex, or severe genotype. Although LD does not condition a different clinical course of CF, in some patients it may progress rapidly and require liver transplantation. 2 figures. 4 tables. 46 references.

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Liver and Biliary Problems in Cystic Fibrosis Source: Seminars in Liver Disease. 18(3): 227-235. 1998. Contact: Available from Thieme Medical Publishers, Inc. 333 Seventh Avenue, New York, NY 10001. (212) 760-0888. Fax (212) 947-1112. Website: www.thieme.com. Summary: Liver disease associated with cystic fibrosis (CF) has been increasingly diagnosed during recent years, probably due to the combined effect of systemic hepatic assessment and fewer deaths of CF patients from extra hepatic causes. This article reports on liver and biliary problems in CF. The authors note that in a group of 173 patients regularly followed at their center, cumulative incidence of liver disease was 17 percent over a mean period of 10 years. Although it generally runs a mild course, it is considered a major complication of CF which may limit survival and quality of life of affected patients. CF associated liver disease should be considered as the first inherited liver disorder in which the primary defect affects cholangiocyte transport systems. Although data assessing the effects of defective CF transmembrane regulator (CFTR) on cholangiocyte pathobiology are not yet available, the impaired secretory function of the biliary epithelium is considered responsible for reduced biliary fluidity and alkalinity and for subsequent bile duct damage by cytotoxic compounds or infectious agents. No clear association with specific CFTR mutations has been observed. Treatment with

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ursodeoxycholic acid, aimed at improving biliary secretion in terms of bile viscosity and bile acid composition, is the most useful therapeutic approach in CF associated liver disease. Beneficial effects on liver biochemistry, hepatic excretory function, liver histology, and essential fatty acid status have been reported, but there are no long term data on its effects on clinically relevant outcomes, such as death or need for transplantation. The effectiveness of bile acid therapy may be higher if started in patients with early stage liver disease, before symptoms have become clinically evident. The authors conclude that early diagnosis and identification of CF patients who are more liable to develop liver disease should be actively pursued. 2 figures. 1 table. 84 references. (AA-M). •

Pancreatic Insufficiency in Cystic Fibrosis and Pancreatic Exocrine Enzyme Replacement Source: Practical Gastroenterology. 20(1): 37-42. January 1996. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: This article, one in a series on cystic fibrosis (CF), considers pancreatic insufficiency in CF and the use of pancreatic exocrine enzyme replacement. Pancreatic insufficiency in CF results in maldigestion of nutrients, which can, in turn, result in vitamin and trace element deficiencies, intussusception, distal intestinal obstruction, rectal prolapse, and growth retardation. In patients with CF and pancreatic insufficiency, the improvement in nutritional status following therapy with pancreatic enzymes reduced morbidity and mortality. The currently available pancreatic enzyme extracts decrease fecal nutrient losses, but they fail to fully correct maldigestion and malabsorption. In addition, there are several problems with the current preparations. The pancreatic extracts have fixed enzyme ratios, nonphysiologic route of administration, and variation in their content and manufacture. The normal pancreas secretes about 600,000 units of lipase a day, equivalent to 150 capsules a day of a lowdose, enteric-coated microsphere product (containing 4,000 units of lipase). On the other hand, high-dose enzyme is associated with strictures in the ascending colon. The pancreatic enzymes are delivered as rapid-release enzyme preparations, at times with acid-reducing compounds, and as enteric-coated tablets or microspheres containing the enzymes. 1 table. 26 references. (AA-M).

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Gastrointestinal Function and Malabsorption in Cystic Fibrosis Source: Practical Gastroenterology. 20(3): 39-45. March 1996. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: This article, one in a series on cystic fibrosis (CF), covers gastrointestinal (GI) function and malabsorption in CF. The authors note that, among Caucasians, CF is the most common mendelian lethal genetic disease of childhood. Since it is a systemic disease, affecting multiple organs, its clinical presentation varies widely. Pathology of the gastrointestinal tract, the pancreas, and the liver contributes significantly to the clinical variability of the disease. This review article summarizes current knowledge of the different gastrointestinal functions in CF: the gastric and duodenal secretory abnormalities, the slow intestinal transit, luminal mucus changes, protein, carbohydrate, and fat malabsorption, micronutrient availability, pancreatic dysfunction, bile acid abnormalities, and the newly described colonic stricture complication. 53 references. (AA).

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Laboratory Evaluation of Pancreatic and Gut Function in Cystic Fibrosis Source: Practical Gastroenterology. 20(4): 39, 43-44, 46, 48, 51. April 1996. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: This article, one in a series on cystic fibrosis (CF), addresses the laboratory evaluation of pancreatic and gut function in CF. The authors stress that the laboratory evaluation of the function of the various organs affected by CF is extremely important, as patient management should be tailored according to the severity of malfunction. In this article, the authors present an update focusing on the evaluation of pancreatic function. This includes noninvasive methods such as fecal fat analysis, which is the 'gold standard' study for demonstrating steatorrhea. The alternative fatty meal test is also described. Other studies of pancreatic function are discussed, of which the pancreozymin-secretin test is the most reliable but has the disadvantage of being invasive. Noninvasive alternatives are discussed. Specific tests covered are fecal fat analysis, immunoreactive assays for serum immunoreactive trypsinogen, the duallabeled Schilling test, the NBT-PABA test (bentiromide test), the pancreolauryl test, the fatty meal test, the Lundh test, the pancreozymin-secretin test, and a direct endoscopic secretin test. 1 table. 30 references. (AA-M).

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Hepatobiliary Complications of Cystic Fibrosis Source: Practical Gastroenterology. 20(6): 41-42, 44-46, 48-49. June 1996. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: This article, one in a series on cystic fibrosis (CF), covers the hepatobiliary complications of CF. Liver disease in CF is caused by viscous, inspissated bile that interferes with bile flow and drainage and alters normal bile composition. The clinical spectrum includes fatty liver, cholestasis, cirrhosis, portal hypertension, and cholelithiasis. The consequences of liver involvement in CF are portal hypertension and its sequelae, such as variceal bleeding, deteriorating nutrition and growth, deteriorating respiratory status, and, to a much lesser degree, liver failure. Each patient must periodically undergo assessment of liver status (e.g., liver enzyme measurements and abdominal ultrasound). If there is evidence of liver impairment, a much more thorough evaluation should be performed, including scintigraphy or liver biopsy. If Doppler ultrasound demonstrates portal hypertension, an endoscopic assessment of varices is indicated. The therapeutic approach should initially be aimed toward prevention of the development of liver disease. This can be accomplished by controlling the nutritional status with pancreatic enzymes and vitamin supplements. Longterm administration of urodeoxycholic acid should be started at the first sign of liver involvement. In cases of decompensated cirrhosis, the patient should be referred for assessment for liver transplantation. The authors conclude that somatic gene therapy, at present in an experimental stage, may be the optimal solution to all liver-related problems in patients with CF. 2 tables. 23 references. (AA-M).

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Cystic Fibrosis-Related Diabetes and Abnormal Glucose Tolerance: Overview and Medical Nutrition Therapy Source: Diabetes Spectrum. 15(2): 124-127. 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org.

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Summary: Cystic fibrosis (CF) is an autosomal recessively inherited disease the results in thick, sticky secretions in many organs, including lung, liver, gastrointestinal tract, and pancreas. Eighty-five percent of CF patients have exocrine pancreatic insufficiency. This article reviews CF-related diabetes (CFRD) and abnormal glucose tolerance, focusing on the use of medical nutrition therapy (MNT) to manage these problems. Maintaining optimal nutritional status and weight in patients with CF is the goal of treatment and can dramatically improve longevity. A high-calorie, high-fat, highsodium diet is essential to maintaining weight and nutritional status in CF. However, patients with CFRD are at risk for diabetes microvascular disease, so optimal control of blood glucose is important to prevention complications and to normalize metabolism of nutrients. The authors stress that a team approach to these patients is recommended, ideally with the pulmonary (lung) team working closely with an endocrinologist and other diabetes team members who are well acquainted with CFRD. 3 tables. 33 references. •

Energy Expenditure and Substrate Utilization in Adults with Cystic Fibrosis and Diabetes Mellitus Source: American Journal of Clinical Nutrition. 69(1): 64-69. January 1999. Contact: Available from American Journal of Clinical Nutrition. Production Office, 9650 Rockville Pike, Bethesda, MD 20814. (301) 530-7038. Fax (301) 571-8303. Website: www.ajcn.org. Summary: The onset of cystic fibrosis-related diabetes mellitus (CFDM) is often associated with a decline in clinical and nutritional status. This article reports on a study undertaken to characterize energy expenditure (EE) and substrate utilization during rest, exercise, and recovery from exercise in patients with CF diagnosed with diabetes mellitus. The study included 10 people with CF, 7 with CFDM, and 10 control subjects; all were between 18 and 45 years of age. In all 3 periods, minute ventilation was higher in the CF and CFDM groups than in the control subjects. During rest and exercise, the CF and CFDM groups maintained EE values at the high end of the normal range of the control subjects. However, during recovery, EE was higher in the CF and CFDM groups than in the control group. The authors conclude that EE may be higher than usual for the patients with CF and CFDM during periods of recovery from mild exercise or activity because of increased work of breathing consistent with higher ventilatory requirements. This information may be useful for patients receiving nutritional counseling who may choose to exercise regularly, but are concerned about possible weight loss. 4 tables. 33 references.

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Diabetes Mellitus in Cystic Fibrosis Source: European Journal of Gastroenterology and Hepatology. 8(8): 744-747. August 1996. Summary: This article updates readers on diabetes mellitus (DM) in patients with cystic fibrosis (CF). Diabetes mellitus in cystic fibrosis (CF-DM) increases in prevalence with age; develops insidiously; and is characterized by insulinopenia, normal insulin sensitivity, increased insulin clearance rate, and concomitant exocrine pancreatic insufficiency. Since CF-DM impairs overall CF clinical status, including lung function, and may result in late diabetes complications, the condition should be screened through annual oral glucose tolerance tests (OGTTs) beginning at age 10, and be treated with insulin from the time of diagnosis of CF-DM. In patients with CF-DM, self-care

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modifications and compromises are often necessary to help the patients obtain a life as normal as possible while managing both diseases. 42 references. (AA-M). •

Management Dilemmas in the Individual with Cystic Fibrosis and Diabetes Source: Journal of the American Dietetic Association. 94(1): 78-80. January 1994. Summary: In this article, glucose tolerance in patients with cystic fibrosis (CF) and the program of intensive insulin therapy recommended for them by the Diabetes Management Center of University Hospitals of Cleveland, Ohio, are reviewed. The authors note that, as their life expectancy has improved, patients with CF have experienced an increasing incidence of diabetes. The authors describe the use of a flexible meal-planning system to establish individualized carbohydrate targets with specific insulin boluses titrated to each meal to control postprandial blood glucose excursions. The records of 22 patients followed for more than 1 year are reviewed. The authors conclude that strict metabolic control is an attainable goal in patients with CF and is associated with positive weight gain. 26 references.

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Diabetes Secondary to Cystic Fibrosis: An Increasing Clinical Problem Source: Diabetes Educator. 16(6): 478-482. November-December 1990. Summary: This article discusses the clinical management of diabetes when it arises secondarily to cystic fibrosis (CF). As children with CF survive longer, some who reach young adulthood are developing diabetes. The challenge to diabetes educators in managing these patients is to incorporate basic diabetes treatment into a life-style that includes chronic infections, variable food intakes, multiple demands on time for selfcare procedures, and the psychosocial problems caused by cystic fibrosis. Of particular concern is a meal plan that will attain and maintain a desirable body weight and yet control blood glucose levels. 1 table. 7 references. (AA-M).

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Patient with Cystic Fibrosis: A Case Study Source: Access. 15(8): 58-59,65. September-October 2001. Contact: Available from American Dental Hygienists' Association. 444 North Michigan Avenue, Chicago, IL 60611. Summary: This article summarizes a case report of a 33 year old Caucasian male who presented with the chief complaint of 'needing to have his teeth cleaned.' The patient had been last seen in a private dental office approximately 18 months previously; a history of annual prophylaxes since adulthood was reported. The medical history was significant for cystic fibrosis, for which the patient was taking 2.5 milligrams of Pulmozyme through a nebulizer once daily. He was also taking 4,000 units of Creon, a pancreatic enzyme, before meals and snacks, as well as fat-soluble vitamins (A, E, K) daily. The author describes the patient's oral health history, extraoral findings, intraoral findings, dental hygiene care planning, radiographic findings, implementation of the care plan, patient education and oral hygiene instructions, and prognosis. The author concludes with a brief description of cystic fibrosis and the implications of this disease for dental hygiene practice. 1 figure.

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Federally Funded Research on Cystic Fibrosis The U.S. Government supports a variety of research studies relating to cystic fibrosis. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to cystic fibrosis. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore cystic fibrosis. The following is typical of the type of information found when searching the CRISP database for cystic fibrosis: •

Project Title: A CILIATED CELL-SPECIFIC PROMOTER FOR GENE THERAPY OF CF Principal Investigator & Institution: Ostrowski, Lawrence E.; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): The long-term objective of this research is to develop a ciliated cell-specific promoter that will improve the effectiveness of gene therapy or cystic fibrosis (CF). In normal airways, the cystic fibrosis transmembrane conductance regulator (CFTR) protein is expressed primarily at the apical surface of ciliated cells and in the submucosal glands. For gene therapy of CF to be successful, the normal CFTR protein must be expressed in the proper location. However, many of the gene therapy vectors currently under investigation have no specificity for the differentiated airway epithelium. In addition, these vectors frequently use viral promoter elements or promoters of constitutively expressed genes to drive high-level expression of reporter genes. A major drawback to the use of these vectors therefore is that they may result in high levels of CFTR expression in unwanted cell types (e.g., macrophages, basal cells). These promoters may also be less efficient at providing stable, long-term expression in the non-dividing ciliated cell population. Our hypothesis is that the use of a specific promoter to direct expression of the CFTR protein to the ciliated cells located at the apical surface of the airways will correct the CF phenotype. In addition, we hypothesize that by using an endogenous promoter in an integrating vector, we will achieve stable long-term expression of the CFTR protein. The use of a ciliated cell-specific promoter will also increase the safety of gene therapy for CF by preventing potentially deleterious expression of CFTR in the wrong cell types. To test our hypothesis, we propose the following specific aims: Specific Aim 1: To identify and clone the promoter regions of ciliated cell-specific genes. Specific Aim 2: To identify the essential regulatory elements responsible for ciliated cell specific gene expression. Specific Aim 3: To demonstrate correction of the CF phenotype in both in vitro and in vivo models by targeted expression of the normal CFTR gene in ciliated cells.

Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: A NEW CHLORIDE SWEAT TEST FOR CYSTIC FIBROSIS SCREENING Principal Investigator & Institution: Warwick, Warren J.; Polychrome Medical, Inc. 2700 Freeway Blvd, Ste 750 Brooklyn Center, MN 55430 Timing: Fiscal Year 2003; Project Start 01-FEB-2000; Project End 30-JUN-2005 Summary: (provided by applicant): The CF Quantum(r) sweat test system is a rapid, easily administered, cost effective method to diagnose cystic fibrosis (CF). The CF Quantum(r) patch (Q-patch) uses an ion-exchange reaction to produce a white precipitate which varies in size based on the chloride ion concentration of the sweat sample. Reacting the Q-patch with a chloride-containing solution (i.e. sweat) yields two concentric circles on the patch. The ratio of the area of the inner circle to that of the outer ring provides a decimal ratio, which has a linear relationship with the chloride concentration. It is therefore possible to react the Q-patch with a chloride solution and find its concentration, expressed in millimoles, by applying a linear regression formula to the areas of the two concentric circles. This phase of the project will refine the Q-patch system to make it commercially viable. The system includes 1) sweat stimulation, 2) sweat collection and 3) sweat analysis. The stimulation method and collection cycle time will be optimized by comparing three new methods of transporting pilocarpine to the sweat glands and comparing the results to the current iontophoresis method. Improved data analysis involves the integration of the software program developed in phase I with a secure web based data transport system. The Q-patch will be scanned into an optical scanner, sent via the internet to a host server where the software program will "read" the Q-patch and calculate the chloride concentration automatically, eliminating all manual measurements and calculations. The results are immediately returned to the clinic along with a digital picture of the Q-patch. Clinical comparisons of the Q-patch to the standard Gibson- Cooke sweat test (GCST) method will also be conducted to ensure the accuracy of the Q-patch in a clinical setting. Through this endeavor, PolyChrome Medical, along with the University of Minnesota Cystic Fibrosis Center, intends for the Q-patch to replace the GCST method as the standard test for diagnosing cystic fibrosis. The ease of use and quick results of the Q-patch, together with its improved accuracy, will allow for a faster, more reliable diagnosis, which in turn will provide cystic fibrosis patients with earlier access to the therapy that they need. Early diagnosis in conjunction with aggressive therapy has proven to add significantly to the median life expectancy of CF patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ADENO-ASSOCIATED VIRUS VECTORS FOR CYSTIC FIBROSIS GENE THERAPY Principal Investigator & Institution: Flotte, Terence R.; Professor; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001 Summary: AAV vectors have shown promise for cystic fibrosis (CF) gene therapy in tissue culture, small animals, primates and CF patients, particularly with regard to safety and persistence. However, gene transfer in the airways for CF patients has been less efficient than was predicted from the in vitro studies and the animal data. There are a number of possible explanations for this. First, it is possible that the luminal surface of the lower airways of humans is deficient in receptors for AAV. In the case of adenovirus

Studies 11

(Ad) vectors, vector tropism for the human nasal epithelium appears to be substantially lower than that observed for the bronchial epithelium of experimental animals. If an analogous discrepancy is present in the case of AAV, then alteration of the viral capsid may be required to enhance entry into human bronchial epithelial cells. Secondly, the exposure of AAV particles to free neutrophil elastase, extracellular leukocyte DNA, bacterial exoenzymes, or hyper- sulfated proteoglycans present in CF bronchial secretions may pose a particular obstacle to in vivo transduction in the lungs of CF patients. Thirdly, the small packaging capacity of AAV has led to the use of minimal endogenous AAV promotor elements for expression of CFTR within AAV vectors, which may be suboptimal for expression. Since the combination of larger promoter with full-length CFTR would produce vector cassettes which exceed the 5-kb packaging limit of AAV, the use of partially-truncated versions of the CFTR will need to be examined. These issues will be addressed in the following specific aims: 1. To assess the tropism of AAV vectors for the normal human bronchial epithelium in vivo. A new reporter system, based on fluorescent bronchoscopic detection of the Green Fluorescent Protein (GFP), will be used to assess gene transfer efficiently in normal human volunteers. 2. To determine whether there are specific barriers to AAV transduction which are greater in individuals with CF as compared with normal individuals. 3. To alter the tropism of AAV vectors to target specific receptors on the basolateral membrane in bronchial epithelial cells. In collaboration with Dr. Thomas Ferkol we will attempt to enhance AAV uptake and bypass mucosal barriers by coupling of vectors with antibodies directed against cellular receptors, such as the epidermal growth factor receptor (EGFR) and the polymeric immunoglobulin receptor (pIgR). To optimize the expression of CFTR from the AAV vector system, particularly in the context of using more active promoters to drive expression of CFTR minigenes. We anticipate that the completion of these aims will remove the remain obstacles to the development of a clinically useful AAV-based gene therapy for cystic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADHERENCE IN CHILDREN WITH CYSTIC FIBROSIS AND ASTHMA Principal Investigator & Institution: Modi, Avani C.; Clinical & Health Psychology; University of Florida Gainesville, FL 32611 Timing: Fiscal Year 2002; Project Start 01-MAR-2002 Summary: Rates of adherence to treatment for children with chronic illnesses range from 10-83%, with a majority of studies reporting that only 50% of children adhere to their prescribed treatment regimen. Adherence is poor in pediatric pulmonary diseases, such as cystic fibrosis (CF) and asthma, because of the intensity and complexity of prescribed treatments. The consequences of poor adherence are serious, leading to increased emergency room visits, more frequent hospitalizations, declines in pulmonary functioning, and shorter life span. In order to effective address these problems, it is critical to adequately measure rates of adherence, as well as the key barriers to good disease management. Although a few anecdotal reports have described possible reasons for poor adherence, there are no comprehensive studies identifying the key barriers to adherence for children with CF or asthma. Previous research indicates that many factors may be implicated, including course and type of illness, patient-provider miscommunication and regimen characteristics. The primary goal of the current proposal is to assess the extent of adherence problems in children with CF and asthma, systematically compare patterns of adherence in these two pediatric pulmonary

12 Cystic Fibrosis

populations, and identify the key barriers associated with poor adherence. Identification of these barriers will be directly applicable to the development of effective interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AEROSOL INFECTION MOUSE MODEL FOR CYSTIC FIBROSIS Principal Investigator & Institution: Yu, Hongwei; Micro/Immunol/Molec Genetics; Marshall University Huntington, WV 25701 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: Chronic respiratory infections with Pseudomonas aeruginosa are the primary causes of high morbidity and mortality in cystic fibrosis (CF). We have recently developed a unique pulmonary infection mouse model that depends on the artificially generated P. aeruginosa aerosol to cause a uniform whole-lung infection in mice. The focus of this revised proposal is to test a group of 90 clinical CF isolates of P. aeruginosa for innate lung clearance, cytokine profiles and histopathology in this aerosol infection model. The hypothesis to be tested here is that the hypervariable chromosomal restriction fragment length polymorphisms (RFLPs) of the clinical CF sputum isolates may contribute to i) variations in bacterial respiratory colonization capacity, ii) altered levels of cytokine production by the host, and iii) the different outcomes of lung pathology. This is based on our following recent observations. First, we have applied the technique of pulsed field gel electrophoresis (PFGE) to analyze a collection of 90 clinical CF isolates for their genomic profiles. We have established a database composed of 75 unique Spe-I restriction digest PFGE profiles. Out of 90 strains tested, we identified one isolate CF32 that had identical Spe-I, Xba-I and Dpn-I digest PFGE patterns as P. Aeruginosa PAO1, a standard reference strain of a wound origin. Secondly, we passed PAO1 and 3 other CF isolates including the PAO-1 like CF isolate through the aerosol infection system to test for the pulmonary clearance and production of tumor necrosis factor (TNF)-a. PA01 and CF32 showed a similar pattern of lung clearance and TNF-a induction in the C57BL/6J and BALB/cJ mice. However, the other 2 CF isolates were more resistant to the clearance by the BALB/cJ mice. One isolate (CF45) caused a significant induction of TNF-a by the murine lungs. These results indicate that the genomes of the CF isolates are highly diversified, and the genomic diversity may affect their intrinsic biological properties. More importantly, it's feasible to use the aerosol apparatus to assess the remaining CF isolates for their virulence properties. The future directions that this project may lead to include i) investigations of the novel Pseudomonas genes induced due to lung colonizations; ii) exploration of the novel DNA fragments missing in the PAO1 genome but present in a subset of the CF isolates; iii) DNA immunization and testing for protection, and iv) evaluation of some selected CF isolates in the aerosol mouse model. By achieving the research objective of this Academic Research Enhancement Award (AREA) that is to establish and infection database for the CF isolates in the aerosol model, we will have an essential base of knowledge from which to prepare a future R01 application to investigate the novel virulence mechanisms associated with the clinical CF isolates of P. aeruginosa. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AEROSOLIZED TGAAVCF FOR CYSTIC FIBROSIS THERAPY Principal Investigator & Institution: Moss, Richard B.; Professor of Pediatrics; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2001

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Summary: This study is a multi-center open-label single dose, dose-escalation cohort protocol to evaluate the safety and preliminary biological efficacy of a gene transfer of the cystic fibrosis gene using recombinant adeno-associated virus vector (a small, nondisease causing virus which has been emptied of its own DNA and packed instead with the DNA for the gene which is defective in cystic fibrosis) delivered to the lower respiratory tract of patients with cystic fibrosis by jet nebulization (mist). Evidence of gene transfer has been sought by measurements of wild-type CF gene DNA in brushed bronchial epithelial cells (airway cells obtained through a scope inserted into the lungs) by a laboratory test called direct PCR, and expression of wild-type CF messenger RNA (meaning the gene is working) in these cells by another, similar test called RT-PCR. In addition, other potential biological measurements of potential efficacy include levels of inflammatory mediators (disease-causing chemicals) in bronchoalveolar lavage fluid (fluid from the lung). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AEROSOLIZED TGAAVCF FOR TREATMENT OF CYSTIC FIBROSIS Principal Investigator & Institution: Dovey, Mark; Children's Hospital (Boston) Boston, MA 021155737 Timing: Fiscal Year 2001 Summary: This is a single administration, multi-center, open label, dose escalation study designed to examine the safety of Targeted Genetics Corporation's recombinant adenoassociated virus with the cystic fibrosis transmembrane regulator gene (tgAAVCF), administered as an aerosol to patients with cystic fibrosis. Secondarily, samples will be obtained to evalate both delivery of the CFTR gene to the pulmonary epithelium, as measured by DNA PCR and expression of the CFTR gene, as measured by RT-PCR. Background: Cystic fibrosis (CF) is the most common autosomoal recessive disease, affecting between 1 in 2,000 and 1 in 4,500 children of Caucasion origin. The main characteristics are malabsorption due to exocrine pancreatic insufficiency, recurrent bacterial infections of the lower respiratory tract, abnormal regulation of salt transport across the gastrointestinal and respiratory epithelium, and male infertility due to absence or stenosis of the vas deferens. Early in the disease, the airways become filled wtih thick purulent mucus. There is chronic bacterial colonization of the airway epithelium, particularly with Pseudomonas aeruginosa, and intense neutrophil infammation. Over time, injury to the airwayss caused by inflammation results in bronchiectasis, parenchymal scarring and destruction, and consequent progressive respiratory failure. The gene involved in CF, the cystic fibrosis transmembrane conductance regulator (CFTR) gene was discovered in 1989. Gene therapy holds the promise of addressing the primary defect in CF by reconstituting proper chloride transport in vivo. For treatment of lung disease in patients with CF, a vector will most likely have to be administered as an aerosol. An ongoing clinical trial of bronchoscopic administration of tgAAVCF to the right lower lobe of the lung suggests that tgAAVCF is safe for pulmonary delivery. Thus, the current protocol will test the delivery of aerosolized tgAAVCF in a dose escalation clinical trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AIRWAY INFLAMMATION IN CYSTIC FIBROSIS Principal Investigator & Institution: Ordonez, Claudia; Children's Hospital (Boston) Boston, MA 021155737 Timing: Fiscal Year 2001

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Summary: The purpose of this study is to determine whether sputum induction is a reproducible method to study airway inflammation in cystic fibrosis. Sputum induction using nebulized hypertonic saline represents a non-invasive method of studying airway inflammation in pulmonary diseases. It has been well established as a method to study airway inflammation in asthma, a disease that is also characterized by airway inflammation and chronic airway obstruction. Studies in asthmatics provide evidence that sputum induction samples the small airways rather than other compartments in the lung. Studies have also demonstrated this method to be safe and reproducible in children with asthma. For studies of airway inflammation in cystic fibrosis patients, investigators analyzed bronchoalveolar lavage fluid and spontaneously expectorated sputum for markers of inflammation. In studying the effects of anti-inflammatory medications, these methods are limited in their applicability. Bronchoscopy cannot be easily repeated in the same subject in a short enough interval to assess changes following an intervention. Additionally, it is invasive and can result in complications. The collection of spontaneously expectorated sputum is less invasive, however, only the more severe patients with cystic fibrosis produce sputum spontaneously, limiting the usefulness of this method. Bronchoalveolar lavage fluid and spontanously expectorated sputum sample the alveolar compartment or upper airway, respectively, not the small airways where disease occurs in cystic fibrosis. Despite the potential of using induced sputum to study airway inflammation in cystic fibrosis, almost no studies have utilized this methodology. If sputum induction proves to be a reproducible method of studying airway inflammation in patients with cystic fibrosis, it will be a powerful tool in studying the effects of new anti-inflammatory medications, specifically anti-elastases, where showing a change in markers of inflammation may be a more useful outcome measure than pulmonary function, which would need to be measured over a long period of time. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AIRWAY SUBMUCOSAL GLANDS AND CYSTIC FIBROSIS DISEASE Principal Investigator & Institution: Ballard, Stephen T.; Associate Professor; Physiology; University of South Alabama Mobile, AL 366880002 Timing: Fiscal Year 2001; Project Start 10-JUN-2001; Project End 30-APR-2005 Summary: adapted from applicant's abstract): Mortality in cystic fibrosis (CF) typically results from the pulmonary complications of the disease, which include progressive obstruction of the airways with a thick dehydrated mucus, reduced mucociliary transport, chronic airway infections, and bronchiectasis. While CF is known to be caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator protein (CFTR), a cAMP-regulated anion channel, the functional link between defects in this channel function and the pulmonary pathogenesis of CF is unclear and controversial. Using porcine airways, the principal investigator has recently shown that CFTR normally mediates secretion of both Cl- and HCO3 by submucosal glands of the airways and that this process drives secretion of gland liquid. When gland liquid secretion is blocked by applying selective C1- and HCO3 secretion inhibitors, airways undergo changes that parallel those observed in early CF airway disease-- mucus obstruction of gland ducts, production of an abnormally thick dehydrated mucus, and reductions in mucociliary transport. From these observations, the principal investigator hypothesizes that CF lung pathology is the inevitable consequence of impaired Cl- and HCO3 secretion from submucosal glands. In support of this hypothesis, the applicant proposes the following aims. First, the mechanism by which gland liquid secretion

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inhibitors reduce mucociliary transport will be determined. Second, the role of secretory vesicles in mucus gel formation will be studied to better understand the mechanism and dynamics of mucus maturation in airways. Third, the efficacy and mechanism of potential airway secretogogues will be evaluated to identify possible CFTR-independent routes which could be manipulated for therapeutic induction of liquid secretion. Fourth, the ability of inhibitors of Cl- and HCO3 secretion to reproduce mucus obstruction of airways will be determined in isolated, perfused lung lobes. These proposed studies will provide critical information for understanding the role of glandular Cl- and HCO3 secretion in the etiology of CF. If this hypothesis is confirmed, these studies could form the important basis of therapeutic strategies for the treatment of this lethal disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALPHA 1 ANTITRYPSIN GENE IN NASAL EPITHELIUM--CYSTIC FIB Principal Investigator & Institution: Brigham, Kenneth L.; Professor; Vanderbilt University 3319 West End Ave. Nashville, TN 372036917 Timing: Fiscal Year 2001 Summary: HYPOTHESIS: We are developing the nasal lavage model as a means of studying the inflammatory response of respiratory epithelium in vivo. In preliminary studies, we have found that concentrations of the pro-inflammatory cytokine interleukin-8 (IL-8) are higher in nasal lavage fluid from CF patients than from normals. In this proposal, we plan to define the inflammatory state of the nasal mucosa more thoroughly in CF patients, then test our hypothesis that the AAT gene can be delivered to the nasal mucosa in CF subjects using plasmid/cationic liposome complexes and that expression of the AAT gene locally in respiratory epithelium will suppress inflammation. SPECIFIC AIMS: 1) To characterize the inflammatory and protease/antiprotease state of the nasal mucosa in patients w/CF by: a)measuring in nasal lavage fluid the concentrations of inflammation-related cytokines, AAT protein and free elastase; and b) determining in nasal mucosal scrapings the numbers of inflammatory cells present and which inflammation-related cytokine genes are expressed. 2) To determine whether the AAT gene canbe delivered to the nasal mucosa of patients w/CF using cationic liposomes; to define the magnitude and time course of transgene expression; and to determine whether AAT gene expression in nasal mucosa decreases inflammation. We are currently conducting the experiments outlined in Specific Aim #1. Specific Aim #2 will require the facilities in the GCRC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ALTERED EPITHELIAL STAT1 DEPENDENT SIGNALING IN CYSTIC F Principal Investigator & Institution: Kelley, Thomas J.; Assistant Professor; Pediatrics; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: (Adapted from the Applicant's Abstract): Cystic fibrosis (CF) is an inflammatory disease initiated by the loss of cystic fibrosis transmembrane conductance regulator (CFTR) function in epithelial cells. CFTR is a chloride channel whose activity is stimulated by PKA-mediated phosphorylation, and how a loss of this single chloride channel leads to the variety of symptoms associated with CF remains a mystery. The investigators have previously shown that nitric oxide (NO) production and the expression of the inducible form of nitric oxide synthase (NOS2) are reduced in CF

16 Cystic Fibrosis

airway epithelium. NO is known to regulate several transepithelial ion transport properties and act as a powerful anti-microbial agent, which may have biological significance in CF since CF is partially characterized by altered non-CFTR ion transport abnormalities and susceptibility to airway bacterial infections. Airway epithelium from other inflammatory airway diseases such as asthma have been shown to have increased expression of NOS2, but the mechanisms responsible for decreased NOS2 expression in the presence of such a robust inflammatory response seen in CF remain unclear. The investigators believe that alterations in the signal transducer and activator of transcription-1 (Stat 1) signaling pathway in CF epithelium are responsible for the puzzling lack of NOS2 expression. Their data indicate that increased levels of the protein inhibitor of activated Stat1 (PIAS1) bind the available activated phosphorylatedStat1 (p-Stat1) in CF epithelial cells preventing Stat1 signaling which is necessary for NOS2 expression. This hypothesis also suggests that portions of interferon-y (IFN-y) dependent signaling would be lost in CF. This conclusion is supported by recently published data by Schwiebert et al. demonstrating reduced RANTES expression in response to IFN-y in CF epithelial cells compared to non-CF controls. Understanding the link between lost CFTR function and overexpression of PIASI will be a focus of this proposal, as will be determining the influence of IFN-y signaling on characteristics of CF-related disease. The aims of this proposal are: 1) to determine the influence of CFTR activity and function of PIAS1 expression and Stat1 pathway activity in epithelial cells; and 2) to determine the role of IFN-y/Stat1-dependent pathways and the effects of PIAS1 in regulating cellular responses with respect to known CF-related abnormalities. Learning how a loss of CFTR function leads to altered cell signaling processes and how these processes unfluence disease may increase our understanding of CF and lead to more precise therapeutic interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALTERNATE CHLORIDE ION SECRETORY PATHWAYS IN CYSTIC FIBROSIS Principal Investigator & Institution: Benos, Dale J.; Professor & Chair; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2001 Summary: The main goal of the proposed research is to understand the mechanisms and regulation of ion permeation through C1- channels other than the cystic fibrosis transmembrane conductance regulatory (CFTR) present in secretory epithelia. These alternative C1- channels may be useful and important targets for pharmacological therapy in cystic fibrosis (CF). Our laboratory has successfully isolated and cloned a protein from bovine trachea that behaves as a Ca2+ -sensitive C1- channel (CaCC), and has semi-purified and reconstituted an outwardly-rectified C1- channel (ORCC). This application has four specific aims: (1) to test the hypothesis that the translated bovine tracheal cDNA forms an anion channel of identical characteristics to the native protein, that the 38 kDa subunit of the native tracheal CaCC protein is the result of posttranslational processing of the cloned 100 kDa CaCC cDNA product, and to determine the biochemical properties of both native and cloned CaCCs. The functional properties of the proteins will also be characterized following reconstitution into planar lipid bilayers or transfection into eukaryotic cells; (2) to identify a full-length cDNA corresponding to the human CaCC homolog and to characterize the translated protein. The molecular structure and function of the human homolog of the bovine CaCC will be determined by screening of appropriate human epithelial cDNA libraries; (3) to purify a protein that behaves as an ORCC from bovine tracheal apical membrane vesicles and to

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identify and characterize the full-length cDNA that encodes this protein. Candidate proteins will be used to raise polyclonal antibodies that will be used to screen a bovine tracheal cDNA expression library. The ultimate goal is to isolate a full-length cDNA that encodes an ORCC and to characterize the translated protein with the aim of understanding is potential interaction with CFTR and/or other ion channels; (4) to determine if heterologous intestinal specific expression of the CaCC can overcome the lethal intestinal obstruction found in the CF knockout mouse model. We will test the hypothesis that tissue specific expression of the bovine CaCC in the intestine will prevent the lethal consequences of intestinal obstruction by ameliorating the adverse effects of impaired chloride secretion in the intestine. These studies will further our knowledge of the physiological, biochemical, and molecular properties of these important C1- transport pathways and increase our understanding of fluid secretion across airway and intestinal epithelial so that potential avenues of alternate therapy in CF can be devised and evaluated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALTERNATE CI-SECRETORY PATHWAYS IN CYSTIC FIBROSIS Principal Investigator & Institution: Nelson, Deborah J.; Professor; Neurobiology/Pharmacology/Phys; University of Chicago 5801 S Ellis Ave Chicago, IL 60637 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 31-MAY-2005 Summary: The cystic fibrosis (CF) phenotype is characterized by a regulatory defect in apical membrane Cl- permeability in secretory epithelia associated with a reduction in fluid secretion. Recent investigations on Cl- secretory epithelial cells in culture have characterized the regulation of anion channels by changes in cellular volume, increases in intracellular free Ca2+, and increases in intracellular cyclic nucleotides. It is our hypothesis that Ca2+-dependent Cl- channels (I-Cl, Ca) will provide for an alternative regulated Cl- conductance pathway to correct the transport dysfunction in CF affected cells. This pathway is not defective in CF tissue and may, in fact, be upregulated in human airway tissue. Ca2+-dependent Cl- conductances in secretory epithelium can be separated into two distinct populations: those that are directly regulated by Ca2+ and those which are inhibited by CaMKII inhibitors. In preliminary studies we have cloned the human isoform of the ClC-3 chloride channel from the human colonic cell line T84, and carried out electrophysiological studies which demonstrate that CaMKII is involved in the activation of hClC-3. In the proposed studies, we will further characterize the cloned channel and I-Cl,CaMKII by investigating its gating mechanism and pharmacological properties. (1) We will examine the identity of hClC-3 and I-Cl,CaMKII by antisense and knock-out mice to eliminate endogenous hClC-3. We will characterize the response of recombinant hClC-3 to specific CaMKII inhibitors. (2) We will determine the role of CaMKII in gating and/or translocation of the channel using established cell lines and primary culture from ClC-3 (-/-) knockout mice using whole cell and single channel analysis. (3) We will further investigate the role of CaMKII phosphorylation in the activation of hClC-3 by site-directed mutagenesis and phosphorylation assays as well as electrophysiological studies. We will evaluate the physiological role and possible interplay between phosphorylation-dependent activation of the channel by CaMKII and the inhibition of channel activation by annexin IV and IP4. (4) We will investigate an approach to augment I-Cl,CaMKII in CF cells via either a constitutively active CaMKII or peptide that blocks the interaction between hClC-3 and its specific inhibitors, such as annexin IV and IP4. The ultimate goal of this investigation is to provide candidate

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intracellular therapeutic targets which may be useful in ameliorating the chronic pathological condition associated with CF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AMINOGLYCOSIDE ANTIBIOTICS FOR CYSTIC FIBROSIS Principal Investigator & Institution: Sorscher, Eric J.; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2001 Summary: Approximately five to ten percent of patients with cystic fibrosis are believed to have the disease because cells lining their airways are not capable of synthesizing a protein called the cystic fibrosis transmembrane conductance regulator (CFTR) due to premature stop mutations. We have discovered that in some cases it may be possible to stimulate cells to make the normal protein by treating them with the same antibiotics which cystic fibrosis patients routinely receive as part of their therapy. Aminoglycoside antibiotics (Tobramycin, Gentamicin, Amikacin) are routinely given to cystic fibrosis patients for the treatment of lung infections. The purpose of this study is to determine whether these same antibiotics might also help a subgroup of cystic fibrosis patients by allowing their lung cells to produce a normal CFTR protein. To date, 7 patients have completed the study. We intend to study 20 additional patients in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANTI-INFLAMMATORY GENE THERAPY FOR CYSTIC FIBROSIS Principal Investigator & Institution: Virella-Lowell, Isabel L.; Pediatrics; University of Florida Gainesville, FL 32611 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: (provided by applicant) Cystic Fibrosis (CF) is an autosomal recessive disorder caused by defects in the CF transmembrane conductance regulator (CFTR) gene. The CFTR gene encodes a protein that functions as a cAMP-activated chloride channel and a regulator of other chloride channels. Patients with CF are predisposed to chronic endobronchial infections with organisms such as Pseudomonas aeruginosa and exhibit an exaggerated inflammatory response to these pathogens. This response is characterized by excessive NFkB activation with the subsequent release of potent proinflammatory cytokines. These cytokines promote a massive influx of neutrophils in the conducting airways. Once in an airway lumen, neutrophils release a variety of substances that either directly or indirectly damage the lungs. These substances include neutrophil elastase (NE), which can cause bronchiectasis, airway obstruction, and impaired clearance of infected secretions. In time, it Is lung destruction by neutrophil by-products and airway obstruction rather than infection that causes respiratory failure in a majority of CF patients. The objective of this proposed research project is to determine whether CF lung disease can be ameliorated by the controlled expression of anti-inflammatory molecules from rAAV vectors. In addition to pursuing the outlined research project, my immediate goals for the future as include obtaining further training in the methodology of translating experimental findings in biomedical research into clinically useful applications. A K30 program designed to educate new faculty in the principals of translational research is available at the University of Florida. I will be enrolled in this program, which includes didactic courses in statistics, clinical study design and ethics. This program should prove invaluable in instructing me how to design, implement and interpret clinical studies aimed at examining the role of anti-

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inflammatory gene therapy for lung disease. I will devote 80 percent effort over the 5year award period to the accomplishment of the above goals. The experience and skills acquired during this time period will provide me future opportunities to develop other patient-oriented research projects in my area of interest and to obtain independent funding for these projects. In the long term, I look forward to continuing an academic career focused on translational research in the area of anti- inflammatory gene therapy for lung disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APPLIED GENOMICS IN CARDIOPULMONARY DISEASE Principal Investigator & Institution: Haponik, Edward F.; Professor of Internal Medicine; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: The Clinical Core will serve as the coordinating center for patient recruitment, specimen procurement and data base management. It is the mission of this Core to identify and provide disease-specific candidate genes from patients with such clinical disorders as acute lung injury, COPD, cystic fibrosis, asthma, pulmonary hypertension, pulmonary fibrosis, ischemic heart failure and both lung and cardiac transplant rejection. This core will also be responsible for the establishment of a Cardiopulmonary Tissue Repository that will maintain an archive of cryopreserved tissues and maintain an accurate data base of patient demographic and clinical data for correlation with biological end points produced by cDNA microarray. Following patient consent and registration, tissue samples and peripheral blood are delivered to the Core laboratory. The freezing facility will also serve as a repository for cyropreserved human lung and cardiac specimens. The Core Investigators will meet regularly to review all diagnostic materials on each specimen procured including histochemical stains and biopsies in order to determine a precise diagnosis and relevant demographic and clinical data for entry into the Project's data base which will include critical variables for the analysis of the biological data obtained. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ASL PHYSIOLOGY STUDIED BY NOVEL FLUORESCENCE METHODS Principal Investigator & Institution: Verkman, Alan S.; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001 Summary: The application remains focused on the mechanisms by which the Cystic Fibrosis genotype leads to clinical abnormalities. Aim 1 is a direct extension of recent work indicating that CFTR is a modulator of intracellular vesicle fusion. Aims 2 and 3 concern the biophysics of the airspace surface liquid (ASL) layer. The proposed studies utilize novel optical methods including fluorescent indicators of [Cl/-] and vesicle fusion, photobleaching and time-resolved fluorescence measurements of viscosity, and 3-d tracking. Specific Aim 1. To investigate the mechanisms and significance of the CFTR-dependent stimulation of intracellular vesicle fusion. We reported that expression of cAMP activation of CFTR in stably transfected 3T3 fibroblasts increases endosome fusion by greater than 2-fold. New technical developments will be used to determine whether CFTR regulates endosome fusion in native CFTR-expressing versus 'CF' epithelial cells and whether vesicle fusion in the secretory pathway is regulated by CFTR. The hypothesis will be tested that syntaxins are involved in the CFTR- regulation

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of endosome fusion. Specific Aim 2: To develop quantitative fluorescence methods to measure ASL fluid thickness, ionic composition and viscosity. Novel Cl/- and Na+sensitive indicators will be used to measure ASL fluid composition in situ without fluid sampling and other perturbations. Photobleaching recovery and time-resolved fluorescence anisotrophy will be used to measure ASL fluid viscosity. Measurements will be carried out on primary cultures of human and bovine tracheal epithelia for comparison with intact bovine and monkey trachea. The role of submucosal glands in ASL fluid properties will be studied. Specific Aim 3. To study the regulation of ASL fluid thickness, composition and viscosity, and to characterize their abnormality in Cystic Fibrosis. The methods developed in Aim 2 will be used to compare CFTRexpressing versus CF-epithelia. The hypotheses will be tested that ASL salt concentration and viscosity are elevated in CF, epithelial, and that UTP normalizes ASL fluid properties. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BEHAVIORAL TREATMENT FOR DIETARY ADHERENCE IN CHILDREN Principal Investigator & Institution: Powers, Scott W.; Associate Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, OH 45229 Timing: Fiscal Year 2001; Project Start 15-AUG-2001; Project End 30-JUN-2006 Summary: (provided by applicant) The Specific Aims of this Midcareer Investigator Award in Patient-Oriented Research are 1) to develop and evaluate the efficacy of behavioral interventions designed to increase dietary adherence, improve health outcomes, and enhance quality of life for young children with cystic fibrosis, type 1 diabetes, and those at risk for obesity, and 2) to provide the candidate protected time and resources necessary to mentor postdoctoral fellows and junior faculty members in psychology and pediatrics who are pursuing clinical investigation in behavioral nutrition interventions for children. The Candidate's programmatic research has focused on identifying behavioral factors that compromise dietary adherence and translating this knowledge into behavioral interventions that can be tested in rigorous clinical trials. During the course of this award, the candidate will complete ongoing research studies with young children with cystic fibrosis, type 1 diabetes, and those at risk for obesity. For each population, the objective is to establish the efficacy of behavioral treatments through well-designed clinical outcome studies and disseminate the findings so that standard care for these children can be improved. The candidate also has an established track record of providing mentorship to postdoctoral fellows and junior faculty in psychology and pediatrics. The Training Plan will further the candidate's knowledge of clinical trial design and analysis of health outcomes relevant to the illnesses under study, and allow him to use these additional skills in his mentoring efforts. The Research Plan includes two ongoing projects: an NIH/NIDDK-funded R01 study, "Behavioral Treatment of Eating Problems in Toddlers with Cystic Fibrosis," and a novel study focusing on "Barriers to Dietary Adherence in Young Children with Type 1 Diabetes." In addition, the candidate will continue his collaborative research, funded by the United States Department of Agriculture, on obesity prevention in low-income children. The Mentoring Plan for beginning clinical investigators will consist of 1) individualized mentoring of 2 postdoctoral fellows in psychology and a junior faculty member in pediatrics within the context of the current research plan, 2) training and supervision of the postdoctoral fellows in the development of their own independent research proposals, and 3) participation of postdoctoral fellows in established didactic programs on manuscript and grant writing, design of clinical trials and clinical research

Studies 21

methodology, and ethics in clinical research. Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine provide an ideal setting for this award because of the commitment to patient-oriented research, the presence of a strong pediatric General Clinical Research Center, and the institution of new initiatives to promote innovative clinical research including the newly developed Behavioral Core of the GCRC and the training grant in Gastroenterology and Nutrition (T32). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BILIARY SECRETORY PATHWAYS IN CYSTIC FIBROSIS Principal Investigator & Institution: Cho, Won K.; Medicine; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, IN 462025167 Timing: Fiscal Year 2001; Project Start 01-MAY-1999; Project End 31-DEC-2003 Summary: Cystic fibrosis (CF) is the most common lethal inherited diseases in white population. As CF patients live longer, liver disease has become the second leading cause of death. The development of CF disease is believed to result from the secretory defects in the bile ducts leading to the obstructions of bile ductules by tenacious bile secretions, thereby secreting in focal periportal biliary fibrosis/cirrhosis. This explanation in addition to the recent finding that CFTR is only expressed on bile duct cells, but not on hepatocytes, suggest that studying biliary secretion is crucial to understanding the pathophysiology and developing therapeutic strategies for CF liver. A novel polarized isolated bile duct unit (IBDU) prepared from rat liver has demonstrated to be an ideal tool to study bile ductular secretion but the lack of CF rat model limited its use in CF studies. By applying these isolation methods, recently, IBDUs have been isolated from normal and CF mice. Therefore, the aims of this research are to further characterize bile duct cells (BDC) and IBDU from normal and CF knockout mice, to characterize ion transporters in BDC, and to study the actions and mechanisms of various secretagogues including neuroendocrine peptides in biliary secretion in order to find ways to activate alternative, cAMP-independent biliary secretory pathways in CF mice. Preliminary experiments to isolate IBDU from normal mouse yielded intact polarized functional IBDU that responds to secretin, vasoactive intestinal peptide, and DBcAMP-IBMX. Similar IBDUs were also isolated from CF mice but need further characterization. Quantitative videomicroscopy will be used to screen potential secretagogues to stimulate biliary secretion in normal and CF mice and to characterize their underlying ion transporters by using ion substitutions and inhibitor studies. These ion transporters will be further studied by BCECF dual ratio methods for measuring pH, micropuncture, and patch clamping techniques. Signal transduction systems involved in their action will be studied by monitoring changes in the concentrations of secondary messengers. Understanding transport systems and their underlying mechanisms of biliary secretion in normal and CF mice will help to formulate therapeutic approaches to overcome the CFTR defect. This project, in turn, will provide the candidate with an excellent opportunity to broaden and develop research and cognitive skills to become independent researcher, as well as help to successfully compete for future research grants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOAVAILABILITY OF URSOCARB VS ACTIGALL IN CHRONIC CHOLESTATIC LIVER DISEASE Principal Investigator & Institution: Balistreri, William F.; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, OH 45229

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Timing: Fiscal Year 2001 Summary: The objective of this study is to determine the bioavailability of a polymer coated and buffered UDCA (URSOCARB) as compared to ACTIGALL on percent UDCA enrichment in the bile, proportion and concentration of UDCA in serum, and compare the differences between the results for these two treatments in patients with cystic fibrosis and chronic liver disease. Following a four-week treatment with ACTIGALL at 15-30 mg/kg/day (given in two divided doses), the subjects will have samples of bile (string test), blood and urine collected. The subjects will then have a 24hour wash-out period, and be switched to URSOCARB at 15-30 mg/kg/day (given in two divided doses). At the end of four weeks of treatment, the subjects will have samples of bile (string test), blood and urine collected. The samples of bile will be analyzed for the degree of UDCA enrichment. Serum and urinary excretion will be measured; enhanced renal output of UDCA will support the contention that greater solubility of UDCA in the intestine increases absorption and bioavailability. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOCHEMICAL ROLE OF AIRWAY MUCINS IN CYSTIC FIBROSIS Principal Investigator & Institution: Sachdev, Goverdhan P.; Pharmaceutical Sciences; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, OK 73126 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2004 Summary: (provided by applicant): Cystic Fibrosis (CF) is the most lethal genetic disease in Caucasians and is characterized by production of excessive amounts of viscous mucus secretions in the airways of the patient. This causes airway obstruction as well as chronic bacterial infections which eventually lead to respiratory failure. Mucins provide protection to epithelia through interaction of their saccharides with bacterial adhesins. Chronic colonization with Pseudomonas aeruginosa, is considered the principal cause of death in CF patients. Our laboratory and others have shown that P. aeruginosa had considerably stronger binding affinity for CF airway mucin than normal airway mucin. These observations implicate altered glycosylation of CF mucins. Indeed, aberrant glycosylation has been reported for CF mucin. However, to date, the molecular basis of increased interaction between P. aeruginosa and CF airway mucin has not been established. We hypothesize that altered glycosylation of CF mucin is responsible for its stronger binding with P. aeruginosa. We will determine structural features of the CF mucin carbohydrate ligand(s) that provide increased binding to P. aeruginosa by preparing glycopeptides and individual saccharides from CF and control mucins. The glycopeptide(s) which show high inhibition of asialo-GM; binding to P. aeruginosa will be used to isolate 0-linked glycans for further testing of inhibitory activity and structural determination using state-of-the-art highly sensitive mass spectrometry and enzymnatic methods. Affinity gels containing selected mucin glycopeptide or mucin saccharide will be used to purify the P. aeruginosa adhesins which interact with airway mucins and glycolipids, respectively. The primary structure of the major adhesins will be determined using molecular cloning techniques. Structural characterization of major adhesins will open additional approaches to prevent the binding of P. aeruginosa to airway epithelial cells and mucins of CF patients. Information on the adhesin binding sites will permit molecular modeling, design and synthesis of potent 0-glycan inhibitors of the P. aeruginosa infection. The overall long-term goal of this study is to prevent and/or treat lung infections in CF patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOCHEMISTRY OF AMILORIDE SENSITIVE NA+ CHANNELS IN CF Principal Investigator & Institution: Rao, Subrahmanyeswara U.; Biochem and Molecular Biology; University of Nebraska Medical Center Omaha, NE 681987835 Timing: Fiscal Year 2001; Project Start 01-MAY-1997; Project End 31-MAR-2003 Summary: Cystic fibrosis (CF) is a fatal disease of abnormal epithelial ion- transport, characterized principally by reduced Cl- and increased amiloride-sensitive Na+ conductances in pulmonary epithelia. Since the gene coding for the cystic fibrosis conductance regulator (CFTR) was identified, intense efforts have been directed toward understanding the malfunction of Cl- secretion. However, the abnormalities associated with Na+ transport are poorly understood. Recent identification of alpha, beta and gamma subunits that are presumed to constitute the functional epithelial Na+ channel (ENaC) makes possible the mechanistic studies of the abnormally raised and cAMP regulated Na+ transport associated with CF. In heterologous systems, ENaC activity is high and stimulated by cAMP, whereas, in the presence of CFTR, ENaC is downregulated and cAMP effects reversed mimicking the in vivo observations of CF and normal airway epithelia, respectively. These observations form the basis for the long term goal of this grant application. Two heterologous expression systems, MDCK and Sf9 insect cells expressing ENaC and CFTR, will be utilized to undertake a detailed biochemical investigation of the structure and regulation of the ENaC. Utilizing these experimental systems, a research plan has been organized around 3 specific aims. 1. We shall isolate the functional ENaC and determine its composition and stoichiometry of the subunits. 2. We shall investigate the mechanism by which cAMP stimulates the ENaC. We shall identify the amino acid residues that are phosphorylated in the ENaC, and correlate the phosphorylation events to the function by site- directed mutagenesis. 3. We shall determine the mechanism by which CFTR regulates ENaC function. We shall investigate the hypothesis that CFTR regulates the ENaC by the mechanisms involving phosphorylation and dephosphorylation of amino acids in the ENaC subunits. We shall also test the hypothesis that physical interactions of CFTR with ENaC are responsible for down-regulation of ENaC function by immunological methods. It is anticipated that this research will aid further in understanding the ENaC-mediated Na+ absorption process across the reabsorbing epithelia and ameliorating the diseases associated with ENaC dysfunction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOGENESIS AND MOLECULAR PATHOGENESIS OF CFTR Principal Investigator & Institution: Skach, William R.; Associate Professor; Medicine; Oregon Health & Science University Portland, OR 972393098 Timing: Fiscal Year 2001; Project Start 01-DEC-1996; Project End 31-MAR-2005 Summary: Cystic Fibrosis (CF) is a prototype for inherited disorders of protein folding. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a polytopic protein expressed in the apical membrane of human epithelial cells. CFTR biogenesis occurs in the endoplasmic reticulum and is facilitated by a complex set of cellular machinery. Greater than 70% of wild type and up to 99% of common mutant forms of CFTR fail to fold properly and are recognized by cellular quality control machinery and degraded by the ubiquitin- proteasome pathway. These observations raise several questions central to CF pathogenesis and treatment. How does cellular machinery coordinate CFTR folding in different cellular compartments? How is misfolded CFTR protein identified by the cell? How is this recognition event coupled to

24 Cystic Fibrosis

degradation? And how might the efficiency of CFTR folding be improved in patients? The long term goal of this proposal is to characterize the composition, recruitment and function of cellular folding and quality control machinery that regulates the fate of newly synthesized CFTR in the endoplasmic reticulum. The specific aims of this study will use complimentary heterologous expression systems to: l) define the role of the Sec61 translocation machinery in directing early events of CFTR assembly into the ER membrane, 2) identify the dynamic nature of cellular chaperone complexes that govern the fate of newly synthesized CFTR, and 3) examine the role of ER machinery in CFTR degradation by the 26S proteasome complex. Proposed experiments will incorporate photoactive crosslinking probes at precise locations within CFTR to characterize cellular machinery that orients and assembles the nascent chain into the lipid bilayer. Additional studies will use in vitro and in vivo systems to analyze the changing composition of cellular chaperones associated wild type and mutant CFTR during sequential stages of maturation and degradation. Finally lumenal and membrane-bound ER quality control machinery will be identified by biochemical complementation. Together these studies will generate a comprehensive picture of how cellular machinery coordinates and monitors folding events in multiple compartments and ultimately governs the balance between productive and non-productive pathways. Identification of key components that regulate this decision process will be a major step in the development of pharmacologic strategies aimed at improving folding and trafficking of mutant proteins in patients with inherited disorders such as CF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BUILDING A 3-DIMENSIONAL MODEL OF THE PORE OF CFTR Principal Investigator & Institution: Mccarty, Nael A.; Associate Professor; School of Applied Biology; Georgia Institute of Technology 225 North Ave Nw Atlanta, GA 30332 Timing: Fiscal Year 2001; Project Start 15-SEP-2001; Project End 31-AUG-2006 Summary: The CFTR protein forms a chloride ion channel in the plasma membranes of many epithelial cells, including cells of the kidney and gut. Mutation of the gene encoding CFTR is the primary defect in Cystic Fibrosis (CF), the most common lethal, autosomal recessive disease among Caucasians, affecting approximately 30,000 Americans. Alteration in CFTR function also plays an important role in the pathophysiology of secretory diarrhea and polycystic kidney disease (PKD). The basic mechanisms of permeation in this channel are not clear. It is not known which portions of the protein contribute to forming the pore, and which amino acids in those domains are involved in the biophysical processes of ion permeation. The long-term objective of this laboratory is to determine the mechanisms of permeation in CFTR. For this proposal, Specific Aim number 1 is to determine the oligometric structure of the functional CFTR channel. Specific Aim number 2 is to identify transmembrane (TM) helices that line the pore, by localization of binding sites for open-channel blockers. Specific Aim number 3 is to identify groups of amino acids that serve as determinants of anion selectivity. The proposed approach relies upon the use of molecular biological techniques (site-directed mutagenesis) combined with expression in Xenopus oocytes and quantitative biophysical assays. The working hypothesis is that the pore is lined by TM domains 5, 6, 11, and 12. To achieve these goals, whole-cell and single-channel currents will be measured to determine the kinetics of two structurally-distinct classes of pore-blocking molecules, and to determine whether their binding domains contribute to the permeation pathway. Structural elements that contribute to the architecture of the pore will be defined by comparing the ability of wildtype and mutant channels to interact with open-channel blockers. Previous studies from this laboratory have shown

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that blocker kinetics are highly sensitive to the structure of the pore. A region within TM6 has been identified that is critical for discrimination between different anions. This region also appears to lie close to the binding sites for pore-blocking molecules. To accurately describe the structure of this region of the channel, it is necessary to consider to contributions made from portions of the channel other than TM6. These studies will be guided by a three- dimensional model of the pore, proposed in the application, which takes into account the experimental data for TM domains 5, 6, 11, and 12. This approach hypothesizes that multiple helical domains contribute both to the binding sites for drugs and to the determinants of selectivity in the channel. A specific subset of residues that may determine the biophysical features of permeation is proposed. Testing the importance of these residues will allow the construction of a detailed map of the conduction pathway. An improved understanding of the function of this channel will aid in the design of novel therapies for Cystic Fibrosis, secretory diarrhea, and polycystic kidney disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BUILDING LIFE SKILLS IN CHILDREN WITH CYSTIC FIBROSIS Principal Investigator & Institution: Christian, Becky J.; None; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2001; Project Start 01-MAR-1998; Project End 30-NOV-2002 Summary: (Adapted from the Investigator's Abstract): This project will test the effectiveness of an intervention to improve psychosocial adjustment and functional and physiologic health in children (8 to 12 years) with cystic fibrosis (CF) by teaching them life skills to manage their chronic illness in their everyday lives. The goal is to help children develop strategies for managing their health status and life experience to maximize their development progress and quality of life. It is hypothesized that at the end of treatment, children who receive the KIDS with CF -- Building Life Skills protocol will show significantly greater improvement in psychosocial adjustment (self-esteem and self-competence, loneliness, impact of illness), functional health (functional disability, treatment adherence), and physiologic health status (pulmonary function and physical growth) over time than those receiving usual CF care. A two-group experimental, repeated measures design will compare children who receive the intervention with those who receive usual care; 116 children will be randomly assigned to the experimental or control groups. Treatment will include social problem-solving training and social skills training delivered in individual and small group sessions over a 5-week time span with 1-week intervals between sessions. At each group session, FEV1, height, and weight will be measured and children will have a brief interview on medication use, performance of chest physical therapy, and physical activity. At baseline assessment, immediately after, and at 3-, 6-, and 9-months after the intervention, children will complete the Self-Perception Profile for Children, Loneliness in Children Scale, Perceived Illness Experience Scale, and Functional Disability Inventory; pulmonary function FEV1, height, and weight will be measured; and a brief interview focusing on medication use, performance of chest physical therapy, and level of physical activity will be conducted. Multivariate ANOVA will be used to compare the pre-intervention equivalence of the study groups. Repeated measures MANOVA will compare each psychosocial, functional, and physiologic health outcome variable for the intervention and control groups. Interview data will be analyzed using content analysis. This life skills intervention should also have applicability for children with other chronic illnesses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CALCIUM KINETICS AND BONE DENSITY IN GIRLS WITH CF Principal Investigator & Institution: O'brien, Kimberly O.; Professor of International Health; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001 Summary: Reduced bone mineral density and impairments in linear growth are common in children with cystic fibrosis (CF). Although calcium is the major mineral of bone, the role of calcium metabolism in CF has not yet been explored. The secondary consequences of CF on bone development and calcium status may be especially detrimental in girls, who have a lower peak bone mass than males and whose growth may be most delayed during the pubertal growth spurt. To address these issues, stable isotopes of calcium will be used to examine calcium absorption and rates of bone calcium turnover in girls with CF who are between the ages of 7-18 years. Biochemical markers of bone turnover (osteocalcin and N-telopeptide), pubertal maturation (estradiol and tanner stage), growth factors (insulin-like growth factor-1), calcium metabolism (vitamin D and parathyriod hormone), inflammation (C-reactive protein) and bone density will also be assessed and correlated with the calcium kinetic measurements. Stable isotopic techniques allow for the precise measurement of calcium absorption, distribution of calcium within the body and rates of bone calcium deposition and resorption. These techniques will provide useful information to better understand the mechanisms behind the reduced bone mineral density found in children with CF. As the lifespan of individuals with CF increases, it becomes more important to prevent chronic conditions such as osetoporosis that are largely irreversible once established. Results from this study will provide valuable data that will in turn help physicians to suggest interventions to maximize calcium retention and peak bone mass in children with cystic fibrosis." Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CAMP STIMULATED SWEAT RATE IN CYSTIC FIBROSIS Principal Investigator & Institution: Brass-Ernst, Lois A.; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001 Summary: The goal of this project is the development of a cyclic-AMP(cAMP)stimulated "sweat rate" test that will discriminate between fully functional, partially functional, and non-functional forms of the Cystic Fibrosis Transmembrane Conductance Regulator(CFTR). Sweat production can be stimulated by both cholinergic & adrenergic agonists. Collection of cholinergic stimulated sweat & the subsequent measurement of sweat cholride concentration is the basis of a standard diagnostic test for cystic fibrosis (CF), the pilocarpine iontophoresis sweat test. Stimulation of sweat production with pilocarpine leads to initial production of an isotonic secretion in the sweat gland. In non-CF patients, as the secretion traverses the sweat duct, chloride is reabsorbed leading to low concentrations of chloride in sweat as it appears on the skin. This chloride resorption is dependent on the presence of functional CFTR. In CF patients, who lack functional CFTR, the sweat chloride concentration remains high, & distinguishes most, but not all, CF from non-CF patients. However, this technique does not distinguish heterozygote carriers of CFTR mutations from non-carriers, nor does the sweat chloride concentration correlate with disease severity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CELL BIOLOGY OF CFTR IN POLARIZED EPITHELIA Principal Investigator & Institution: Collawn, James F.; Associate Professor; Cell Biology; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2003; Project Start 20-DEC-2002; Project End 30-NOV-2007 Summary: (provided by applicant): Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel found in epithelial cells. Previous studies from our laboratory have demonstrated that CFTR undergoes rapid endocytosis, suggesting that this provides a mechanism for regulating CFTR surface expression. In CF, more than 70% of patients have one specific mutation, deltaF508, which results in the production of a misfolded protein that fails to exit the endoplasmic reticulum (ER). An obvious therapeutic approach, therefore, is to develop methods for releasing deltaF508 CFTR to the cell surface, since deltaF508 has biological activity. Recent studies, however, have demonstrated the deltaF508 CFTR that reaches the cell surface after chemical chaperone or low temperature treatment is rapidly removed from the surface and degraded, unlike the wild type protein. Since little is known about how wild type CFTR surface expression is regulated, the defect in deltaF508 CFTR surface stability is unclear. Our hypothesis is that wild type CFTR is stabilized at the cell surface through interactions with epithelial-specific proteins such as EBP50, is internalized through clathrincoated pits because of sorting signals in its cytoplasmic tail regions, and is efficiently recycled back to the cell surface via vesicle trafficking. Further, we hypothesize that the phosphorylation status of CFTR regulates these processes and more importantly, mutations within CFTR dramatically influence CFTR trafficking and stability at the cell surface. To test these hypotheses, we will (1) define wild type CFTR trafficking in airway epithelial cells and (2) define how mutations in CFTR affect endocytosis and recycling. We will focus on three key aspects of CFTR cell biology: (1) plasma membrane residence time; (2) cellular mechanisms of endocytosis; and (3) degree of CFTR recycling. Using simplified biotinylation internalization assays of CFTR in human airway epithelial cells, we will assess the cell biological and physiological properties of CFTR trafficking of wild type CFTR versus a select panel of CFTR mutants that include deltaF508, R31L, Y1424A/I1427A, and deltaTRL. Understanding the normal dynamics of CFTR surface expression, internalization, and stability in epithelial cells where CFTR normally resides will provide valuable information regarding the fundamental cell biology of CFTR and will provide potential therapies for the most common mutation in CF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CF EPITHELIAL CELLS: INTERACTIONS WITH PSEUDOMONAS Principal Investigator & Institution: Prince, Alice S.; Professor; Pediatrics; Columbia University Health Sciences New York, NY 10032 Timing: Fiscal Year 2001; Project Start 01-JUL-1991; Project End 30-NOV-2005 Summary: (Applicant's Abstract): The respiratory epithelium provides a major defense mechanism against the many pathogens that are inadvertently inhaled, responding with the expression of chemokines such as IL-8 and mucin. In cystic fibrosis, there is excessive inflammatory response to these organisms, particularly P. aeruginosa, which initiates the airway inflammation characteristic of this disease. In the experiments described, the ligands and receptors involved in this host-pathogen interaction will be defined in detail. Caveolae, spatially organized clusters of membrane glycolipids, scaffolding proteins, and signaling kinases appear to be important in mediating bacterial

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attachment and directing the epithelial IL-8 response. The components of caveolae that present the GalNAcGal bacterial receptor will be established, and how they may differ in cells with CFTR mutations will be explored. As several different P. aeruginosa ligands interact with epithelial components, additional receptors will be sought, including those which may activate other epithelial signaling cascades. Many of the known P. aerugunosa ligands are glycosylated, such as pilin, flagellin, and lipopolysaccharide (LPS). Exactly how glycosylation affects the adhesin function of these gene products or their ability to stimulate the host immune response is not well established. By using genetically defined mutants of P. aeruginosa, and comparing glycosylated and nonglycosylated ligands, especially flagella, we will determine how glycosylation affects bacterial-epithelial interactions, and if these carbohydrate structures may serve as targets for the development of therapeutic strategies. LPS is an important glycosylated virulence factor that activates both immune and epithelial cells. The role of specific carbohydrate components of P. aeruginosa LPS in pathogenesis will be examined and how LPS carbohydrate side chains alter host pathogen interactions in normal and CF cells will be explored. Other bacterial virulence factors, such as phospholipases, are important is activating epithelial responses. P. aeruginosa express several PLC'S which can interact with membrane components and activate cytokine signaling. Using genetically defined mutants, the contribution of PLC to epithelial damage in normal and CF cells will be examined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CFTR AND CHRONIC RHINOSINUSITIS Principal Investigator & Institution: Cutting, Gary R.; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001 Summary: Chronic rhinosinusitis affects about 15% of the adult population in the United States. It is likely that a variety of abnormalities give rise to this disorder. Chronic rhinosinusitis is an almost invariable feature of the autosomal recessive disorder Cystic Fibrosis (CF), which is caused by mutations in the CFTR gene. We have been exploring the possibility that patients with rhinosinusitis have a higher rate of defects in the CFTR gene than the normal population. Studies performed during the prior grant period identified an increased frequency of carriers of CF mutations among patients with chronic rhinosinusitis (n=11). Excessive genetic analysis and studies that evaluated CFTR function in vivo (sweat chloride test and nasal potential difference measurement) has been complemented on none patients, and none have evidence of CF. These data suggest that CFTR plays an etiologic role in chronic rhinosinusitis in the absence of cystic fibrosis. The overall goal of the current proposal is to explore the relationship between CFTR and chronic rhinosinusitis by pursuing the following aims: 1. To establish the prevalence of CF carriers among patients with chronic rhinosinusitis by genetically screening at least 100 additional rhinosinusitis patients and an additional 120 controls enrolled by the Clinical Core. 2. To determine whether chronic rhinosinusitis patients with a CF mutation have clinical and/or biochemical features that distinguish them from patients without CF mutations. 3. To determine whether family members that have inherited a CF mutation have a higher frequency of chronic rhinosinusitis than those that have not inherited a CF mutation. 4. To determine whether the prevalence of chronic rhinosinusitis in obligate carriers of CF mutations (i.e. parents of Cystic Fibrosis patients) is higher than in the general population. Use of complementary approaches and sufficiently large populations should minimize the chance of erroneously accepting or rejecting the hypothesis that chronic rhinosinusitis

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patients have an increased frequency of CF mutations. This is critical since the potential health impact of this hypothesis could be substantial, and if correct, may enable the identification of patients who could benefit from therapies that are not currently employed in the treatment of rhinosinusitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CFTR AND DUODENAL ANION TRANSPORT Principal Investigator & Institution: Clarke, Lane L.; Associate Professor; Dalton Research Center; University of Missouri Columbia 310 Jesse Hall Columbia, MO 65211 Timing: Fiscal Year 2001; Project Start 01-AUG-1995; Project End 30-NOV-2004 Summary: (Adapted from the Applicant's Abstract): The central role that the cystic fibrosis transmembrane conductance regulator (CFTR) plays in gastrointestinal anion transport physiology is evident from the intestinal and pancreatic manifestations of the genetic disease cystic fibrosis (CF). CFFR is essential to normal Cl- and HCO3- secretion across epithelial surfaces. Loss of this function in CF has been closely associated with disease processes such as distal obstructive syndrome, meconium ileus, pancreatic insufficiency, gallbladder disease and duodenal ulceration. Furthermore, the inability of the senescent epithelial cells to unload base may interfere with apoptosis, leading to necrotic cell death and accompanying inflammatory reactions that underlie CF pathogenesis. The present proposal focuses on the role that CFTR plays in mechanisms of Cl- and HCO3- secretion in the duodenum. Although anion secretion across this intestinal segment maintains a critical barrier to gastric effluent, little is known of the electrochemical gradients for anion secretion, the identity of anion exchange proteins that coordinate activity with CFTR, or the distribution of these processes along the crypt-villus axis. Studies will be performed on intact duodenum from geneticallyaltered CF mouse models because they accurately reproduce human CF intestinal disease. Knockout mouse models of other anion transport proteins will be used to dissect the mechanism of Cl- and HCO3- secretion in a physiological setting. We will test several hypotheses predicted from our proposed model of duodenal anion secretion. Microelectrodes and fluorescent dye markers will be used to investigate the hypothesis that CFTR functions as both a Cl- and HCO3- conductance. RT-PCR and immunoblots of normal and CF duodenal epithelia will be used to identify the effect of CFTR activity on anion transport protein expression along the crypt-villus axis. In addition, membrane vesicle and transepithelial flux studies will be used to test the hypothesis that the anion exchanger AE2 provides an alternative Cl- uptake mechanism for transepithelial Cl- secretion whereas the anion exchanger DRA, possibly driven by carbonic anhydrase, operates in parallel with CFTR for transepithelial HCO3- secretion. The successful completion of our proposed studies will firmly establish the mechanisms involved in Cl- and HCO3- secretion across the duodenum. The results will further define the role of CFTR in these processes and therefore have important implications for our understanding of intestinal pathophysiology in CF disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CFTR AND INFECTION OF CYSTIC FIBROSIS PATIENTS Principal Investigator & Institution: Pier, Gerald B.; Professor; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2002; Project Start 01-JUL-1999; Project End 30-NOV-2005 Summary: (provided by applicant): The long-term goal of this project is to understand the molecular and cellular basis of the hypersusceptibility of cystic fibrosis (CF) patients

30 Cystic Fibrosis

to chronic infection with Pseudomonas aeruginosa. This infection is responsible for greater than 80 percent of the morbidity and mortality that occurs in CF patients. A key component of this hypersusceptibility is the role and function of the cystic fibrosis transmembrane conductance regulator (CFTR) in host resistance to P. aeruginosa. CFTR in epithelial cell membranes binds directly to P. aeruginosa and mediates bacterial internalization, an interaction critical for microbial clearance in individuals with wildtype CFTR. Although the major components of the ligand-receptor interaction have been identified the work proposed in this application will explore more of the complexities of this interaction. One focus will be on bacterial factors that provoke the cellular response leading to ingestion of whole P. aeruginosa cells and LPS. A second focus will be on the CFTR-dependent eukaryotic cellular responses to P. aeruginosa infection. The first set of aims will encompass: a) identification of P. aeruginosa proteins that provoke translocation of CFTR from cytoplasmic stores to plasma membranes, by identifying and measuring the ability of purified bacterial products to provoke membrane localization of CFTR and determining their role in the pathogenic process using cell culture and animal models of infection; b), a detailed structural analysis of the chemical components of the P. aeruginosa LPS involved in binding to CFTR using NMR and mass spectrometry techniques. The second aim will focus on the cellular activation and signaling molecules elicited in response to the P. aeruginosa-CFTR interaction and their role in host resistance to infection. Specific areas of investigation encompass: a) studies using FACS and confocal microscopy on how CFTR extracts and internalizes the LPS from the bacterial outer membrane leading to NF-kappa B and other eukaryotic cellular responses critical for coordination of innate immunity; b) the molecular and genetic factors involved in progression of cells with wild-type CFTR to apoptosis which does not occur comparably in CF cells; and c) the role of the Fas-Fas Ligand system in CFTR-controlled apoptosis and resistance to P. aeruginosa infection. From these studies we anticipate ascertaining how wild-type CFTR coordinates immunity to P. aeruginosa lung infection and how this process is defective in CF patients. Such insights may lead to interventions to prevent the common occurrence of chronic P. aeruginosa infection in CF patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CFTR REGULATION OF ION CHANNELS Principal Investigator & Institution: Egan, Marie E.; Associate Professor; Pediatrics; Yale University 47 College Street, Suite 203 New Haven, CT 065208047 Timing: Fiscal Year 2001; Project Start 07-APR-1998; Project End 31-DEC-2002 Summary: The gene that is defective in patients with cystic fibrosis (CF) encodes a protein termed the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a member of a superfamily of transmembrane proteins known as the ATP Binding Cassette (ABC) Transporters. It is clear that CFTR functions as a cAMP dependent protein kinase A stimulated chloride (CI-) channel. Although abnormal CI- channel activity, specifically cAMP- dependent protein kinase A (PKA) stimulation of CIsecretion, is a predominant feature of CF- affected epithelial cells and believed to be a direct result of the dysfunctional CFTR protein, there are a number of other ion transport abnormalities that are characteristic of CF- affected epithelial cells. There is increasing evidence that CFTR can interact with other channel proteins and act as a channel regulator as do a number of the ABC transporters. Our hypothesis is the CFTR is a bifunctional peptide that acts as a regulator of ion channels and transporters as well as a regulated CI- channel. Furthermore it is likely that the ability to act as a channel regulator depends on domains that are common to many members of the ABC

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transporter superfamily. The studies proposed in this application will examine how CFTR acts as a channel regulator. Voltage clamp and patch clamp techniques will be used to dissect the mechanisms that control CFTR's interactions with ion channels and identify which domains of CFTR participate in these interactions. The ultimate goal of this project is to apply insights gained from these basic science studies of CFTR function to improve the clinical management of cystic fibrosis patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CFTR/REGULATION OF CL SECRETION IN NORMAL AND CF AIRWAYS Principal Investigator & Institution: Guggino, William B.; Professor of Physiology and Pediatrics; Physiology; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001; Project Start 01-APR-1991; Project End 28-FEB-2005 Summary: The central focus of the renewal will be on understanding how CFTR interacts with other proteins. The concept of how transport proteins work together to coordinate the transport of solutes and water across epithelial cell membranes has been a question fundamental to epithelial physiology. A combination of molecular and physiological experiments will give us the opportunity to address long standing questions regarding transporter homeostasis To address this issue we will focus on proteins that bind to CFTR and enable it to function in a macro-molecular complex. During the previous budget period we have discovered a new protein called CAL (CFFR associated ligand). CAL is a new member of the PDZ domain protein family. in addition to a single PDZ domain, CAL is predicted to have other protein interacting regions (coiled-coil domains). CAL binding to the cytoplasmic carboxy-terminus of CFTR via its PDZ domain organizes CFTR into protein clusters. Apical localization indicates that CAL serves as a scaffold protein that interacts with CFTR at the epithelial plasma membrane. CFTR, an epithelial Cl- channel defective in cystic fibrosis (CF), has been functionally linked to other proteins. The Project has three goals to determine the functional consequences of the interaction between CAL and CFTR, to identify the structural domains of CFTR critical for the regulatory interaction between CFTR and CAL and to determine what are the functional consequences of multiple PDZ domain proteins that bind to CFTR. These studies will employ a combination of approaches. The ultimate goal of these studies is to provide novel insights into how CFTR functions in a macromolecular complex. The reasons for gaining more information on the terminal amino acids of CFTR and proteins such as CAL that bind to it are at least two-fold. First, CFTR is a transport protein that functions in a variety of epithelial cells. More importantly, information how CFTR interacts with other proteins will increase our information on how mutant CFTR causes CF. This is particularly important to our understanding of lung pathobiology whose severity of disease often does not correlate with genotype. Finally, the novel proteins that bind to CFTR provide important targets for pharmacologic therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHAPERONES AND MEMBRANE PROTEIN BIOGENESIS Principal Investigator & Institution: Cyr, Douglas B.; Associate Professor; Cell and Developmental Biology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2003; Project Start 01-JAN-1998; Project End 31-DEC-2006

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Summary: (provided by applicant): The objective of the proposed work is to define how cytosolic molecular chaperone proteins function in protein quality control to facilitate the folding and degradation of membrane proteins. The approach to taken to solve this problem is to study the biogenesis of normal and disease causing mutant forms of the cystic fibrosis transmembrane conductance regulator (CFTR). Our previous studies which utilized cultured cells and cell free systems defined roles for the cytosolic Hsc70 chaperone system in facilitating both the folding and degradation of nascent endoplasmic reticulum (ER) forms of CFTR. Data generated in the last funding period indicate that Hsc70 acts in complex that contains the ER localized Hsp40 Hdj-2 to promote CFTR folding/assembly. In addition, we found Hsc70 to interact with a new type of co-chaperone termed CHIP that contains an E3 ubiquitin ligase domain termed the U-box, to facilitate CFTR ubiquitination and degradation. These data demonstrate that cytosolic Hsc70 functions in both the folding and degradation of membrane proteins and provide evidence that co-chaperones help mediate the partitioning of nascent membrane proteins between folding and degradation pathways. We now seek additional funding to extend these studies and propose a series of experiments that are designed to further elucidate the pathways for CFTR folding and degradation. These studies will be carried out in 3 specific aims. Aim 1. Investigate roles that cytosolic and lumenal ER chaperones systems play in CFTR folding. Aim 2. Determination of the mechanism by which the Hsp70/CHIP complex controls the partitioning of nascent CFTR between folding and degradation pathways. Aim 3. Identify the components that facilitate the delivery of ubiquitinated CFTR to the proteasome. Overall, these studies will provide a comprehensive view of how the cell mediates the folding and degradation of CFTR. The long term objective of these studies is to provide information that can identify targets for development of therapeutic to treat CF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CL-/HCO3- EXCHANGE IN CYSTIC FIBROSIS SWEAT GLANDS Principal Investigator & Institution: Quinton, Paul M.; Professor, Nancy Olmsted Endowed Chair i; Pediatrics; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, CA 92093 Timing: Fiscal Year 2001; Project Start 28-JUL-1998; Project End 31-AUG-2004 Summary: The most common and characteristic physiological defect of Cystic Fibrosis (CF) is dysfunction of the CFTR C1-channel which blocks C1- transport. On the other hand, it is not widely appreciated that HCO3 ion-transport is also defective in most, if not all, organs affected in CF. In view of its critical role in setting pH and its known ability to exchange for C1-ions, abnormalities in HCO3 ion-management may be closely integrated with CF pathogenesis. The link between these two defects is not known, but the human sweat duct offers a unique opportunity to observe normal and defective C1and HCO3 ion-transport in a native human tissue where the effects of CF markedly disturb electrolyte transport. Our data and other evidence indicates that HCO3 ion-is most probably transported via a C1-/HCO3 ion-anion exchange (AE) as it is in most other tissues. We propose to define AE function in sweat ducts from normal subjects and CF patients. We will characterize AE activity and HCO3 ion-transport in the plasma membranes of duct cells. Then, since electrochemical results show that not all C1absorption in the duct can occur electroconductively through CFTR, we will determine whether AE activity accounts for the difference. Because phosphorylation state, ATP, and pH strongly influence CFTR activity and because C1-conductance and HCO3 iontransport function together, we will determine whether any of these parameters regulate or influence HCO3 ion-transport also. Lastly, the severity of the HCO3 ion-transport

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defect appears to vary with distinct genotypes so we will use ducts from patients with known mutations in CFTR to determine if these mutations exert distinct effects on HCO3 ion-transport in the sweat duct. At present it is difficult to rationalize how a simple singular defect in C1-conductance can cause the myriad of abnormalities found in CF: namely, salty sweat, autolysis of the pancreas, atresia of the vas deferens, meconium ileus, depressed female fertility, and lung disease as well as a host of other abnormalities. Defining HCO3 ion-transport and its relevance to CFTR function should lend much to explaining, and hopefully, ameliorating these problems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLC-2 IN MEDIATING EPITHELIAL CHLORIDE SECRETION Principal Investigator & Institution: Bear, Christine E.; Assistant Professor; Hospital for Sick Chldrn (Toronto) 555 University Ave Toronto, Timing: Fiscal Year 2001 Summary: There is compelling evidence for variability in the severity of Cystic Fibrosis (CCF) disease amongst CF patients and differences in the nature of the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene mutation cannot account for all of this variation. Using a murine model of CF, our group has shown that secondary genes can ameliorate the severe intestinal phenotype,, the major cause of mortality in this species. These modifier genes have not yet been identified. However, as our comparative studies of the intestinal mucosa of CF mice with mild disease and CF mice with severe disease show a correlation between disease amelioration and chloride ion secretion, we suggest that disease modification may occur through modulation of the chloride channel(s) on the apical membrane of intestinal epithelial cells is a fundamental to developing our understanding of how disease severity can be ameliorated in intestinal epithelial cells. So far, our findings suggest a correlation between ClC-2 expression and intestinal chloride secretion. Specifically, we found that chloride (Cl) secretion by intestinal mucosa obtained from CF mice with mild disease can be blocked by inhibitors of ClC-2 function and the ClC-2 protein is localized toward the apical pole of these epithelial cells. Hence, ClC-2 protein is appropriately localized to mediate chloride secretion. However, ClC-2 can only mediate secretion if it is activated in epithelial cells and so far, we have only a poor understanding of how ClC-2 channel activity is regulated. Our overall goals of this study are to understand how ClC-2 is regulated and to determine if this channel protein can mediate secretion in intestinal epithelial tissue. Specific Goals: 1) to study the regulation of ClC-2 channel function in vitro and in vivo. We have determined that purified, reconstituted ClC-2 protein can mediate Cl ion electrodiffusion. Our reconstitution system will permit detailed analysis of its permeation and gating properties. We also found that Clc-2 is endogenously localized at the apical surface of the Caco-2 cell line ane have developed tools to study its regulation in the model epithelial cell line. 2) to determine whether ClC-2 in Cl secretion in Caco-2 cells by modifying its expression through transfection. Furthermore, the role of ClC- 2 in secretion by native tissues will be investigated by generating transgenic mice over-expressing ClC-2. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLEARANCE OF APOPTOTIC CELLS IN CYSTIC FIBROSIS Principal Investigator & Institution: Vandivier, Richard W.; Medicine; University of Colorado Hlth Sciences Ctr Uchsc at Fitzsimons Aurora, CO 800450508 Timing: Fiscal Year 2003; Project Start 17-FEB-2003; Project End 31-JAN-2008

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Summary: (provided by applicant): Cystic fibrosis (CF) is an autosomal recessive disorder caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) that is associated with chronic, debilitating airway inflammation. In CF, airway inflammation begins almost immediately following birth and continues inexorably until death ensues from pulmonary failure in the majority of patients. Studies have observed the accumulation of inflammatory cells and mediators in the airways of CF neonates in the absence of detectable infection, suggesting that CFTRdeficiency may have the capacity to disturb normal regulatory mechanisms, and initiate airway inflammation. Resolution of inflammation normally involves the orderly removal of apoptotic inflammatory cells, thereby suppressing their ability to do damage. This process promotes the resolution of inflammation by, 1) preventing spillage of proinflammatory cell contents, and by 2) inducing the phagocyte to produce antiinflammatory mediators such as TGFI3 and PGE2, through interaction with the phosphatidylserine receptor. We have observed that apoptotic inflammatory cells accumulate in the airways of young adults with CF, and have shown that protease cleavage of the PS receptor is involved. We now provide evidence that CFTR-deficiency impairs apoptotic cell ingestion by airway epithelium, and prevents apoptotic cell suppression of inflammatory mediator release. A role for CFTR in epithelial cell clearance of apoptotic cells may be related to the fact that CFTR is a member of the ATPbinding cassette (ABC) protein superfamily, which includes members known to be involved with apoptotic cell removal (e.g. ced7 and ABC-1). These findings and the known role for epithelial cells in apoptotic cell clearance suggest that failed phagocytosis by epithelial cells may contribute to the accumulation of apoptotic cells and persistent inflammation in CF airways. Therefore, we propose to 1) test the effect of CFTR on ingestion mechanisms unique to uptake of apoptotic cells, to 2) test various mechanisms whereby apoptotic cells may enhance the inflammatory response in CFTRdeficient epithelial cells, and to 3) determine the effect of dysfunctional CFTR on apoptotic cell clearance and inflammation in vivo. These studies will help to elucidate the role of CFTR in a previously unknown function, phagocytosis of apoptotic cells and regulation of inflammation, and in the future may help direct therapies toward mitigating this process and diminishing the long-term effects of chronic airway inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONSUMER PERSPECTIVES ON THE PROMISE OF CF GENE THERAPY Principal Investigator & Institution: Stockdale, Alan; Education Development Center, Inc. 55 Chapel St Newton, MA 02458 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAY-2003 Summary: (Adapted from the Investigator's Abstract): Although gene therapy has been widely publicized as an impending cure for numerous diseases, including cystic fibrosis (CF), little empirical research has been conducted to determine the impact of this publicity, and its promise of cure, on patients and their families. Such knowledge of consumer perspectives is essential for enhancing trust in the biomedical establishment, for protecting vulnerable consumer groups from potential harms, and for the design of effective consumer and clinician educational materials. The Education Development Center, Inc., in collaboration with the International Association of Cystic Fibrosis Adults (IACFA), Temple University, St. Vincent's Hospital, and Brigham and Women's Hospital propose a study to (a) assess how gene therapy research, and the publicity surrounding it, are perceived by adults with CF, parents of children with CF, and CF

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Center physicians; (b) determine the knowledge, beliefs and attitudes that inform consumer perceptions and felt needs; (c) discover how those needs and perceptions affect patients' and families' treatment decisions and life plans; and (d) identify the ethical and psychosocial implications of gene therapy developments on patients, families, and their physicians. The team will do a content analysis of information materials disseminated to CF patients and the public; conduct qualitative interviews with 30 adult CF patients, 30 parents of children with CF, and 30 physicians. These interviews will be used to develop a survey questionnaire to be administered to al consenting adult CF patients and parents of children with CF cared for at all 13 New England CF treatment centers (N=1595) and to IACFA members in the U.S. (N=713). Findings will be presented to an expert advisory group of CF consumers, researchers, clinicians, ethicists, and representatives of other disease perspectives, such as AIDS and cancer. This goup will assist the study team in drafting recommendations for how best to reconcile the promise with the reality of CF gene therapy and identify the possible implications for other areas of gene therapy research. Recommendations will focus on consumer and clinician education; however, they will also have relevance for a broader array of issues, such as recruitment into gene therapy trials and priorities for research and care delivery. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONTROL OF IMMUNE RESPONSES TO GENE THERAPY OF THE LUNG Principal Investigator & Institution: Rodgers, John R.; Associate Professor; Microbiology and Immunology; Baylor College of Medicine 1 Baylor Plaza Houston, TX 77030 Timing: Fiscal Year 2001; Project Start 07-DEC-1998; Project End 30-NOV-2002 Summary: Successful gene therapy of cystic fibrosis (CF) or alpha1-antitrypsin inhibitor (AAT) deficiencies will require that patients immunologically tolerate gene grafts for the cystic fibrosis transmembrane conductance regulator (CFTR) or AAT. This proposal uses the mouse models to investigate mechanisms of natural and induced tolerance of CFTR and AAT. In Aim 1 we will determine the basis of non-H-2-linked tolerance of human AAT in the C57BL/6 mouse, and apply these lessons to the AAT.PiZ transgenic mouse strain, an immune model for the human AAT-deficiency. The most common mutant form of CFTR is deltaF508. deltaF508 has been identified as a severe folding mutant that degrades within the endoplasmic reticulum. It does not enter the endosomal compartment where antigen processing for class II major histocompatibility complex molecules and CD4+ T cells occurs. Such processing is required for selftolerance. To develop means of inducing tolerance to CFTR in deltaF508 patients, Aim 2 uses CFTR knock-out and deltaF508 transgenic mice to determine mechanisms of deltaF508 antigen processing and induced tolerance of wild-type CFTR protein. Most forms of tolerance induction involve the induction of anergy or apoptosis in responding T or B cells. When T cells first recognize antigen they transiently become sensitive to killing by the "death ligands" tumor necrosis factor alpha (TNFalpha) and Fas ligand (FasL). Some tissues and tumors appear to resist T cell attack by expressing FasL ectopically, suggesting that co-expression of death ligands with therapeutic genes might induce tolerance of gene therapy. Experimental tests of this approach indicate efficient tolerance induction will require proper co-stimulation of T cells to induce sensitivity to FasL and TNFalpha. Aim 3 will improve the efficiency of FasL/TNFalpha- induced tolerance to gene therapy by determining the requirements of co- stimulation. These studies will provide information crucial to the success of gene therapy of the lung. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE CENTER - CYSTIC FIBROSIS Principal Investigator & Institution: Davis, Pamela B.; Professor; Pediatrics; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001; Project Start 01-JAN-1983; Project End 31-MAR-2006 Summary: The Core Center for Research in Cystic Fibrosis (CF) at Case Western Reserve University has existed since 1964, in one form or another, through its structure and core functions have evolved as the research base has changed. The current Center, which garners over $9 million in external grants and contracts in support of CF-related research, consists of 42 investigators from 9 departments with focus in three main scientific areas. The area of cell and molecular biology of CFTR, with leadership from Mitchell Drumm, M.D., co-director of the Center, and Ulrich Hopfer, M.D., a member of the Executive Committee, is supported largely through R01 and Cystic Fibrosis Foundation (CFF) grants, and studies CFTR molecular conjugates, and modifier genes. The second main area, with leadership from Melvin Berger, M.D., Ph.D., underlying basis, and how it might be modified therapeutically. This work is the topic of a SCOR grant (funded 1998) and CF, the third area of focus, which receive support from the CFF Therapeutics Development Network (funded 1998), industrial sponsors, and federal and CFF grants. The Center is directed by Pamela Davis, M.D., Ph.D., who also directs the CFF Research Development Program, the SCOR in inflammation, and the T32supported training program. The Core Center consists of five cores besides the administrative: Biostatistics (Mark Schluchter, Ph.D., Director); Epithelial Cell Culture (Calvin Cotton, Ph.D., Director); Imaging (Ulrich Hopfer, M..D., Ph.D., Director); BAL/Inflammatory Mediator (Ronald Walenga, Ph.D., Director) and Animal (Mitchell Drumm, Ph.D., Director), each of which provides services to at least ten funded projects. In addition, the Center operates a pilot and feasibility program to encourage new ideas in CF research. In addition, the Center operates a pilot and feasibility program to encourage new ideas in CF research. Of past P&F projects, 74% received additional grant support (60%, federal grants) and more than 90% continue involvement in CF research. The Center emphasizes translational research, and the next five year cycle should see the testing of new therapeutic strategies developed in the Center in CF patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--ANIMAL Principal Investigator & Institution: Bedwell, David M.; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2001 Summary: Three investigators within the overall SCOR proposal require the use of cystic fibrosis mice for their individual components. Dr. Bedwell (Project 1) intends experiments with a G542X CF mouse, in order to test whether aminoglycoside antibiotics can activate read-through of this truncated CFTR in vivo. Dr. Benos (Project 3) intends to develop a transgenic mouse possessing the Ca2+ - activated C1- channel (CaCC) under the regulatory control of the fatty acid binding protein promoter in order to determine whether it is possible to rescue cystic fibrosis mice by activating an alternate C1- secretory pathway. Dr. Sorscher (Project 4) will use the CF Animal Core facility for studies of a delta F508 maturational agent (DMSO) in cystic fibrosis mice. The CF Animal Core is intended to expand and genotype colonies of cystic fibrosis mice and to assist SCOR investigators with development of these two new strains (G542X, CaCC) of CF mice. The Core will also assist with nasal potential difference (PD)

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measurements on CF and normal mice in order to test interventions designed to correct the CF defect. While the primary responsibility of the CF Animal Core will be to assist SCOR investigators, many other faculty on the UAB campus will benefit from the existence of a core facility designated to develop and breed CF mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--ANIMAL Principal Investigator & Institution: Drumm, Mitchell L.; Associate Professor; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001; Project Start 01-JAN-1983; Project End 31-MAR-2006 Summary: The Animal Core was started in 1997 to accommodate the growing need of Center investigators for CF mice, with support from the Cystic Fibrosis Foundation, and in1 998, it received additional support from our new SCOR grant. However, the utilization of this Core kept growing and it is now proposed for inclusion in the CF Core Center. This Core has as its goals the provision of animals of various CF genotypes to CF investigators, the provision of genetically engineered animals of relevant genotypes apart from CF for CF-related investigations, the provision of the pseudomonas-agar bead model to Center investigators, and the training and assistance of technicians, trainees, and investigators in various aspects of mouse care, handling, medical procedure, and research procedures. The Core also serves as a focal point for communication among investigators about mouse issues and has been instrumental in minimizing the use of animals as research subjects by maximizing the utilize of each individual mouse for use by different investigators, if feasible. In order to meet its goal the Core performs such activities as breeding, backcrossing, genotyping, special husbandry activities required by the fragile condition of the CF mice, database and web page maintenance, liaison with the Animal Resource Center personnel and condition of the CF mice, database and web page maintenance, liaison with the Animal Resource Center personnel and management, monitoring of mice and early identification of difficulties, training and education. The Corer Director is Mitchell Drumm, Ph.D., himself a major user and a geneticist, and the Supervisor is Anna van Heeckeren, D.V.M., who is expert not only in mouse health but in the creation and standardization of the agar bead model. This Core, in its brief existence, has already supported more than a dozen funded investigators and the demand is growing. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--ANIMAL MODEL AND DELIVERY Principal Investigator & Institution: Matalon, Sadis; Acting Associate Provost for Research; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2002 Summary: (Taken directly from the application) Five of the pilot projects in the current application, and ten investigators with funded RO1s or other grants for gene transfer, have indicated a need for assistance with 1) instillation or aerosolization of gene delivery vehicles, 2) detection of reporter transgenes, 3) ion transport measurements in CF mice, or 4) histopathology in order to test safety and biologic effect of gene transfer to mammalian airways. The purpose of this core is to provide that expertise in a central, standardized fashion. The Core will process murine lungs for reporter gene activity (including luciferase, chloramphenicol acetyltransferase (CAT), and LacZ). We will also develop and test a new, highly sensitive reporter construct ($ -lactamase) for activity in vivo. Nasal potential difference measurements will be performed before and after gene

38 Cystic Fibrosis

transfer to cystic fibrosis and normal mice. This assay will be designed to test for functional correction of cystic fibrosis defects after CFTR gene expression in vivo. Finally, we will provide expertise in histopathology, so that lungs treated with gene transfer vectors can be processed and sectioned for qualitative and quantitative analysis of the extent and duration of the host inflammatory responses. These core functions are designed to facilitate the transition from in vitro proof of concept trials to in vivo analyses of CF gene transfer. The protocols described here are a crucial aspect of the development of gene therapy in cystic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--ANIMAL MODELS Principal Investigator & Institution: Engelhardt, John F.; Associate Professor; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2001 Summary: Animal models of human disease are a critical component in the development of effective gene therapies. Genetically defined animal models which reproduce the clinical manifestations of a disease help to elucidate the pathophysiologically relevant cellular targets for gene therapy and aid in development and testing of gene vector technologies for therapeutic efficacy. The Animal Models Core will provide support to investigators using animal models for the development of gene therapies for several genetic diseases with an emphasis on cystic fibrosis. In this regard, the Core will provide centralized production, care, breeding, genotyping and quality control of transgenic and knockout animals for use by investigators in the Center. The core will also provide a mechanism for the receipt or distribution of new experimental transgenic and knockout models with the Jackson Laboratory Induced Mutant Resource, a national resource for transgenic and knockout mice, to Center investigators. BL2 animal containment facilities for experiments with recombinant viruses will also be consolidated within the Core for use by investigators of the Center. For CF-based research, the core will provide several animal models for cystic fibrosis, including colonies of CF mice which harbor either null or clinically relevant point mutations, and human bronchial xenografts. These models will play a large programmatic role for studies on CF airway pathogenesis and gene therapy. In addition to the obvious emphasis this Center will have in gene vector development, it is also recognized that a concrete understanding of CF airway pathophysiology is also critical to the overall goals of this Center. Such information on the basic pathobiology of CF airway disease will lead to the identification of the relevant cellular targets and CFTR functions in the lung necessary for successful gene therapy approaches. Although this Core plans to direct the majority of its efforts toward gene therapy of cystic fibrosis, it will also play a broader role in the development of gene therapies for several other genetic diseases of programmatic emphasis to this Center. The main responsibilities of the Core will be: . Generation of transgenic mice . Generation of gene-targeted mice . Genotyping transgenic and knockout animals . Rederival of genetic stocks . Maintenance, cryopreservation, and provision of genetic stocks . Quality control of genetic lines . Generation of human bronchial xenograft models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--BAL/INFLAMMATORY MEDIATOR Principal Investigator & Institution: Walenga, Ronald W.; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106

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Timing: Fiscal Year 2001; Project Start 01-JAN-1983; Project End 31-MAR-2006 Summary: The BAL/Inflammatory Mediator Core plays a central role in the Cystic Fibrosis Research Core Center by providing the ability to sample directly the infected and inflamed airway in CF patients and control subjects by bronchoscopy, bronchoalveolar lavage (BAL) and bronchial brushing and to analyze the cells and inflammatory mediators found at that site. This Core disseminates samples to many researchers, but within this Cystic Fibrosis Center and world wide, for whom such patient materials might otherwise by unavailable. In addition, to provides sensitive, standardized, quality-controlled assays of cytokines and lipid-derived inflammatory mediators to Center investigators. This function has become especially important as the Center's focus on inflammation has developed over the last five years, with the funding of a SCOR grant on this topic and increased attention to this area from non-SCOR investigators as well. The objectives of the BAL/Inflammatory Mediator Core are (1) to obtain maximum information and benefit from precious patient and control BAL specimens by obtaining, processing and distributing BAL samples from CF patients and normal volunteers; coordinating the efforts of Center investigators to optimize the use of these invaluable specimens; assuring that the samples are processed and stored in such a way that they are available for future assays-including samples processed to preserve lipids, samples to preserve proteins, and samples to preserve proteases; and (2) to provide prompt, standardized, reliable, cost-effective assays of cytokines, other inflammatory mediators, proteases and protease inhibitors for Center investigators. Core Director Ronald Walenga, Ph.D.., supervises the overall function of the Core as well as the assay portion with its extensive quality control, and co-director Michael W. Konstan M.D., coordinates the bronchoscopy portion of the Core, performing many of them, or delegating them to co-investigators James F. Chmiel, M.D. This Core performs over 25,000 assays for more than a dozen funded projects, and provides BAL samples to 7 funded investigators at CWRU, as well as others outside the institution. We project this utilization to continue and expand in the next grant period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--CELL CULTURE Principal Investigator & Institution: Randell, Scott H.; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2001 Summary: The Cell Culture Core supports Gene Therapy for Cystic Fibrosis investigators by supplying cultured epithelial cells and cell lines from humans and animals in conditions appropriate to the planned experiments. This overall goal is achieved through four Specific Aims: 1) tissue acquisition; 2) patient characterization; 3) primary cell culture; and 4) cell line development and culture. Normal and cystic fibrosis (CF) patients scheduled for elective nasal or lung surgery are identified and characterized by established clinical and laboratory criteria. Epithelial cells are isolated from excess excised tissues and cultured by established techniques that preserve the physiological properties that are essential to the proposed studies. Specialized cell purification and culture techniques are used as needed to achieve specific experimental goals. Canine and mouse [normal or cftr(-/-)] airway epithelial cells are isolated and cultured by analogous techniques. Epithelial cell lines that express the essential characteristics of the native tissue are developed or obtained, and provided to PPG investigators as needed to meet overall experimental goals. These activities reflect the centralized provision of established techniques that have successfully supported CF research for more than 9 years, and the adaptation of newer reagents to these goals.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--CLINICAL FACILITY Principal Investigator & Institution: Leopold, Donald; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001 Summary: Chronic rhinosinusitis is a major health problem that affects approximately 15% of the US population. It is the hypothesis of this Program Grant that chronic rhinosinusitis represents a disease of epithelial cell and mucosal dysfunction. Together the 3 Projects that comprise this program provide an integrated approach to evaluate if this epithelial dysfunction arises as a result of an inherent genetic defect(s), environmental influences, or a combination of the two. This CORES serves as an essential clinical resource and will provide support for each of the 3 projects by pursuing the following aims: We will recruit and characterize the chronic rhinosinusitis patients that are required by all of the Projects, as well as the healthy, normal subjects and patients with perennial allergic rhinitis that are required as control populations for the second and third projects. We will assist the second project in ensuring the aggressive follow up of subjects recruited to assess the role of viral infections in the induction and recurrence of chronic rhinosinusitis; and of corticosteroids in reducing disease recurrence after surgery. We will also provide the sinus mucosal biopsies required as part of this protocol. We will assist the first Project in surveying, by questionnaire, members of families that have inherited a mutation in the cystic fibrosis transmembrane regulator (CFTR), and will clinically characterize family members with a positive history to verify that they have chronic rhinosinusitis. Enrollment of these family members will also serve the needs of the third Project. We will clinically characterize obligate carriers of CFTR mutations (i.e. parents of cystic fibrosis patients), recruited by the first project who have a positive history by questionnaire to verify that they have chronic rhinosinusitis. We will continue to maintain, refine and update a relational database that is being used to record demographic and clinical information on patients with chronic rhinosinusitis who are recruited into our studies. The use of well characterized patients is critical to any attempt to examine the pathogenesis of chronic rhinosinusitis, or to test therapies that may improve the management of this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--HUMAN AIRWAY CELL AND TISSUE Principal Investigator & Institution: Pilewski, Joseph M.; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001 Summary: The purpose of the Human Airway Cell and Tissue ore is to provide human airway cell models and establish a bank of Cystic Fibrosis (CF) and non- Cystic Fibrosis (non-CF) lung tissue for a number of research projects within the Cystic Fibrosis Research CENTER. Accordingly, the specific aims are: 1. To establish primary cultures of human airway epithelium from cystic fibrosis and non-cystic fibrosis lung for studies of CFTR function in F and non-CF airway. Studies of CFTR function are best performed in human airway epithelium. To create a laboratory model of human airway, cells derived from human airway are grown in the laboratory on permeable supports to induce differentiation and recapitulate airway surface epithelium in vitro. This model will be used for Center projects that seek to evaluate the cellular physiology and mechanisms of membrane trafficking of CFTR. 2. To determine the genotype of the CF

Studies 41

airway epithelial cells. To permit correlation of genotype with drug-induced changes in ion transport and CFTR function in primary airway cells, mutation analysis for the 70 most common CF mutations will be obtained from a reference laboratory. 3. To create a frozen bank of CF and non-CF airway cells and airway tissue. Isolated airway cells and segments of dissected lung will be frozen with and without prior fixation to establish a cell and tissue bank for future use that attempts to understand more about how mutations in the CF gene cause lung disease and allow comparison of mRNA and protein expression in CF and non-CF lung tissue. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--TISSUE ACQUISITION AND CELL CULTURE Principal Investigator & Institution: Finkbeiner, Walter E.; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001 Summary: Basic research toward understanding the pathobiology of cystic fibrosis requires a continuing and dependable source of cells, affected and unaffected by the disease. Thus, the primary objective of the Core Cell Culture Facility is to acquire airway tissues and culture airway surface epithelial and tracheobronchial gland cells. A tissue procurement system has been established for obtaining normal and cystic fibrosis airway tissue. Once obtained, surface epithelial tissue is enzymatically digested and liberated cells are established in primary culture. Tracheobronchial gland cells are isolated as acini and expanded through a single passage. Surface epithelial and gland cell cultures are evaluated for differentiated properties using light microscopy, electron microscopy and measurements of short circuit current and transpithelial resistance. Cells showings satisfactory features are distributed to investigators. If surplus cells are available, these are frozen for use later. Additionally, established cell lines routinely used by investigators are maintained in the Core Cell Culture Facility. The final aim of the Cell Culture Core Facility is to continue efforts to improve cultures, particularly those derived from tracheobronchial gland cells and to develop cell culture model systems applicable to the studies proposed by SCOR investigators. With respect to improving in vitro cell differentiation, both soluble factors (growth factors, hormones, chemicals) added to culture medium and insoluble factors (extracellular matrix components, air interface culture) are tested for their effects on airway gland cell growth and differentiation. Culture conditions that allow full expression of ion transport and mucus secretory function are two of the goals of this aim. However, the highest priority will be given to determining the culture conditions that promote serous gland cell differentiation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--TISSUE CULTURE Principal Investigator & Institution: Yankaskas, James; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2001 Summary: Epithelial cell cultures are instrumental in defining the pathophysiology of CF. A Tissue Procurement and Cell Culture Core was established at the University of North Carolina (UNC) in 1984, under the auspices of the Cystic Fibrosis Foundation, to provide standardized cell cultures to CF researchers. The Core has supported projects of the UNC Cystic Fibrosis Research Center since 1988, and has increased its output and capabilities to meet growing research demands. The Tissue Culture Core will support

42 Cystic Fibrosis

the SCOR projects through three major functions. 1. Tissue procurement. Obtain nasal and lung tissue from normal, disease control, and cystic fibrosis humans as sources of airway epithelial cells. Characterize donors with respect to diagnosis, demographic, and clinical features essential to research uses. 2. Airway epithelial cell isolation and culture. Isolate epithelial cells from large and small airways of human, primate and rodent lungs. Prepare and maintain primary epithelial cell cultures from define airway regions. Prepare differentiated cultures from passaged, or cryopreserved and thawed cells on substrates as dictated by investigator needs. Prepared and provide airway epithelial cell lines from gene knockout mice. 3. Cell culture technical development. Optimize epithelial culture conditions to replicate the gene expression, morphological differentiation, and ion and mucus secretory functions of normal and CF large and small airways. Produce genetically manipulated, well-differentiated primary airway epithelial cell cultures. Provide very high humidity culture environments needed to assess airway surface liquid topography in the absence of evaporation artifacts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COUPLING OF ADENOSINE RECEPTORS WITH CFTR Principal Investigator & Institution: Huang, Pingbo; Pediatrics; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2001; Project Start 01-MAR-2000; Project End 31-JAN-2003 Summary: The candidate Dr. Pingo Huang proposes highly original studies of the physiological regulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by tightly compartmentalized signaling pathway in the apical membrane of human airway epithelia. The candidate is uniquely qualified due to his extensive training in protein chemistry and in patch-clamp electrophysiology. He will work at the Cystic Fibrosis Pulmonary Research Center at UNC (Director, Richard Boucher, M.D.) under the direction of M. Jackson Stutts, Ph.D. This is a strong and nurturing environment for the development of the candidate s career. He interacts on a daily basis with internationally recognized CF investigators and cell biologists such as Sharon Milgram, Ph.D. The candidate s long-term goal is to carry out independent research on apical membrane compartmentalized signal tranduction pathways that are important for CFTR function and pathophysiology of epithelial diseases. His immediate career goal is to establish an independent track record of publications and funding based on the research proposed here. The research he proposed is an exciting hybrid of cell biology and electrophysiology. This experience and the opportunities during this award period (Gordon Conferences, Carolina Workshop) will put him at the forefront on modern techniques of studying epithelial pathophysiology. The work proposed here is based on the candidate s seminal observation that the excised patch clamp technique is a highly effective approach for isolating the signal transduction mechanisms closely associated with CFTR C1- channels in the apical membrane of polarized epithelial cells. The candidate has recognized that this maneuver not only identifies signaling elements compartmentalized in the apical membrane, but also uses the activity of CFTR itself as the highly relevant physiologic readout. The main hypothesis in the proposal is that coupling of luminal adenosine receptors to CFTR in human airway epithelia is mediated by compartmentalized and apical membrane- associated PKA and PKC mediated signaling pathways. Specific aims are: 1. Determine if luminal adenosine receptors are coupled to CFTR by compartmentalized and apical membrane-associated signaling pathways. 2. Determine if a PKA singling pathway is involved in the compartmentalized and apical membrane-associated signaling from adenosine receptors to CFTR. 3. Determine if a PKC signaling pathway is involved in the compartmentalized

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and apical membrane-associated signaling from adenosine receptors with CFTR. The results will provide novel insight into the mechanisms of not only regulation of CFTR by adenosine in particular, but also signal transduction in the apical pole of epithelial cells in general. Furthermore, these studies could potentially provide new maneuvers for pharmacotherapy of cystic fibrosis lung disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYSTIC FIBROSIS GENE MODIFIER STUDY Principal Investigator & Institution: Marshall, Bruce C.; University of Utah 200 S University St Salt Lake City, UT 84112 Timing: Fiscal Year 2001 Summary: The specific aim of this multicenter study is to determine the location of a modifier gene. This will be accomplished by analyzing DNA from siblings with cystic fibrosis, their parents, and from individuals with cystic fibrosis who had meconium ileus at birth and their parents. A genetic modifier of cystic fibrosis in the mouse has been mapped to the proximal portion of mouse chromosome 17, a region syntenic with human chromosome 19q13. The cystic fibrosis modifier locus was mapped to the proximal region of mouse chromosome 7 through linkage studies with SFTR-deficient mice. Studies in humans have indicated that a cystic fibrosis modifier locus associated with meconium ileus, but not with pulmonary function abnormalities, does exist. To refine the mapping of the cystic fibrosis modifier locus, additional sibling pairs with cystic fibrosis were ascertained. A total of 161 cystic fibrosis families with at least two affected siblings (197 sibling pairs) have been collected from ten cystic fibrosis centers, including the University of Utah. This region will now be further refined by analyzing additional markers with testing for allelic associations with the disease locus. The Utah Cystic Fibrosis Center has contributed the majority of the ascertained subjects for this study. No results are yet available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CYSTIC FIBROSIS REGULATOR CHLORIDE CHANNEL

TRANSMEMBRANE

CONDUCTANCE

Principal Investigator & Institution: Gadsby, David C.; Rockefeller University New York, NY 100216399 Timing: Fiscal Year 2001 Summary: The disease cystic fibrosis results from reduced epithelial Cl-permeability due to mutations in the gene encoding the cystic fibrosis traiismembrane conductances regulator (CFTR) Cl-channel. CFTR channels, like all other members of the family of ATP-binding cassette (ABC) transporters, incorporates two nucleotide binding domains (NBDs) but also includes a unique regulatory R domain containing more than 10 consensus sites for phosphorylation by cAMP-dependent protein kinase (PKA) and protein kinase C (PKC). In cells with ' normal CFTR channels, receptor-mediated activation of PKA causes phosphorylation of several R-domain serines, permitting channel opening and closing via cycles involving ATP hydrolysis. We have recently obtained strong evidence that ATP hydrolysis energizes the conforinational change that opens the channel gate, and that the degree of phosphorylation of a channel is one of the determinants of how long the gate stays open. Our working hypothesis is that phosphorylation of particular serines controls, independently, the function of the two NBDs. In a strongly phosphorylated channel with both NBDs functional, then hydrolysis of ATP at one NBD opens the channel, whereupon a second ATP can bind at

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the other NBD and in so ding can stabilize the open conformation. Hydrolysis of that second ATP then abolishes the stabilization, prompting channel closure. We have also hypothesized that distinct cellular phosphatases differentially dephosphorylate the various phosphoserines. Hence, in the cell, activation or inhibition of specific phosphatases could contribute to the complex mechanisms that regulate channel gating. The aim of this project is to learn which serines are phosphorylated under which experimental condition, with the goal of eventually discerning the exact role of each phosphoserine in orchestrating the function of the individual channel domains. The approach is to correlate biochemical information on phosphorylation with precise assays of function at the single channel level. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DESENSITIZATION OF P2Y2 NUCLEOTIDE RECEPTOR & CF THERAPY Principal Investigator & Institution: Gonzalez, Fernando A.; University of Puerto Rico Rio Piedras Rio Piedras Sta San Juan, PR 00931 Timing: Fiscal Year 2001 Summary: Description (Adapted from Application): Extracellular nucleotides activate P2Y2 receptors that modulate important biological processes, such as ion secretion, cellular growth, and vasodilatation, among others. UTP (a P2Y2 receptor agonist) has been shown to induce calcium-dependent anion secretion in airway epithelial cells expressing a defective cystic fibrosis transmembrane conductance regulator, a cAMPdependent chloride channel. This observation suggests that nucleotides may be efficacious in the treatment of cystic fibrosis. One potential limitation of this therapy is that prolonged exposure to nucleotides causes desensitization of the P2Y2 receptor leading to receptor sequestration and downregulation. Considering the therapeutic potential for P2Y2 receptor activation in vivo, the investigators will attempt to understand the molecular mechanisms underlying receptor desensitization. Preliminary results suggest that desensitization is caused by phosphorylation of amino acid residues in the intracellular C-terminal domain of the receptor. In the present application, the PI proposes to apply molecular, biochemical and pharmacological approaches to study the mechanisms of desensitization of a recombinant P2Y2 receptor expressed in human 1321N1J astrocytoma cells that lack endogenous nucleotide receptors. This transfection system will be used to express a variety of P2Y2 nucleotide receptor constructs (e.g., deletion and point mutants) to identify the specific phosphorylation sites and protein kinases that regulate agonist-induced desensitization and sequestration (i.e., uncoupling and internalization). To accomplish this goal they will express a series of epitope-tagged P2Y2 receptor mutants in 1321N1J cells followed by metabolic labeling of the cells and purification of receptor protein to directly determine the sites of phosphorylation. After identifying the P2Y2 receptor phosphorylation sites and kinases that regulate agonistinduced and heterologous desensitization, they will use the accumulated information to address the hypothesis that P2Y2 receptor uncoupling and internalization are distinct biochemical events. Therefore, they will determine how specific P2Y2 receptor domains and phosphorylation sites relate to receptor activation, signaling, desensitization (uncoupling), and sequestration (internalization). The information generated by the proposed experiments will provide an understanding of the molecular mechanisms for desensitization of P2Y2 receptors after acute and chronic exposure to nucleotides These results will be important for the future development of nucleotide therapies for cystic fibrosis and other diseases by elucidating means to optimize the beneficial effects of

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drug administration (i.e., signaling and anion secretion) while minimizing or eliminating the deleterious uncoupling and internalization of the receptor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DESIGN, PREPARATION, AND ASSAY OF SYNTHETIC CI CHANNEL Principal Investigator & Institution: Gokel, George W.; Professor and Director; Molecular Biol & Pharmacology; Washington University Lindell and Skinker Blvd St. Louis, MO 63130 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2006 Summary: Channel or "porin" molecules reside in cellular membranes and regulate the flow of cations, anions, water, and other molecular species through the bilayer. While a great deal is known about what channels do (transport rates, kinetic and open-close behavior, ion selectivity), the chemical mechanisms that underlie these processes remain largely obscure. It is clear that channels are critical for cellular regulation and various diseases result from their malfunction. The amino acid sequences of many channel proteins have been analyzed and various domains within the structures have been identified. Recently, crystal structures for the potassium-selective KcsA channel, a mechanosensitive channel, and of a water-transporting pore have also provided important new insight into the three-dimensional arrangement of the proteins. Important mechanistic insights have accompanied these structural developments. Not withstanding these recent advances, functional understanding of channel behavior remains a profound and important challenge. Of all channel types known in nature, perhaps the least is known about anion channels. We have now succeeded in developing a structurally simple, chemically accessible, modular anion channel we believe will be an important tool for understanding anion channel function. We propose here to develop and study our novel, modular, synthetic chloride-conducting channel using a broad range of techniques applied to natural ion and molecular channels. The biomedical importance of chloride channels became apparent when studies on the pathogenesis of cystic fibrosis demonstrated the CFTR, the cystic fibrosis transport regulator, was a chloride ion channel as well as a regulator of other transport systems. The mutations in this protein that result in systic fibrosis produce the commonest fatal genetic disease of Caucasion humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DETERMINANTS AND MODIFICATION OF CFTR EXPRESSION AT THE CELL SURFACE Principal Investigator & Institution: Rommens, Johanna M.; Scientist; Hospital for Sick Chldrn (Toronto) 555 University Ave Toronto, Timing: Fiscal Year 2001 Summary: Cystic fibrosis (CF) is a common recessive disorder with impaired vectorial transport across epithelial tissue. Over 750 mutations and 100 variations have been found in the affected gene and its product- the cystic fibrosis transmembrane conductance regulator (CFTR). The spectrum of the disease phenotype depends both on the nature of the mutation or combinations of mutations and on role of chloride transport and the regulatory properties of CFTR in individual epithelial tissues. A series of mutations that have been identified in patients that involve missense mutations in the first nucleotide binding fold (NBF1) or premature terminations in the carboxyl terminal region, will be used in model systems to understand the cellular machinery that

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participate in biogenesis and maintenance of CFTR at the cell surface. Preliminary data indicate that these mutations lead to diminished CFTR expression by two distinct mechanisms. Missense mutations in MBF1 accelerate the degradation of the immature CFTR at the endoplasmic reticulum. In contrast, premature termination at the Cterminal tail regions does not affect biosynthesis but leads to destabilization of mature CFTR. The specific aims are to: 1) delineate the mechanism of mutations that show impaired biogenesis with features distinct from deltaF508CFTR, 2) elucidate the role of the carboxyl terminus in maintaining cell surface stability of CFTR, 3) identify the protein-protein interactions that participate in the recognition of the missense mutations or are critical in the maintenance of CFTR density at the cell surface. All aspects of biogenesis, routing and stability of CFTR must be understood and considered to design effective therapeutic strategies to control the symptoms of deficiencies in CF. This is notably challenging as it is readily evident that the biogenesis and routing of the multidomain CFTR protein is a complex process involving a series of interactions and regulatory steps with rigorous quality control checks. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DETERMINANTS OF PANCREATIC INJURY IN CYSTIC FIBROSIS Principal Investigator & Institution: Accurso, Frank J.; Professor of Pediatrics; Children's Hospital (Denver) 1056 E 19Th Ave Denver, CO 80218 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2005 Summary: (provided by applicant): Marked phenotypic variability in individuals with cystic fibrosis (CF) who have the same CF genotype suggests that modifier genes may play a role in this disorder. Since most abnormalities in CF begin early in life, investigation of determinants of disease in infants and young children may provide insight into pathogenesis. We have observed that circulating immunoreactive trypsinogen (IRT) levels in infants with CF identified through newborn screening are correlated with early pancreatic dysfunction and with pulmonary function at six years of age. IRT is therefore a biochemical marker of early pancreatic disease in CF also carrying implications for early pulmonary disease. In addition, we have observed that IRT is heritable. We therefore hypothesize that early IRT abnormalities in CF are explained in part by genes that modify the CFTR gene effect on pancreatic injury. We will test this hypothesis in infants and young children with cystic fibrosis diagnosed through newborn screening. IRT will be modeled with age using longitudinal mixed effects approaches with a log transformation to produce a quantitative phenotype that will be used in a Transmission Disequilibrium Test (TDT) to determine if IRT is cosegregating with each of the candidate modifiers. Specific modifiers to be tested can be categorized as follows: a. Genetic markers lying within the D19S112 region on chromosome 19 that have been linked to intestinal disease in CF, b. Genes coding for pancreatic enzymes that are capable of causing local tissue injury, c. Genes coding for pancreatic proteins capable of modulating local tissue injury, d. Genes coding for pancreatic membrane transporters, and e.Putative modifier genes of other CF organ involvement. Candidate genes with common, known functional variants will be studied through genotyping. Genes with no known functional variants will be sequenced in a subset of patients exhibiting either "rapid" or "slow" decline in IRT to identify potentially useful mutations or polymorphisms. Sequences of interest will then be examined in the entire study population, with priority as follows: obvious mutations (for example nonsense, frameshift and splice type), then promoter or missense alleles, then variants non- randomly segregating among the IRT "rapid" or "slow" decliners, and then more common variants. We also plan to establish a clinical database and a DNA

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repository for infants identified by newborn screening. Achieving our goals will likely provide: 1. Insight into the mechanisms of early pancreatic injury, 2. Clues to the pathophysiology of other organs involved in CF, 3. Valuable prognostic information for counseling families of newly diagnosed infants, 4. Information useful for future investigation of the pancreatic complications of CF in later life including recurrent pancreatitis and cystic fibrosis related diabetes. Our long-term objectives are to find new approaches to the early treatment of CF in order to delay pancreatic injury and the development of lung disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DETERMINATION OF GENOTYPE IN PATIENTS WITH CYSTIC FIBROSIS Principal Investigator & Institution: Winnie, Glenna; Children's Hosp Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, PA 15213 Timing: Fiscal Year 2001 Summary: The goal of this study is to determine the genotypes of the patients with cystic fibrosis followed at the Pittsburgh Center so that this information will be available for translational and clinical studies. Over 500 mutations in the CF gene have been described and there are 4 main types of defects which result from these mutations. Since there are different classes of mutations, it can be expected that some drug therapies will be effective only in treatment of mutations of a specific type. In order to benefit the patients, it is necessary to be aware of their genotypes when specific drug therapies become available for use. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DUODENAL MUSCOSAL DEFENSE MECHANISMS Principal Investigator & Institution: Kaunitz, Jonathan D.; Professor of Medicine; Brentwood Biomedical Research Institute Bldg. 114, Room 218 Los Angeles, CA 90073 Timing: Fiscal Year 2002; Project Start 01-MAY-1999; Project End 30-APR-2007 Summary: (provided by applicant): Peptic ulcer disease is a major cause of morbidity and mortality in elderly and chronically ill populations. Despite major advances made about ulcer pathogenesis, complications of peptic ulcers still represent a significant problem in at-risk populations, especially in the elderly and those with significant comorbidities. Peptic ulceration represents a disturbance in the balance between aggressive factors (acid and pepsin) and defensive factors (mucosal bicarbonate secretion, blood flow, and mucus secretion). Of these, bicarbonate secretion is thought to be a primary defense mechanisms, due mainly to studies in which bicarbonate secretion is correlated to injury prevention, since, in general, increased bicarbonate secretion protects the mucosa from acid-induced injury. Nevertheless, the precise means by which an intrinsically leaky epithelium such as the duodenum can resist damage from intensely acid gastric juice remains unresolved. In the past few years, my laboratory has made the novel observation that provides unique insight into how duodenal villus epithelial cells, the prime targets of gastric acid, can resist injury. We formulated the 'intracellular HCO3' hypothesis in which intracellular, not extracellular bicarbonate serves as the principal duodenal mucosal defense mechanism. To test this hypothesis, we have devised a series of experiments designed to 'uncouple' bicarbonate secretion and mucosal protection. Subjects with the disease cystic fibrosis, despite copious gastric acid secretion and low duodenal pH, only rarely have duodenal ulcers. We believe that this is a result of bicarbonate being trapped in duodenal epithelial cells. We plan to test

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this hypothesis directly in mice deficient for the CFTR or cystic fibrosis gene product. Through the conduct of these studies, we hope to gain further insight into the mechanism of peptic ulceration, in the hopes of finding new treatments designed to prevent ulcer complications in our aging population, and to also gain additional insight into the pathogenesis of cystic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT OF IGF-1 ON MALNOURISHED CHILDREN WITH CYSTIC FIBROSIS Principal Investigator & Institution: Bucuvalas, John C.; Professor of Pediatrics; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, OH 45229 Timing: Fiscal Year 2001; Project Start 01-DEC-2000; Project End 30-NOV-2001 Summary: Our goal was to determine if treatment with insulin-like growth factor (IGF-I) improves nutritional status and promotes growth in undernourished children with cystic fibrosis. We are in the midst of a phase 1-2 double blind crossover study that compares the treatment with IGF-I to placebo in undernourished patients with CF. Malnutrition adversely affects survival and is prevalent among patients with CF who have deteriorating pulmonary function. Nutritional supplementation often requires the use of a gastrostomy or nasogastric tube. However, the feedings are difficult to administer and may further stigmatize children and adolescents with CF. Blood levels of IGF-I, a growth-promoting peptide that is necessary for normal growth, are low in children and adolescents with CF. Since treatment with IGF-I improves nutritional status in undernourished patients, a rationale exists to assess treatment with growthpromoting peptides in those children with CF who are undernourished. Furthermore, IGF-I helps to regulate blood sugar levels. The effect of IGF-I on blood glucose control may be of particular importance since patients with CF have an increased risk to develop diabetes. If IGF-I improves nutritional status, growth, and glucose control, then it will likely enhance functional outcome in undernourished children with CF. IGF-1 promoted linear growth in prepubertal children with CF while decreasing baseline and stimulated insulin levels. Enhanced linear growth may have reflected the growthpromoting effects of IGF-1 or improved metabolic efficiency associated with increased insulin sensitivity. The future plans include completion and analysis of the study within the upcoming year. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ELECTROGENIC BICARBONATE SECRETION IN CALU-3 CELLS Principal Investigator & Institution: Kreindler, James L.; Children's Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, PA 15213

Hosp

Timing: Fiscal Year 2003; Project Start 12-AUG-2003; Project End 11-AUG-2006 Summary: (provided by applicant): Abnormal bicarbonate secretion has long been recognized as a key component of cystic fibrosis (CF) pancreatic dysfunction, but has only recently been investigated as a component of CF lung disease. The submucoal glands of the lungs are responsible for secretion of a complex airway surface liquid (ASL) that lines the airway epithelium and plays a significant role in mucociliary clearance. The serous cell is the predominant cell type of the submucosal gland and the predominant site of cystic fibrosis transmembrane conductance regulator (CFTR) expression. The Calu-3 cell, an immortalized serous cell line, is therefore a good model for the study of the physiology of ASL production and regulation. This proposal is divided into two complementary aims. The first aim is to use microelectrode

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measurements to establish the transport physiology of bicarbonate entry on a sodiumbicarbonate cotransporter, and then to use short, inhibiting RNA technology to determine the identity of the sodium-bicarbonate cotransporter. The second aim is to use short, inhibitory RNA technology to knock-down CFTR and to use these knockdown cell lines in Ussing chamber experiments and microelectrode experiments to test the hypothesis that CFTR is the apical bicarbonate channel. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENAC & CFTR: MOLECULAR INTERACTIONS IN HEALTH & DISEASE Principal Investigator & Institution: Reddy, Madireddi; Pediatrics; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, CA 92093 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2006 Summary: The amiloride sensitive epithelial sodium channel (ENaC) and the CFTR (Cystic Fibrosis Transmembrane conductance Regulator) chloride channel are expressed in the apical membranes of epithelial cells in salivary gland ducts, sweat duct, kidney, distal colon, and airways. Abnormalities in channel functions can be life threatening in diseases such as Liddle's syndrome, pseudohypoaldosteronism (PHA), cystic fibrosis (CF) and renal and cardiovascular pathology. Little is known about the mechanisms regulating ENaC and its interaction with CFTR in a native human tissue due to relative scarcity and inaccessibility of human epithelial tissues expressing these channels in spite of its vital role in health and disease. Recently we showed that basolaterally permeabilized human sweat ducts contain regulated ENaC and CFTR in the apical membrane. Besides, this human tissue is most easily accessible. We found evidence that ENaC activation requires CFTR channel function. This project is designed to explore the molecular interactions between CFTR and ENaC in health and disease by testing the following hypotheses that: 1.) the activities of CFTR and ENaC are coupled, 2.) the stimulation of CFTR C1- channel function is required for ENaC activation, and 3.) the ion composition alters the interaction between CFTR and ENaC. We will investigate the hypotheses by employing electrophysiological, immunocytochemical and fluorescent techniques on basolaterally a-toxin permeabilized sweat ducts derived from normal human subjects and patients with CF, PHA and Liddle's syndrome. We will test the hypotheses by determining whether: 1.) ENaC activation is dependent on CFTR activation by protein kinases A, G, C or G-proteins, 2.) Mutations in CFTR (e.g. DF508, R117H, G551D) alter ENaC function and vice versa (ENaC mutations in PHA and Liddle's syndrome alter CFTR function), 3.) CFTR activation of ENaC requires CFTR C1channel function induced by phosphorylation and ATP hydrolysis, and 4.) changing ion-composition (Na+, C1-, K+, Ca++ and pH) alter the activities of CFTR and ENaC in parallel. We believe that elucidating the molecular interactions between these channels will contribute to understanding several disease processes evolving from disturbance in NaC1 retention and elimination. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENERGY COUPLING OF THE CFTR Principal Investigator & Institution: Ketchum, Christian J.; Program Director; Physiology; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001; Project Start 01-MAY-2001 Summary: Cystic fibrosis (CF) is a disease of salt and water transport. The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel encoded by the

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gene defective in patients with CF. It is generally well- accepted that nucleotide binding and hydrolysis coordinates CFTR gating via long-range conformation changes. The molecular mechanism by which CFTR couples catalysis and transport, however, remains poorly characterized. It is essential to understand this link between nucleotide binding/hydrolysis and CI-transport. In working towards this goal, I will purify biochemical quantities of both wild-type CFTR and the delta508 derived, which is responsible for most instances of CF, using conditions that maximize recovery of active material. The adequacy of this protocol will be determined with parallel tests of two other ABC transporters, MDR1 (the human multi-drug exporter) and STE6 (the yeast pheromone exporter). With active material on hand, the ATPase activity of wild type and delta508 will be fully characterized in terms of kinetic parameters, pH dependence, requirements for divalent cations, nucleotide specificity, and modulation by known activators and inhibitions of ABC-type transporters. This will allow the specificity, and modulation by known activators and inhibitors of ABC- type transporters. This will allow the derivation of models concerning CFTR nucleotide binding domain function and to assess the step(s) that may be abnormal in the delta508 mutant. In parallel, we will devise an in vitro assay for C1-transport to study how catalysis and transport are coordinated under the same conditions. By completing these three primary steps, we will have established a model system for screening potential CFTR modulators, which may ultimately lead to identification of pharmacological agents that correct the fatal defects of salt and water transport in CF patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXTRACELLAR NUCLEOTIDE SIGNALING IN CYSTIC FIBROSIS Principal Investigator & Institution: Schwiebert, Erik M.; Associate Professor; Physiology and Biophysics; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2001; Project Start 15-JAN-2000; Project End 30-NOV-2004 Summary: Cystic fibrosis (CF) is a disease of exocrine epithelia. Not only is a lack of cyclic AMP-activated chloride (C1-) channel activity observed in CF epithelial cells, but dysregulation of other epithelial C1- and Na+ channels, epithelial vesicle trafficking, and epithelial immune function are also observed in CF. The PI has shown recently that there is a loss of ATP release across the apical membrane of CF epithelia under basal or isotonic and hypotonic conditions and that extracellular ATP signaling may be lost in CF. Without basal or stimulated ATP release in CF epithelia, we hypothesize that the pathogenesis of CF epithelial dysfunction may lie in defective ATP signaling and defective cell volume regulation by the CF epithelia. An ionic imbalance in the airway surface liquid has been observed; we hypothesize that this reflects an osmotic imbalance due to an inherent defect in autocrine ATP control of epithelial cell volume regulation. As such, this completely re-constructed proposal focuses on one concise, central hypothesis: ATP release and signaling is essential for autocrine control of cell volume regulation. Two aims derive from this hypothesis: (1) Test the hypothesis that RVD requires ATP release, ATP receptors, and CFTR expression in the plasma membrane, and (2) Test the hypothesis that ATP release occurs via transport- and exocytotic-driven mechanisms. To fulfill these Aims, parental CF epithelial cells will be compared to CF cells complemented transiently or stably with wild-type CFTR. A synergistic combination of cell volume regulation assays, bioluminescence detection assays of ATP released from cells, patch-clamp electrophysiological assays of ATP whole cell current and membrane capacitance, and exocytosis assays will be used to address each Aim. These assays will identify the ATP release mechanisms, the dependence of these

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mechanisms upon CFTR expression, and the purinergic receptors involved in autocrine ATP control of cell volume regulation. We are confident that novel results will be found concerning the cellular and molecular mechanisms of autocrine ATP release, signaling, and regulation of cell volume. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FAMILY BASED ANALYSIS OF MODIFIERS OF CF LUNG DISEASE Principal Investigator & Institution: Levy, Hara; Children's Hospital (Boston) Boston, MA 021155737 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Cystic fibrosis (CF) is an inherited multisystem disease characterized by progressive deterioration in lung function and pancreatic insufficiency attributed to dysfunction of a single gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Although CF is considered a monogenic disorder, phenotype expression is considerably diverse even in patients with the same CFTR mutation. Patients with the most common mutation, delta 508 a deletion of a phenylalanine at position 508 of CFTR, often have markedly different clinical courses; some, have less aggressive lung disease and survive into their 50s, while others have a precipitous decline in lung function and die of respiratory failure in their early 20s. What accounts for this phenotypic heterogeneity is unclear. The goal of this proposal is to identify non-CFTR candidate genes that may impact the severity of CF lung disease and account for phenotypic heterogeneity. Any modifier gene identified will have important implications for defining the pathophysiology of CF lung disease, stratifying patients, and identifying new targets for therapy. To initially test our hypothesis, we propose to evaluate candidate genes that are immune-related and non-CFTR genes. Our strategy will use a family based association analysis to test for association of candidate genes to severity of pulmonary disease. We propose to combine new genotyping technology, well-powered samples, and a haplotype-based approach to comprehensively and definitively determine variation in the most promising candidate genes modifying CF lung disease. A unique contribution of this research will be the examination of genetic modifiers in CF in parent child-trios to evaluate polymorphisms in genes that may impact phenotype and hence CF lung disease. The overall hypothesis to be tested is that polymorphisms in genes associated with a well-defined phenotype represent modifying factors that account for the variability in expression of CF lung disease as measured by lung function, forced expiratory volume in one second (FEV1), in patients with the delta 508 genotype. To test this global hypothesis, we have established three specific aims: 1) Establish and characterize a CF database and define key features of the quantitative and qualitative components of our CF phenotype; relate phenotype to variation in disease severity as defined by levels of FEV1 adjusted for age and gender in CF patients homozygous for delta F508 CFTR allele. 2) Genotype single nucleotide polymorphic markers (SNPs) from five promising genes (selected based on data from Aim 1, the PGA, microarray analysis, and the literature) found to be associated with lung function in a sample of 100 individuals homozygous for delta 508 and identify common haplotypes and htSNPs that tag these haplotypes for these genes. 3) Genotype these htSNPs identified in AIM 2 in a sample of homozygous delta F508 individuals and their parents, and perform family based association analysis for CF phenotype and pulmonary function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FLUCTUATION AND IMPEDANCE ANALYSIS OF CHLORIDE SECRETION Principal Investigator & Institution: Bridges, Robert J.; Professor; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001 Summary: Transepithelial secretion of Cl- is of major importance in the normal physiology and pathology of a number of organs, most notably the gastrointestinal tract and the airways. The discovery of the Cystic Fibrosis Transmembrane Conductance Regulator, CFTR, as a key apical membrane Cl-channel has been a major advance in the study of Cl-secretion. The goal of this project is to study the regulation and pharmacological modulation of CFTR in the context of a secreting epithelial monolayer utilizing the non- invasive methods of fluctuation and impedance analysis. Preliminary results will demonstrate the feasibility of performing fluctuation and impedance analysis on human colonic epithelial cells (T84 cells) and patient derived primary cultures of airway cells expressing wt and mutant forms of CFTR. Three hypotheses will be investigated: (1) CFTR is the major, if not sole, apical membrane Cl-channel mediating the secretion of Cl- and that regulation of the activity of CFTR is mediated by altering N and not P/o. (2) Benzimidazolone and psoralen stimulation of Cl-secretion is mediated by the activation of CFTR and that these agents act to cause a unique state of activation of CFTR. (3) Regulation and modulation of CFTR are cell specific. Studies for Specific Aims 1 and 2 will be performed on T84 cells and the results compared with those obtained with airway cells, Specific Aim 3. Specific Aim 1 will determine th4e contribution of CFTR and other potential Cl-channels to transepithelial Cl- secretion, identify those kinases and phosphatases involved in their regulation and determined by what mechanism (N versus P/o) they are regulated. Sp3ecific Aim 2 will determine whether CFTR is the Cl-channel activated by the above pharmacological agents, how they regulated CFTR's channel properties and whether they cause a state of activation different from that caused by cAMP-mediated agonists. Specific Aim 3 will determine the contribution and properties of CFTR in airway cell Cl-secretion, the kinases and phosphatases specifically involved in airway cell CFTR regulation, the influence of the above pharmacological agents on CFTR in airway cells and determine the properties, regulation and modulation of mutant forms of CFTR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FUNCTIONAL GENOMICS OF CYSTIC FIBROSIS Principal Investigator & Institution: Mickle, John E.; Pediatrics; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2003 Summary: (taken from the application) Candidate: Dr. John Mickle earned his Ph.D. through the Cell and Molecular Biology Program at Boston University and simultaneously received comprehensive training in human molecular genetics at the Center for Human Genetics, Boston University School of Medicine. He has been a very productive post-doctoral fellow in the laboratory of Dr. Garry Cutting at Johns Hopkins School of Medicine for the past four years. Dr. Mickle has taken an interdisciplinary approach to study the consequence of disease-associated mutations upon the chloride channel (CFTR) that is defective in the inherited disease cystic fibrosis (CF). Dr. Mickle worked in the laboratory of Dr. William Guggino in the Department of Physiology at Hopkins to become proficient in electrophysiology. Dr. Mickle's research has focused on the interaction between CFTR and outwardly rectified chloride channels in the same

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cell, and he has investigated this interaction by evaluating the function of diseaseassociated mutations and divergent forms of CFTR. Dr. Mickle is a member of the Mount Desert Island Biological Laboratory and has established collaborations with Dr. Karl Karnaky Jr. of the Medical University of South Carolina and Dr. Jack Riordan of the Mayo Clinic in Scottsdale, Arizona. Pursuit of an individual research project is the appropriate next phase for Dr. Mickle in his development as a successful independent investigator. Emphasis will be placed on manuscript writing, research talks, and teaching in preparation for independence. Environment: Dr. Cutting's laboratory is wellequipped for both molecular biology and electrophysiology, ample research space is available for Dr. Mickle to perform his research project. A confocal laser microscope facility is available in an adjacent building, and additional expertise in electrophysiology is available from the laboratories of Dr. Bill Guggino and other principle investigators in the Cystic Fibrosis research group at Hopkins. Research: Life-limiting pulmonary disease is a hallmark of the common genetic disorder cystic fibrosis (CF). The disorder is caused by dysfunction of the CF transmembrane conductance regulator (CFTR). In airway epithelial cells CFTR is both a chloride channel and a regulator of several different ion channels. Both functions implicate CFTR as a key component in the coordination of ion movement across apical membranes of airway cells. Thus, pulmonary disease may be influenced by mutations in CFTR that effect the channel and/or regulatory function. Proteins involved in the regulatory pathways also may influence lung function independent of CFTR. The overall goal of the proposed research is to explore to relationship between CFTR, its regulation of separate channels and phenotype. This research will increase our understanding of CF pathophysiology, elucidate intra- and intermolecular interactions of therapeutic significance, and alter diagnostic criteria for CF and related disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR CYSTIC FIBROSIS Principal Investigator & Institution: Boucher, Richard C.; Director; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2001; Project Start 30-SEP-1993; Project End 31-MAR-2004 Summary: The goal of the PPG (Gene Therapy for Cystic Fibrosis) is to create gene transfer vectors that will efficiently transduce cells of the lung. Major but not exclusive therapeutic targets are the epithelia of the large and small airways, which are sites of cystic fibrosis lung disease. The major hypotheses tested in the PPG are: (1) new vectors are needed, including higher capacity, better expressing AAV vectors; high titer, safe lentiviral vectors; and adenoviral vectors specifically targeted to airway epithelial receptors; and (2) that a rate-limiting variable for gene transfer efficiency in the lung is at the site of initial vector-cell interaction, including both binding and entry across the plasma membrane. Three Projects and four Cores are proposed. Project I (Parvovirus) Vectors for Airway Delivery, R.J. Samulski, P.I.) proposes to design and produces new AAV vectors that increase the vector packaging size, augment the efficiency of vector entry, and increase the efficiency of expression (conversion from single strand to double strand DNA templates) using chimeric virion capsids, targeting ligands and modified viral terminal repeats. (Equine Lentiviral Vectors for Gene Delivery, J.C. Olsen, P.I.) proposes to develop high titer, efficiently expressing, and are equine lentiviral vectors. The important targets for the lentiviral vectors will be airway epithelial cells, which throughout the airways exhibit low rates of proliferation. Project III (Cell Biology of Airway Epithelial Gene Transfer, R.C. Boucher, P.I.) proposes to define the barriers and targets in the apical domain of airway epithelia, modify the barriers using either oxidant

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injury or more specific modulators of the tight junctions, and finally, modify vectors to target a class of receptors on the apical membrane that exhibit cellular internalization in response to agonist addition. The Projects are supported by the Administrative Core; the Cell Culture Core that will supply human airway cultures to all Projects, small airway cultures, and smooth muscle cells, the Vector Core that will generate AAV, lentiviral and adenoviral vectors (radio-labeled/fluorescently labeled); and the Morphology Core that will provide histology, electron microscopy, and confocal microscopy. The PPG is a highly interactive program designed to modify vectors and test their interactions with target cells in vitro and in murine models in vivo. Achievement of the PPG goal will be to bring to the next clinical trials vectors that are safer and more efficient for the treatment of lung disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR CYSTIC FIBROSIS AND OTHER GENETIC DISEA Principal Investigator & Institution: Wilson, James M.; John Herr Musser Professor and Chair; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001; Project Start 30-SEP-1993; Project End 31-AUG-2003 Summary: The Institute for Human Gene Therapy was established in 1993 under the direction of Dr. James M. Wilson. Tremendous progress has been made over the last five years in the development of its basic, translational, and clinical research programs. The initial P30 award in gene therapy for Cystic Fibrosis (CF) and genetic diseases provided critical early support to establish an infrastructure, as well as encourage new research initiatives. A fully integrated approach to gene therapy has been developed which is based on fundamental investigation and supported by a number of basic science core laboratories. A translational research program was created to facilitate the transfer of basic discovery to proof-of-concept experiments in humans. This includes a pilot manufacturing facility called the Human Applications Laboratory, a Toxicology Program, a Quality Assurance and Compliance Unit and an effort in regulatory affairs. Twelve tenure track faculty have been recruited over the last five years in the area of CF and genetic diseases. The Institute will increase its total research space from 25,000 to 50,000 net square feet by next Spring, providing additional opportunities for expansion of this program. Tremendous scientific progress has been made in the first term of this grant. Four clinical trials have been started or completed with plans to initiate pilot human experiments in at least three other genetic diseases. This renewal represents a continuation of our initial application. Support is requested for basic science cores including Vector, Cell Morphology, Immunology and Transgenic, as well as the Human Applications Laboratory and Toxicology Program of the Translational Research Program. Our pilot grant program through the NIH and Cystic Fibrosis Foundation has been spectacularly successful; we propose to continue this program in the renewal application. The research base of P30 participants in gene therapy (16 in CF and 37 in genetic diseases. is approximately $26 million (annual direct costs) of which $3.9 million is from NIDDK, $3.7 million is from NHLBI, $3.1 million from NICHD, and $15.2 million from other Federal and non-Federal sponsors. The leadership which has directed the successful implementation of the first phase of this grant will continue in the renewal with Dr. James M. Wilson serving as the Program Director and Dr. John Wolfe serving as the Associate Program Director. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE THERAPY FOR CYSTIC FIBROSIS USING AAV VECTORS Principal Investigator & Institution: Miller, Arthur D.; Member; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001 Summary: Gene Therapy for Cystic Fibrosis using AAV Vectors. Cystic fibrosis (CF) affects 1 in 3,200 births and leads to debilitating lung disease and premature death at a median age of 32 years. Gene therapy may provide a cure for this disease by replacement of the defective protein, the cystic fibrosis transmembrane regulator (CFTR). The long-range objective of this application is the development of lung-targeted gene therapy for treatment of CF using viral vectors derived from a non-pathogenic human parvovirus, adeno-associated virus (AAV). AAV vectors have been shown to promote gene transfer and long-term expression in several animal models, in particular, AAV vectors can transduce airway and alveolar epithelial cells in the lungs of mice at rates of greater than or equal to 5% and lasting for over 8 months. However, clinical trials involving AAV vector-mediated transfer of the CFTR gene to humans have yet to show useful levels of CFTR expression or clinical efficacy. This lack of expression is likely due to the difficulty of making AAV vectors that express CFTR because of the large size of the CFTR cDNA, and the difficulty of measuring small changes in CF disease severity that might result from gene therapy. To circumvent these difficulties and to provide a more direct test of the utility of AAV vectors in humans, the specific aims of this proposal include clinical trials in healthy subjects and CF patients which will address the safety, efficacy, and immune responses to nasal and bronchial administration of AAV vectors that encode an easily detected histochemical marker gene, human placental alkaline phosphatase (hpAp). We have found that vectors derived from AAV serotype 6 show improved transduction rates in mouse airway compared to commonly used AAV serotype 2 vectors, although more extensive safety data in humans is available for AAV2. Here we propose to compare expression of hpAP extensive safety data in humans is available for AAV2. Here we propose to compare expression of hpAP delivered by both AAV2 and AAV6 in healthy subjects. The vector serotype with the better safety and gene expression profile will be tested subsequently in patients with CF. Another specific aim will address the development of effective AAV vectors for transfer and efficient expression of the CFTR cDNA. These approaches are designed to most efficiently test and develop AAV vectors for treatment of CF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE TRANSFER TO AIRWAY EPITHELIAL CELLS Principal Investigator & Institution: Cheng, Pi-Wan; Professor; Biochem and Molecular Biology; University of Nebraska Medical Center Omaha, NE 681987835 Timing: Fiscal Year 2000; Project Start 01-JAN-1998; Project End 31-DEC-2003 Summary: (Applicant's abstract): Cystic Fibrosis (CF) is the most common lethal genetic disease among Caucasians. Lung diseases account for greater than 95 percent of the morbidity and mortality. Hence, CF lungs have been targeted for gene therapy. Current gene therapy vectors suffer from low transfection efficiency or induction of host immune response, which preclude them from being used for gene therapy in vivo and invite development of alternative vectors. We have developed a novel gene transfer vector composed of a receptor ligand and a cationic liposome, which yields high transfection efficiency in HeLa cells and immortalized tracheal epithelial cells of a cystic fibrosis patient (CFT1). The formation of liposome-transferrin-DNA complexes correlates with high transfection efficiency. The transfection vectors which contain

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transferrin, insulin, or cholera toxin could correct the cAMP-dependent chloride conductance defect in CFT1 cells. We propose to test the hypothesis that the liposomereceptor ligand-DNA complex by Sepharose gel chromatography and then characterize the physicochemical properties of the putative transfection complex by biochemical and transmission electron microscopic methods. We will examine if this complex alone or in combination with the receptor ligand and/or liposome yields high transfection efficiency in CFT1 cells, primary cultures of mouse and human airway epithelial cells, respiratory epithelial explants, and then in mouse airway epithelia in vivo. We will also characterize the kinetics of the receptor ligand-facilitated gene transfer using confocal microscopic, biochemical, molecular biological, and immunological techniques to identify the step(s) responsible for the enhancement of the transfection efficiency of liposome-mediated gene transfer. The efficacy of the gene therapy protocols employing a plasmid containing the cDNA encoding wild-type cystic fibrosis transmembrane conductance regulator will be examined in the primary cultures of airway epithelial cells and nasal and tracheal epithelia of CF mouse in vivo. The gene transfer vectors will be assessed for inflammatory and immune responses and cytopathology in normal and CF mouse. Correction of cAMP-dependent chloride conductance defect coupled with no immune response to the vectors in CF mouse should be the crucial information needed for planning future human gene therapy trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE TRANSFER TO HUMAN AIRWAY EPITHELIA IN VIVO Principal Investigator & Institution: Mccray, Paul B.; Professor; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-MAR-2002 Summary: Studies have shown that transfer of the human cystic fibrosis transmembrane conductance regulator (CFTR) cDNA into cystic fibrosis (CF) epithelial corrects the defective cAMP-mediated chloride (CI-) transport that characterizes CF. However, no long term approach to somatic cell gene transfer has been developed. Gene transfer with integrating vectors such as retrovirus offers the exciting potential to provide long term correction. However, studies to date suggest that gene transfer with Moloney murine leukemia virus (MMLV) based vectors is inefficient in differentiated airway epithelia, in part because of the low rates of proliferation. Our recent demonstrate that we can overcome the limitation of low rates of cell division by stimulating cells with growth factors that cause differentiated epithelia to divide. Another limitation is the apparent lack of accessible receptors on the apical surface. We found that cells stimulated to divide with growth factors can be readily infected by applying the vector to the basolateral surface or by apply vector to the apical surface when tight junctions are transiently opened by Va/2+ chelation. An exciting recent development is the hybrid lentivirus-based vectors that can infect non- dividing cells. Our preliminary studies show these vectors share the same problem as MMLV with access to receptors from the apical surface. It is not yet clear if lentiviral vectors will be useful for gene transfer to airway epithelia. Now with this preliminary data and these insights into airway epithelial cell biology, we have the tools and reagents to address several important questions. In specific aims we will answer 3 questions: 1) Does infection of dividing cells with integrating vectors produce persistent expression and correction of the CF defect?, 2) Can an integrating vector target non-dividing cells and produce persistent expression and correction of the CF defect? 3) Can integrating vectors correct the CF defect in differentiated epithelia in vivo? The results from these studies are relevant to future work with any integrating vector.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENERAL CLINICAL RESEARCH CENTER Principal Investigator & Institution: Harrington, John T.; New England Medical Center Hospitals 750 Washington St Boston, MA 021111533 Timing: Fiscal Year 2001; Project Start 01-DEC-1991; Project End 28-FEB-2001 Summary: The GCRC serves a the core clinical research facility for clinical investigators at New England Medical Center Hospital and Tufts University School of Medicine. The Center has been in continuous operation since 1961, and supports the conduct of clinical research protocols based on evaluation of scientific merit by the multidisciplinary Scientific Advisory Committee. The eight major proposals contained in the present application represent a diversity of scientific and medical disciplines, combining excellence in clinical investigation with links of mechanistic basic science work and application of novel biomedical technologies. These core proposals are: 1. Evaluation of the molecular basis for ethnic differences in lipoprotein metabolism, and the implications of these differences for differential susceptibility to cardiovascular disease (Dr. Ernst J. Schaefer); 2. Evaluation of the mechanisms of bronchopulmonary dysplasia in neonates with respiratory distress syndrome, and the therapeutic potential of inhaled beclomethasone (Dr. Ivan D. Frantz); 3. Mechanisms and implications of systemic cytokine response in the pathogenesis of primary biliary cirrhosis, and modulation following treatment with colchicine, methotrexate, or ursodeoxycholic acid (Drs. Marshall M. Kaplan and David J. Wyler); 4. Initial evaluation of "gene therapy" technology in the treatment of cystic fibrosis. The study will assess the response to topical pulmonary administration of a virus vector designed to express the deficient cystic fibrosis transmembrane conductance regulator protein, the lack of which is the basis for the pathogenesis of cystic fibrosis (Dr. Henry L. Dorkin); 5. Evaluation of the biochemical mechanisms of the cachexia of chronic disease in patients with rheumatoid arthritis, and modulation of biochemical markers in response to treatment (Dr. Ronenn Roubenoff); 6. Prospective validation of a scaling model designed to predict the qualitative and quantitative inhibition of Cytochrome P450- mediated hepatic clearance of drugs by competitive metabolic inhibitors, based on in vitro studies of enzyme kinetics using human liver microsomes. The index compound is midazolam, a P450-3A4 substrate, and the model competitive inhibitor in the azole antifungal agent ketoconazole (Dr. David J. Greenblatt); 7. Comprehensive prospective evaluation of the impact of HIV infection on body composition, nutritional status, gastrointestinal function, protein metabolism, and cytokine function. These outcomes, including response to dietary and exercise interventions, are prospectively studies in populations of HIV-infected individuals and matched controls (Dr. Sherwood L. Gorbach); 8. Modulation of the systemic toxicity of Interleukin-2 by coadministration of soluble Interleukin-1 receptor in patients with metastatic cancer. The study involves clinical assessments of response and toxicity as well as evaluation of alterations in multiple biologic parameters (Dr. Michael B. Atkins). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC EPIDEMIOLOGY OF GLUTATHIONE AND CF LUNG DISEASE Principal Investigator & Institution: Mckone, Edward; Medicine; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007

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Summary: (provided by applicant): This proposal is a five-year training plan designed to prepare the Principal Investigator for a career as an independent patient-oriented researcher with an interest in the genetic epidemiology of lung disease. Through the completion of these projects as well as the pursuit of course work in clinical and genetic epidemiology, the candidate will develop the necessary skills to design and implement family-based genetic association studies, including gene-gene and gene-environment interaction. The proposal is a collaboration between the Division of Pulmonary and Critical Care Medicine and the Departments of Public Health Genetics and Environmental Health and includes experts in cystic fibrosis, genetic epidemiology, environmental health and toxicology. The primary scientific goal of this research is to analyze the genetic determinants of lung disease variability in patients with cystic fibrosis (CF). Aim 1 will be a retrospective cohort study, using the National CF database, to quantify the effect of CF genotype on CF clinical manifestations, including lung function and mortality. Aim 2 will be a prospective study to examine for linkage and association between severe CF lung disease and a candidate gene that influences glutathione synthesis. DNA will be collected from CF patients and their biological parents. Transmission disequilibrium testing (TDT) will be performed on the trios looking for unequal segregation of glutayl-cysteine-ligase catalytic subunit (GLCLC) polymorphisms from parents to CF patients with severe lung disease. Aim 3 will examine for an association between severe CF lung disease and polymorphisms of glutathione-S-transferase M1 and TNF-alpha also using a TDT. As these polymorphisms may influence glutathione synthesis and function, gene-gene interaction with GLCLC polymorphisms will be examined using a case-only study design and logistic regression. Finally, in aim 4, through the use of validated questionnaires and methods of residence location, environmental exposure to tobacco smoke and air pollutants will be measured to test for gene-environment interaction. These projects have strong clinical and public health implications both in terms of predicting high-susceptibility patients that may develop severe lung disease as well as increasing our understanding of the mechanisms of CF lung function decline. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC MODIFIERS OF CYSTIC FIBROSIS Principal Investigator & Institution: Boyle, Michael P.; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2003; Project Start 04-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Dr. Michael Patrick Boyle is an Assistant Professor in the Pulmonary and Critical Care Division of the Johns Hopkins School of Medicine. He is fully committed to an academic career investigating genotype and phenotype relationships in cystic fibrosis (CF). The mentor of this application, Dr. Garry Cutting, is a world-recognized expert in the genetics of CF, professor and director of graduate education at the McKusick-Nathans Institute of Genetic Medicine, and previous mentor of numerous successful K awards. The didactic and mentoring program outlined in this application is the result of close collaboration between Dr. Boyle and Dr. Cutting and will provide the foundation for Dr. Boyle's development as an independent investigator. CF is caused by mutations in the chloride channel CFTR. A wide range of severity of pulmonary disease is seen in CF individuals with identical CFTR genotypes, making it clear that CFTR genotype is not the main determinant of severity of CF lung disease. The overall goal of this proposal is to help identify the basis for variability of CF lung disease in individuals with identical CFTR genotype. We aim to answer: Do genes which modify the severity of CF lung disease exert their influence by altering the level

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of expression and function of CFTR, or through mechanisms unrelated to the underlying CFTR defect (e.g. inflammatory mediators, airway defense)? To do this we will determine if there is a difference in CFTR expression and function in the airway epithelium of homozygous delta F508 CF patients with mild and severe lung disease. First, we will use Nasal Potential Difference Measurement, the most sensitive in-vivo measurement of the ion-transport function of CFTR, to determine if there are differences in CFTR ion-transport. Second, because some cellular functions of CFTR are not reflected in these ion transport measurements, we will evaluate for differences in CFTR expression by comparing mRNA levels. These ion-transport and mRNA studies should allow us to determine if variability in CF lung disease is associated with alterations in level of expression and function of CFTR. Last, we will evaluate three of the strongest current CF candidate modifier genes to determine if the distribution of their functional alleles segregates with severity of lung disease in our CF clinic population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: H AND HC03 TRANSPORT BY AIRWAY EPITHELIA IN CF Principal Investigator & Institution: Machen, Terry E.; Professor; Molecular and Cell Biology; University of California Berkeley Berkeley, CA 94720 Timing: Fiscal Year 2001; Project Start 30-SEP-1996; Project End 30-NOV-2004 Summary: (Applicant's Abstract): Acid - base transport by airway epithelial cells likely play key roles in cystic fibrosis (CF) due to effects on mucus hydration and rheology, ciliary transport, bacterial binding and anti-microbial factors. Airway surface liquid (ASL) appears to be slightly acidic (pH 6.9), and acidity increases in CF. Cells in the submucosal glands secrete mucus, and secretion of (primarily) HCO3 and (some) Cl along with Na through tight junctions (to maintain electroneutrality) and fluid sweeps the mucus out of the glands. Permeability of tight junctions between submucosal gland cells is critical for the glands' ability to secrete ions. In contrast, surface cells seem to have tight junctions that are impermeant to ions, and this assures that these cells operate only to absorb Na (through ENaC), Cl (through CFTR) and water. According to these proposals, the absence of CFTR in CF will cause: (i) decreased HCO3, Na and water secretion by submucosal gland cells (leading to mucus clogging); (ii) increased acidity of ASL (due to reduced HCO3 secretion); (iii) thicker and stickier mucus (due to reversal of fluid secretion to absorption and increased acidity of ASL). According to these hypotheses, it is crucial to determine mechanisms of H and HCO3 transport across the membranes and tight junctions of WT and CF submucosal gland and surface epithelial cells, including the potential role of mucus secretion to the acid-base balance of the ASL. The specific aims of this proposal are: (i) Use fluorescence microscopic imaging, immunomicroscopy and western blots to identify mechanisms for HCO3 and H transport across apical and basolateral membranes of submucosal gland and surface cells of WT and CF airway monolayers. (ii) Using genetic targeting of pH-sensitive dyes and imaging microscopy, measure pH (and regulation) in mucus granules and at the lumenal aspect of WT and CF airway epithelia. (iii) Using isotopic methods, measure secretion of mucus and of constitutive and regulated Golgi-derived vesicles and correlate to H/HCO3 transport. (iv) Using electrophysiological, isotopic flux and immunomicroscopic methods, determine the permeability/conductance properties of the tight junctions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HEPATOBILIARY DISEASE IN PATIENTS WITH CYSTIC FIBROSIS Principal Investigator & Institution: Heubi, James E.; Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, OH 45229 Timing: Fiscal Year 2001 Summary: Hepatobiliary disease may complicate cystic fibrosis and lead to end-stage liver disease. The goal of this project is to prospectively follow patients with cystic fibrosis, both with evidence of liver disease based upon laboratory and clinical evaluation, as well as patients who did not have evidence of liver disease. This threecenter study (with ours being the coordinating center) is designed to perform serial measurements of standard liver function tests and serum bile acids to determine the potential utility of serum bile acids as indicators of early liver disease. Anticipated enrollment will be completed with collection of all serial physical examinations and serum samples in the next 12 months. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HOST-PATHOGEN INTERACTIONS IN CYSTIC FIBROSIS Principal Investigator & Institution: Moskowitz, Samuel M.; Pediatrics; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001; Project Start 05-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): The goal of this application is to establish the independent research career of the candidate in the study of chronic lung disease, including that affecting individuals with cystic fibrosis (CF). The candidate is a pediatric pulmonary fellow with the career goal of developing an active program of disease-related basic research as a faculty member at a medical school. The training environments are the laboratory of the sponsor, Dr. Samuel Miller, at the University of Washington School of Medicine, and the CF Center at Children's Hospital and Regional Medical Center in Seattle, directed by the co-sponsor, Dr. Ronald Gibson. The proposed project seeks to clarify molecular mechanisms underlying chronic lung infection and inflammation in individuals with CF. The opportunistic pathogen Pseudomonas aeruginosa (PA) infects the lungs of most individuals with CF, frequently (but not invariably) causing severe progressive lung injury and premature death. Study of the interaction between PA and the CF lung is necessary to understand both the cellular processes that promote or permit CF lung infection, and the precise means by which PA interacts with lung cells to cause airway damage. The structure of lipopolysaccharide (LPS), the principal constituent of Gram-negative bacterial surfaces, appears to play a pivotal role in both microbial and human aspects of this interaction. The candidate's preliminary results indicate that resistance of laboratory and clinical isolates of PA to antimicrobial peptides (key components of host innate immunity) correlates with alterations in the structure of the lipid A moiety of LPS. Moreover, mutation of a PA locus that regulates LPS-modifying enzymes influences the antimicrobial peptide resistance phenotype. The microbiological phase of the project thus seeks to define PA genes necessary for this putative resistance mechanism, and to identify potential inhibitors using antimicrobial peptide-resistant strains. The human phase of the project builds on the clinical observation that some individuals with a severe CF genotype and chronic PA airway infection nevertheless have minimal lung disease. A case-control design will be utilized to test the hypothesis that polymorphisms in innate immune genes may limit CF lung disease. Those innate immune genes encoding the LPS receptor are leading candidates as CF modifier loci, based on the recent finding that CF-specific PA LPS structures have increased inflammatory activity. When prevalence of an LPS

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receptor variant differs in mild and severe CF lung disease, receptor function will be assayed in cell culture models of LPS signaling. Identifying innate immune genes as modifiers of the CF lung phenotype may suggest new avenues for treating the inflammatory consequences of CF airway infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IB367 IN ADULT PATIENTS WITH CYSTIC FIBROSIS Principal Investigator & Institution: Konstan, Michael W.; Associate Professor; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001 Summary: This is a Phase I, randomized, placebo-controlled, double-blind, multicenter, safety and tolerability study of ascending inhaled doses of IB-367 in adult patients with cystic fibrosis. Patients will be enrolled in groups of eight. In each group, patients will be randomized in a 3:1 fashion (6 active; 2 placebo) to receive IB-367 or placebo. All patients will be monitored as in-patients during the study. Each patient will participate in one treatment period only. This study will be conducted in two parts (A & B). During Part A, a group of 8 patients will be monitored in a single-blind, dose escalation phase for observation of any adverse events. Doses in this part of the study will vary by increasing administration of a single concentration of study drug. If IB-367 is well tolerated during the single-blind dose escalation, then subsequent cohorts of patients will receive single ascending doses administered in a double-blind manner (Part B). Patients in both parts of the study will be pre-treated with an inhaled bronchodilator prior to administering each dose. Persistent airway infections remain a major clinical problem for patients with cystic fibrosis. These infections are particularly difficult to treat because conventional antibiotics often do not achieve adequate delivery of drug to the site of infection and because the risk of inducing bacterial resistance often limits long-term therapies. IntraBiotics is developing a series of antimicrobial peptides based on protegrins, a family of naturally derived host-defense peptides initially isolated from procine neutrophils. One such protegrin analog, IB-367, has been formulated as a solution for inhalation to be used in the treatment of respiratory infections, such as those in patients with cystic fibrosis. As a class, peptides of this group are broad spectrum, microbicidal agents that kill microorganisms rapidly by disrupting membrane integrity. Recent research has shown that high salt concentrations in the airways of patients with cystic fibrosis causes local inhibition of an endogenous antimicrobial substance, and that this inhibition may be one of the factors predisposing patients with cystic fibrosis to pulmonary infections. The bactericidal activity of IB-367 is not significantly affected by sodium chloride concentrations up to 182 mM, the level reported in cystic fibrosis airway surface fluid. We hypothesize that inhaled IB-367 could replace the inactivated, naturally occurring antimicrobial host defense molecules in patients with cystic fibrosis and provide a substantial improvement in patient outcome. The primary objectives are: 1) to determine the safety and tolerability of ascending doses of inhaled IB-367 in adult patients with cystic fibrosis 2) To determine whether potential bronchial reactivity to IB-367 is prevented by the prophylactic use of an inhaled bronchodilator in adult patients with cystic fibrosis as measured by change in FEV1 pre-and post-dose. The secondary objectives are: 1) to monitor for evidence of systemic absorption of IB-367 characterized by vasodilatory response or other toxicities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IDENTIFICATION OF CA2+ REGULATED APICAL CL- CHANNELS Principal Investigator & Institution: Gabriel, Sherif E.; Cystic Fib/Pulmonary Trtmt Ctr; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: (Adapted from applicant's abstract): Cystic fibrosis (CF) is characterized as a defect of electrolyte transport of epithelial cells of exocrine tissues. Central to the pathophysiology of CF is the absence of cAMP- stimulated Cl- secretion and an enhanced rate of Na+ absorption. The cloning of the CF gene and characterization of the gene product, the cystic fibrosis transmembrane conductance regulator (CFTR), has revealed that CFTR functions as a cAMP-stimulated Cl- channel. Cloning of the CF gene led to the creation of an animal model for CF, the CFTR (-/-) knockout mouse. Interestingly, the CFTR (-/-) mouse did not exhibit a severe CF phenotype in many epithelial tissues, including the airways. Importantly, the absence of a CF phenotype led to the formal identification of the Ca2+-regulated, or "alternative" Cl- conduction pathway (Cl-A) that is molecularly distinct from CFTR and plays a protective role in preventing CF pathogenesis in the airways of the CFTR (-/-) mouse. This proposal focuses on Cl-A and hypothesizes that Cl-A is an important airway epithelial ion channel resident in the apical membrane and regulated by elevation of intracellular Ca2+. Cl-A will be investigated at three levels, 1) characterization of transepithelial Clcurrents, 2) regulation of Cl-A by Ca2+-mediated signal transduction pathways, 3) patch clamp identification of the Cl-A single channel properties. Confluent polarized epithelial preparations will be used to characterize the Ca2+-stimulated Cl- current and to identify the agonists and signal transducers that regulate this conductance. Patch Cl-Amp technique will be used to identify the Cl-A single channel properties that correlate with Ca2+-stimulated currents from CF murine airway epithelial cells. Importantly all single channel studies will be performed on cells grown on a permeablized support and only channels resident in the apical membrane will be studied. Finally, comparisons between the endogenous Cl-A and heterologously expressed candidate clones will permit the unequivocal identification of the Ca2+-activated airway Cl- channel. A complete characterization of Cl-A will lead to the genesis of new therapies for CF disease that would circumvent a defective CFTR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNOSUPPRESSION EXPRESSION: CYSTIC FIBROSIS

IN

PROLONGING

TRANSGENE

Principal Investigator & Institution: Baskin, Gary B.; Head, Pathology Department; Tulane University of Louisiana New Orleans, LA 70118 Timing: Fiscal Year 2001 Summary: We tested the hypothesis that a humanized non-depleting anti-CD4 antibody (OKT4acdr3) would prolong adenoviral-mediated gene expression in rhesus lungs. We treated rhesus macaques with 12 mg/kg OKT4a IV daily on days -1 to day +11. On day 0, animals were given 5 x 1010 pfu of AdCMVLacZ into the lung. A subgroup was continued on a secondary gene transfer protocol by administering AdCMVLacZ into the other lung. There was less inflammation and greater gene transfer in anti-CD4 treated animals. Secondary gene transfer was not efficiently accomplished in either group. OKT4acdr3 blocked T-cell activation to adenovirus and lacZ and prolonged gene expression. OKT4cdr3 did not attenuate B-cell responses. Possibly OKT4a specifically blocked the generation of a TH1 response. Studies using anti-CD4 antibodies in rodents

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have been performed in naive animals. All our monkeys had baseline non-neutralizing anti-adenoviral antibodies. Thus, another hypothesis is that low numbers of memory Bcells can proliferate in the absence of CD4 dependent help. Since most patients have anti-adenoviral antibodies, we must discern the correct hypothesis for repetitive gene transfer to be developed. FUNDING Cystic Fibrosis Foundation, J. Kolls, PI, $150,000 PUBLICATIONS None Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INHALED DOSES OF IB-367 IN ADULTS W CYSTIC FIBROSIS Principal Investigator & Institution: Regelmann, Warren E.; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, MN 554552070 Timing: Fiscal Year 2001 Summary: Persistent airway infections are a major clinical problem for patients with cystic fibrosis (CF). These infections are particularly difficult to treat because conventional antibiotics often do not achieve adequate delivery to the site of infection and because the risk of inducing bacterial resistance often limits long-term therapies. IB367 represents a new class of medications to treat respiratory infections. It is made from naturally occurring proteins and will be administered as a liquid for inhalation using a nebulizer. Recent research suggests that there is a high salt concentration in the airways of people with CF. The high salt concentration may block natural substances that help to protect the lungs, which may be a contributing factor in the development of chronic lung infections in patients with CF. IB-367 is a substance (a protein analog) that may help to protect the lungs from infections and works in spite of high salt concentrations. This is a phase 1, randomized, placebo-controlled, double-blind, multicenter study. The primary objective is to determine the safety and tolerability of ascending multiple doses of inhaled IB-367 in adult patients with CF. Secondary objectives are to obtain preliminary efficacy data on bacterial density in sputum and pulmonary function following ascending multiple doses of inhaled IB-367 and to monitor for evidence of systemic abortion of IB-367 characterized by vasodilatory response or other toxities. Subjects will be inpatients for 3 days (Day 1-3) for 5 drug doses and safety monitoring. They will return again on Day 6 for a post-study evaluation outpatient visit. We wish to conduct this study at the GCRC to ensure accurate timing of study tests and study drug administration. Conducting this study in the main hospital would be very difficult to do while maintaining strict study schedules. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INHALED IB-367 IN ADULTS WITH CYSTIC FIBROSIS Principal Investigator & Institution: Waltz, David A.; Children's Hospital (Boston) Boston, MA 021155737 Timing: Fiscal Year 2001 Summary: The primary objectives of this study are to determine the safety and tolerability of ascending doses of inhaled IB-367 in adult patients with cystic fibrosis, and to determine whether potential bronchial reactivity to IB-367 is prevented by the prophylactic use of an inhaled bronchodilator in adult patients with cystic fibrosis as measured by change in FEV, pre- and post dose. Background: Persistent airway infections remain a major clinical problem for patients with cystic fibrosis. These infections are particularly difficult to treat because conventional antibiotics often do not achieve adequate delivery of drug to the site of infection and because the risk of inducing bacterial resistance often limits long-term therapies. IntraBiotics is developing

64 Cystic Fibrosis

a series of antimicrobial peptides based on protegrins, a family of naturally derived host-defense peptides initially isolated from porcine neutrophils. One such protegrin analog, IB-367, has been formulated as a solution for inhalation to be used in the treatment of respiratory infections, such as those in patients with cystic fibrosis. As a class, peptides of this group are broad spectrum, microbicidal agents that kill microorganisms rapidly by disrupting membrane integrity. IB-367 was selected as a drug candidate for the treatment of respiratory infections based on its ability to kill respiratory pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae and Streptococcus pneumoniae. Aerosolized IB-367 directed to the site of infection in patients with cystic fibrosis may represent an effective alternative to current antimicrobial therapies. Recent research has shown that high salt concentrations in the airways of patients with cystic fibrosis causes local inhibition of an endogenous antimicrobial substance, and that this inhibition may be one of the factors predisposing patients with cystic fibrosis to pulmonary infections. The bactericidal activity of IB-367 is not significantly affected by sodium chloride concentrations up to 182mM, the level reported in cystic fibrosis airway surface fluid. The study will look at whether Inhaled IB-367 could replace the inactivated, naturally occurring antimicrobial host defense molecules in patients with cystic fibrosis and provide a substantial improvement in patient outcome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INHALED TOBRAMYCIN IN YOUNG CYSTIC FIBROSIS PATIENTS Principal Investigator & Institution: Ramsey, Bonnie W.; Professor of Pediatrics; Children's Hospital and Reg Medical Ctr Box 5371, 4800 Sand Point Way Ne, Ms 6D-1 Seattle, WA 98105 Timing: Fiscal Year 2001; Project Start 17-JUL-2000; Project End 30-APR-2003 Summary: The purpose of this proposal is to determine the short-term microbiologic efficacy and safety of an inhaled antibiotic, tobramycin solution for inhalation (TOBI), in infants and young children with cystic fibrosis (CF) and documented Pseudomonas aeruginosa (Pa) lower airway infection. Because initial colonization with Pa can occur in the first 5 years of life, there is growing interest in investigating anti-pseudomonal therapies in very young children with the long-term goal of delaying or preventing chronic infection that contributes to irreversible lung disease. To test anti- infective therapies in this age group, there is a need to assay the anti- microbial effect by direct lower airway sampling, and to compare these measures with surrogate markers. The current proposal is the first multicenter study of inhaled antibiotics in young children with CF and should serve as a paradigm for future anti-microbial therapeutic trials. TOBI has been selected because it is the only inhaled antibiotic with FDA approval. Although extensive animal toxicity and human safety data are available, no safety or efficacy data have been collected in children less than 6 years of age. Specifically, we hypothesize that administration of TOBI for inhalation twice daily for 28 days to children less than six years of age with CF who are culture positive for Pa in their lower airways will be safe and result in a significant reduction in the mean Pa density in lower airway cultures. Our secondary outcomes will evaluate the effect of antibiotic therapy on lower airway inflammation (cell count, % neutrophils, cytokines, elastase activity), surrogate markers of lower airway microbiology (oropharyngeal cultures, antibodies to Pa exotoxin A), and clinical status (weight gain, modified Shwachman scores, and lung function tests in subjects 3-5 years of age). We propose to conduct a multicenter, double blind, placebo-controlled randomized trial within the seven centers comprising the Cystic Fibrosis Foundation (CFF) funded Therapeutics Development Network (TDN).

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Ninety eight subjects with bronchoalveolar lavage (BAL) cultures positive for Pa will be randomized to receive TOBI or placebo twice daily for 28 days. At the end of treatment, a BAL will be repeated to quantitate Pa lower airway density. This study will provide valuable microbiologic efficacy and safety data for use of inhaled antibiotics in young children with CF, and will provide important data on surrogate markers of lower airway infection and inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERACTION OF CFTR AND EPITHELIAL NA CHANNELS Principal Investigator & Institution: Eaton, Douglas C.; Professor and Deputy Chairman of Physiol; Physiology; Emory University 1784 North Decatur Road Atlanta, GA 30322 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-JUL-2004 Summary: In the U. S., cystic fibrosis is the most common lethal genetic disease in the caucasian population, affecting about 1 in 2500 live births. The genetic locus of the disease, CFTR, is an epithelial anion channel so it is not surprising that CF is characterized by abnormal chloride transport in affected epithelia. But individuals with cystic fibrosis not only have abnormal chloride transport but also have abnormal sodium transport. Certain epithelia, e.g. airway and the distal nephron, express both apical Na channels and CFTR. Activation of CFTR in these cells produces C1 reabsorption and hormones that stimulate CFTR also enhance Na reabsorption. Activation of both CFTR and epithelial Na channels (ENaC) may lead to dramatic increases in NaC1 entry into cells and associated cell swelling, so it is important that cells control NaC1 entry to avoid large changes in cell volume. We hypothesize that regulatory interactions between C1 channels and Na channels provide a mechanism by which epithelia can control net NaC1 entry across the apical membrane. Activation of CFTR is associated with an inhibition of ENaCs, providing a means by which epithelial cells can regulate net NaC1 entry. Preliminary results show that inhibition of ENaC activity is via a paracrine agent whose release is CFTR dependent. The first aim will examine how expression and activation of CFTR alters the activity of ENaC. This aim will determine if ATP released to the outside of cells in a CFTR-dependent manner can inhibit ENaC activity. This will be accomplished by inhibiting the extracellular action of ATP with ATP degrading enzymes; determining the rate of release of ATP from A6 monolayers; examining the coupling of purinergic receptors to ENaC inhibition; and determining if the ATP release is via CFTR-dependent exocytosis. Since modulation of net NaC1 reabsorption has important implications for cell volume regulation, we also hypothesize that ENaCs will regulate CFTR. Preliminary data show that forskolin/IBMX stimulated CFTR C1 currents are significantly increased in the presence of ENaC, suggesting that ENaCs regulate CFTR. The second aim will examine whether ENaC-mediated regulation of CFTR is via changes in the number CFTR channels at the plasma membrane and/or changes in open probability. These studies will provide new information about mechanisms of coordinate regulation of epithelial Na and C1 transport. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: KRUPPEL LIKE FACTOR IN P. AERUGINOSA AIRWAY VIRULENCE Principal Investigator & Institution: Saavedra, Milene T.; Medicine; University of Colorado Hlth Sciences Ctr Uchsc at Fitzsimons Aurora, CO 800450508 Timing: Fiscal Year 2003; Project Start 04-AUG-2003; Project End 31-JUL-2008

66 Cystic Fibrosis

Summary: (provided by applicant): Of the 2,500 children born every year with cystic fibrosis (CF) in the United States, 80% harbor P. aeruginosa by the time they reach 18 years of age. Recurrent Pseudomonas pulmonary infections are the major cause of morbidity and mortality in these patients. Airway structural damage is induced by excessive neutrophil populations in the airway, releasing large amounts of proteases which impair phagocytic killing of organisms. To date, the repertory of antiinflammatory therapies to limit excessive epithelial cell signaling to inflammatory mediators remains limited and imperfect, which may be partially due to a limited understanding of critical pathways to curb inflammation and their role in the pathogenesis of CF. Evidence suggests that the zinc finger protein, lung kruppel like factor (LKLF), described here for the first time as highly regulated by infection, plays a significant role in the regulation of the airway epithelial cell response to Pseudomonas infection. Based on preliminary data, Dr. Saavedra hypothesizes that a) the transcriptional activator LKLF is cytoprotective in normal airway cells, b) that it suppresses nuclear factor kappa B activation and c) that in cystic fibrosis, overexpression of LKLF is not protective due to alternate apoptotic/death pathway activation. These aims will be studied with an in vitro epithelial cell air liquid interface culture model system and the well characterized Pseudomonas strain PAO1. The approach will initially utilize functional genomics to define pathways activated by overexpression of this gene utilizing an LKLF plasmid construct. The true focus will be on elucidating gene function with apoptosis assays, luciferase reporter constructs, EMSA experiments and use of various constructs overexpressing genes involved in NFkappaB activation to ascertain target site of LKLF activity along that pathway. These experiments are designed to further understanding of how epithelial cells drive neutrophil recruitment, knowledge of which may contribute to development of new therapeutic interventions in inflammatory airways diseases such as CF. This project will allow Dr. Saavedra to become an independent investigator and expert in the realm of Pseudomonas and airway epithelial cell biology, via a multi-faceted approach of 75% dedicated laboratory time and didactic training with a special focus on mechanisms of microbial pathogenesis. Outside of the laboratory, 25% clinical time will be spent as an instructor in adult Pulmonary and Critical Care Medicine, taking care of both inpatients and outpatients with CF, with the ultimate goal of a closely knit research and clinical niche as a principal investigator and expert adult CF doctor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LENTIVIRAL VECTORS FOR GENE DELIVERY Principal Investigator & Institution: Olsen, John C.; Associate Professor; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) The overall goal of this project is to advance lentiviral gene delivery systems to a point where they can serve as safe and efficient therapeutic gene delivery systems for human clinical trials. Lentiviral vectors based upon human immunodeficiency virus type I (HIV-1) and equine infectious anemia virus (EIAV) will be studied. Specifically, we are interested in improving the production and bio-safety of lentiviral vectors so that they can be used in treatments for diseases such as hemophilia B and cystic fibrosis. Thus our studies will focus on vector development and testing aspects of gene delivery to the liver and airway epithelium. It is clear that the ability of lentiviruses to transduce non-dividing cells is the main reason for development of lentivirus based gene delivery systems. Lentivirus vectors have proved efficient at transducing various tissues in vivo (brain, liver, muscle, retina, and

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hematopoietic stem cells). Recently, we showed that a single intraperitoneal injection of hemophilic mice with lentivirus vectors resulted in long term expression of therapeutic levels of canine factor IX. The treated mice demonstrated corrected blood clotting indices equivalent to those obtained from heterozygous litter mates. However, we believe that further improvement in vector production, vector safety, and in vivo transduction efficiencies of non-dividing cells can be made. The ability to study different lentivirus vectors in parallel will allow us to identify and to solve basic biological problems common to all lentivirus vectors. This approach permits us to investigate the effects of vector origin on the ability to efficiently transduce and express transgenes in tissues and cells from different species. To facilitate generation of cell lines for vector production, we will optimize the incorporation of Self-Inactivating (SIN) vector cassettes into stable packaging cell lines. To improve the safety of lentivirus vectors we propose to generate novel non-integrating lentiviral vectors that exhibit high levels of transgene expression in vivo. To investigate the effects of vector origin on the ability to transduce non-dividing cells, we will compare vectors derived from primate and non-primate lentiviruses on the ability to transduce non-dividing cells in model systems relevant for treatment of hemophilia B and cystic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LENTIVIRUS VECTORS FOR CYSTIC FIBROSIS GENE THERAPY Principal Investigator & Institution: Bates, Paul F.; Associate Professor; Microbiology; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2003 Summary: Gene transfer with viral vectors has the potential to correct defects associated with genetic diseases such as cystic fibrosis. Because of their ability to efficiently and stably integrate their genomes into the host chromosome retroviruses are ideal vectors for gene transfer. Epithelial cells lining the upper airways represent the appropriate targets for viral delivered genes. However, in vitro and in vivo studies using viral vectors suggest that gene transfer into differentiated airway epithelia with viral vectors is inefficient. One obstacle that appears to severely limit gene transfer into airway epithelial cells by viral vectors is inefficient entry from the apical surface. To circumvent this obstacle, we are developing a unique system for targeted viral infection utilizing influenza hemagglutinin (HA) to mediate viral entry. For this targeting system we have produced a multiply mutated variant of HA that no longer binds its cellular receptor but which can efficiently mediate membrane fusion upon endocytosis. Co-incorporation of a targeting ligand with the mutant HA directs efficient infection of viruses to receptor expressing cells. We will target HIV-1 based retroviral vectors to airway epithelial cells using this novel system to achieve stable gene transfer. To accomplish this task we propose the following specific aims: 1) Define epithelial cell apical surface molecules to utilize for targeting by screening phage display libraries, 2) produce HIV-1 vectors carrying HA and airway epithelial cell targeting ligands and develop two novel systems for incorporation of ligands into virions 3) analyze targeting and infection by these HIV1 vectors using in vitro and in vivo models of airway epithelia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MAPPING CYSTIC FIBROSIS: HISTORY, MEDICINE, ETHICS Principal Investigator & Institution: Robinson, Walter M.; Social Medicine & Hlth Policy; Harvard University (Medical School) Medical School Campus Boston, MA 02115 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 29-SEP-2003

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Summary: (provided by applicant): The history of the diagnosis and therapy of cystic fibrosis (CT ) parallels the history of the major forces shaping clinical medicine in the 20th century. The story of cystic fibrosis can be used as an incisive case study of disease definition and negotiation, medical specialization and sub-specialization, the rise of genetic diagnoses and attempts at gene therapy, the uses of invasive technology in children, the role of private and public funding in directing scientific work, the ethical issues surrounding end of life care, and the competing metaphors of medical practice employed in the treatment of serious childhood illness. The principal aim of this proposal is the research and writing of a book on the history of cystic fibrosis in the 2Oth century, with particular emphasis on the social factors which have defined both the disease and the experience of illness. The principal sources will be published records of clinical and basic science research on CF as well as clinical records of patient care at a large CF Center; in addition, materials from the archives of the National Library of Medicine will be used for documentation of the activities of the major foundations supporting CF research and clinical care. The principal investigator is an experienced CF clinician as well as a medical ethicist with a strong interest in social medicine. His previous work has focused on the interaction of technology and terminal care for CF patients, as well as the ethical issue arising out of advances in therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF CFTR INTERNALIZATION Principal Investigator & Institution: Bradbury, Neil A.; Cell Biology and Physiology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2005 Summary: (provided by applicant): The long-term goal of Dr. Bradbury's laboratory is to understand the mechanism of endocytosis of ion channels, using endocytosis of the cystic fibrosis transmembrane conductance regulator (CFTR) as an experimental system. CFTR is important in the regulation of chloride secretion by the cAMP-mediated second messenger cascade, and mutations in CFTR give rise to the human genetic disease cystic fibrosis (CF). Our working model predicts that cAMP not only increases the open probability (Po) of CFTR, but also regulates the number (N) of CFTR molecules in the plasma membrane. Endocytosis of CFTR is a major mechanism for acutely regulating the distribution of CFTR between the plasma membrane and subcellular organelles such as endosomes and recycling vesicles. Therefore endocytosis may partly determine the magnitude of the secretory response to cAMP mediated agonists. However, the mechanisms of the specific steps of CFTR endocytosis are not yet fully understood. Proposed research will focus on the steps and molecular interactions necessary for the endocytosis of CFTR. The emphasis of the project will be on the search for and characterization of clathrin adaptor molecules that allow effective interaction of CFTR with a plasma membrane clathrin coated pit, a key element of the endocytic apparatus. The general strategy of these studies falls into two related directions. We will determine which sites on CFTR directly bind to plasma membrane adaptor proteins, and determine which subunits of the adaptor proteins are responsible for this interaction. Identification of binding sites for adaptor proteins should provide a basis for understanding the mechanisms of specificity in CFTR endocytosis. We will analyze the role of CFTR phosphorylation in this interaction, to determine if phosphorylation status of CFTR modulates its affinity for adaptor proteins and hence efficiency of endocytosis. These studies will be accompanied by a kinetic analysis of CFTR endocytosis in cells expressing mutants of CFTR which lack plasma membrane adaptor binding motifs. Similarly the endocytic kinetics of CFTR phosphorylation mutants will be evaluated in

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the presence and absence of cAMP raising agents. Studies of the dynamics of CFTR internalization may, in turn, help identify other proteins regulating CFTR endocytosis. Results from our studies should allow us to design experimental approaches to prevent the endocytosis of CFTR mutants that reach the plasma membrane but have a low open probability upon activation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF KINASE-DEPENDENT CFTR ACTIVATION Principal Investigator & Institution: Reenstra, William W.; Associate Professor & Head; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001; Project Start 20-SEP-2001; Project End 30-JUN-2005 Summary: Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Relative to wild type CFTR, the most common mutation deltaF508-CFTR, present in >85% of CF patients is expressed at low levels in the plasma membrane and has reduced in vivo activity. Thus to correct the deltaF508-CFTR mutation both the number of plasma membrane channels and the activity of individual channels must be increased. Our data suggest that the reduced in vivo activity of deltaF508 - CFTR is due to a reduced level of phosphorylation. In this study we will test two hypotheses, 1) that differences in CFTR activity can be caused by differences in channel phosphorylation, and 2) that differences in the activity of wild type and deltaF508-CFTR are due to differences in phosphorylation. By activating CFTR under various experimental conditions and by examining CFTR with serine to alanine mutations at phosphorylation sites, we will generate CFTR with different phosphorylation states. Then by comparing the channel kinetics of different phosphorylation states, we will generate structure function relationships. Our studies will provide. biochemical evidence for the hypotheses that PKC-dependent phosphorylation is required for PKA-dependent activation and that protein phosphatases show selectivity with respect sites of dephosphorylation. These studies will assist in the development of drugs to treat CF patients with deltaF508-CFTR. In specific aim I, two-dimensional peptide mapping, site-directed mutagenesis and mass spectroscopy will be used to identify sites of PKC- and PKA-dependent CFTR phosphorylation and establish experimental conditions where CFTR phosphorylation differs. In specific aim II, channel kinetic parameters will be determined for CFTR that has been phosphorylated on different sites. Alterations in mean open and closed times, Po and the number of active channels will be correlated with phosphorylation at specific sites. In specific aim III, we will compare phosphorylation and channel kinetics of wild type and deltaF508-CFTR to determine if differences in channel activity are correlated with differences in phosphorylation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF NUCLEOTIDE BINDING AND REGULATION OF CFTR Principal Investigator & Institution: Berger, Allan L.; Internal Medicine; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2006 Summary: (provided by applicant): The goal of this application is to support the development of Dr. Allan Berger as a clinician scientist so that at the completion of the award he will be an independent researcher and an outstanding academic scientist and clinician. Dr. Michael J. Welsh will assume responsibility as mentor to ensure the success

70 Cystic Fibrosis

of the development plan. The heart of the proposal is an intensive training experience in the basic research laboratory. Cystic fibrosis (CF) is the most common lethal genetic disease in young Caucasians, and is caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. ATP binding to the two nucleotide binding domains (NBD) of CFTR is required for normal channel function. In this proposal, Dr. Berger will explore the interactions between ATP and CFTR. Preliminary data suggest that certain novel missense mutations in CFTR selectively block ATP binding. There are three Specific Aims. 1) What are the biochemical and functional effects of mutations that block ATP binding to CFTR? 2) What are the effects of the Walker A lysine mutations K464A and K1250A on ATP binding? 3) What residues in CFTR contact the ATP base? Together these aims will determine the functional mechanisms underlying ATP regulation of the CFTR chloride channel and structural mechanisms of ATP binding. Dr. Berger will combine biochemical and functional assays to learn how ATP interacts with the NBDs to control channel activity. Dr. Berger will further develop his skills at using the scientific method to develop hypotheses that can be experimentally tested to yield unequivocal answers. In addition to basic research training, Dr. Berger will improve his skills of presenting data verbally and in writing. He will continue his training by participating in seminars and journal clubs, and will attend national meetings to present his own work and to learn from others. He will receive instruction in the responsible conduct of research. He will also receive instruction and critique in grant writing. In the latter stages of this training he will prepare grant applications for independent research funding. Both the mentor and the institution are highly committed to the applicant's scientific development and academic success. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MEMBRANES AND ACTIVE TRANSPORT OF AMINO ACIDS Principal Investigator & Institution: Ames, Giovanna F.; Professor; Children's Hospital & Res Ctr at Oakland Research Center at Oakland Oakland, CA 94609 Timing: Fiscal Year 2001; Project Start 01-JAN-1977; Project End 31-DEC-2002 Summary: The superfamily of translocators, traffic ATPases (or ABC proteins), the cystic fibrosis transmembrane conductance regulator (CFTR), the P- glycoprotein of multidrug resistance (MDR), and bacterial periplasmic permeases. Multidrug resistance is one of the major problems in cancer chemotherapy an cystic fibrosis is the most common recessive caucasian disease. Periplasmic permeases have been extensively studied and provide a good model system for understanding the mechanism of action of the medically relevant eukaryotic members of the superfamily. One such permease, the histidine permease, has been characterized in detail. As is true for traffic ATPases in general, the histidine permease is composed of two hydrophobic domains that are integral parts of the membrane, and of two hydrophilic domains that are also inserted into the membrane and bind ATP. Hydrolysis of ATP is used as the energy source. Since CFTR appears to be a channel, it is important to determine whether prokaryotic systems also function as channels. This would be an entirely novel concept for the prokaryotic systems. From the known structure of the membrane-bound complex, it is indeed possible that the hydrophobic domains of periplasmic permeases form a channel through which the substrate crosses the membrane, with ATP hydrolysis resulting in the necessary conformational changes. A characteristic peculiar to periplasmic permeases is the presence of a receptor that concentrates the substrate at the external surface of the membrane-bound complex. The receptor sends a signal to the membrane-bound complex, resulting in ATP hydrolysis and translocation. Among the tools that will be

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used in this study are several reconstituted systems and several measurable enzymatic activities that permit in vitro assays of function. The activity of traffic ATPases as channels will be investigated in lipid bilayers. The mechanism of signaling between the soluble receptor and the membrane-bound complex, in particular the energy- coupling component, will be studied by the use of biochemical reactions that distinguish between different conformations of proteins, such as limited proteolysis and covalent labeling, and by genetic analysis through the isolation of mutants with altered signaling processes. Similar biochemical and genetic procedures will be used to study the architecture of the membrane-bound complex. In addition, the components of the membrane-bound complex will be purified and characterized individually. Both twoand three-dimensional crystallography will be attempted to understand the structures of both the complex and the subunits. In addition to solving basic questions related to the mechanism of action of permeases in general, the study of this prokaryotic model system will help the efforts of eukaryotic researchers towards a solution of the medical problems related to multidrug resistance, cystic fibrosis, malarial parasite containment, and others. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MINORITY PREDOCTORAL FELLOWSHIP PROGRAM Principal Investigator & Institution: Adebamiro, Adedotun; Cell Biology and Physiology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2003; Project Start 01-APR-2004 Summary: (provided by applicant): Hypersodium absorption that causes impaired mucocilliary clearance is thought to be a major contributor to the pathophysiology of cystic fibrosis lung disease. Recent observations that proteases and protease inhibitors affect sodium transport rates in numerous epithelia has lead to suggestions that there is a intrinsic protease regulation of sodium transport in the lungs as well as other epithelia. However, the mechanism of this proposed regulation is unknown. We propose to use the method of noise analysis on sodium transporting epithelia and Xenopus oocytes as well as giant-patch patch-clamping to determine the transport parameters regulated by proteases. We will determine the necessary players in protease regulation of sodium transport. The methods we will use are less invasive and would provide highly detailed real time physiologically relevant data on sodium regulation by proteases and as such will provide a unique perspective on ion channel regulation With the data we hope to obtain, we can identify therapeutic targets specific for the protease regulation pathway that will reduce the severity of cystic fibrosis lung disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR BASIS OF SECRETORY DIARRHEA Principal Investigator & Institution: Cohn, Jonathan A.; Associate Professor; Medicine; Duke University Durham, NC 27706 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-DEC-2003 Summary: In secretory diarrhea, the protein mainly responsible for controlling electrolyte and water movement into the intestinal lumen is the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR functions as a Cl- channel subject to regulation by protein kinase A (PKA) and protein kinase C (PKC). CFTR activation requires phosphorylation by PKA and ATP hydrolysis, events occurring in adjacent CFTR domains termed nucleotide binding domain 1 (nbd1) and the R domain. This

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project will use recombinant peptides to study how CFTR is regulated. Peptides containing CFTR(62O-830), termed RD's, will model the R domain, and peptides containing CFTR(417-830), termed NBD/RD's, will model the nbd1/R domain. Modified peptides will contain Ala or Asp substitutions at one or more Ser residues. The project has three aims: AIM #1 will use RD's to study how protein kinases act on the R domain. Phosphorylated RD's will be analyzed by tryptic mapping and HPLC/mass spectrometry to identify phosphorylation events accompanying maximal vs. partial stimulation of CFTR. Additional studies will examine the mechanism by which protein kinases act on RD's and will determine how synergism between protein kinases orchestrates the orderly phosphorylation of CFTR. AIM #2 will study how PKA controls the intrinsic function of the nbd1/R domain. Pilot studies indicate that NBD/RD's exhibit PKA-regulated ATPase activity. These peptides will be used to determine which RD phosphorylation events activate vs. inhibit the nbd1 ATPase, to test whether the regulation of nbd1 by PKA is affected either by PKC or by nbd2, and to test whether the nbd1 ATPase is affected by the deltaF5O8 mutation, the most common cause of cystic fibrosis (CF). Aim #3 will study how protein kinases control the ability of the R domain to activate the Cl- channel function of CFTR. RD's will be added to membrane patches containing a truncated CFTR lacking most of the R domain (deltaR/S66OA CFTR) to compare the ability of different modified RD's to regulate CF transport by CFTR. This project's long-term goal is to clarify how protein kinases act on the nbd1/R domain to regulate CFTR function. Detailed knowledge of CFTR regulation will be fundamental to developing pharmacological strategies to selectively augment or diminish CFTR function. Given the pivotal role of CFTR in the pathogenesis of diarrhea and CF this project has excellent prospects of leading to information of practical benefit in the treatment of these conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR BASIS OF THE CYSTIC FIBROSIS PHENOTYPE Principal Investigator & Institution: Durie, Peter R.; Hospital for Sick Chldrn (Toronto) 555 University Ave Toronto, Timing: Fiscal Year 2002; Project Start 30-SEP-1994; Project End 31-AUG-2004 Summary: The goal of this SCOR application is to understand the clinical, biological and biochemical consequences of mutations in CFTR, the gene defective in cystic fibrosis (CF). The program brings together a group of basic scientists and clinician researchers with a broad range of expertise to the common task of analyzing the CF disease from different angles, through studying the CFTR molecular defects in patients, generating, mouse models, mapping of modifier genes, and using cell culture and in vitro systems for the protein. We combine our strengths in the area of CF patient documentation, human and mouse genetics, biochemistry and cell biology. The SCOR is organized into 4 Research Projects (RP), 3 Pilot Projects (PP) and 3 Core Units, grouped into 3 research areas, namely, clinical and genetic studies of patients, mouse models of identification of CF modifier genes, and direct characterization of CFTR. In the first area, RP1 will establish a comprehensive understanding of the spectrum of CF disease phenotype caused by or associated with the primary and secondary genetic determinants of the disease. In the second, RP2 will study the role of ClC-2 chloride channels in mediating epithelial chloride secretion in a mouse model and RP3 will dissect the physiologic and genetic aspects of lung disease in CF mice of a specific genetic background. In addition, a pilot project, PP3, is included to characterize the liver disease recently observed in one of the congenic CF mouse strains. These studies will discover new pathways through which alternative methods may be devised to treat CF. In the third area, RP4 will pursue

Studies 73

a detailed analysis at the molecular, cellular and functional levels to establish the consequences of the missense mutations that occur in the first nucleotide binding domain (NBD1) of CFTR and mutations causing carboxyl terminal truncations will be used as probes for these studies. This will be complemented by the two pilot projects: PP1 which will explore a new fluorescence transfer technique for the study of transmembrane segment interactions and PP2 which will examine if purified CFTR an mediate energy-dependent transport of large organic anions such as glutamate and glutathione in a reconstituted system. In addition to the Administration Core, the Patient/Biostatistics Core, and the Mouse Core will serve to support the hove projects. The results from Score should yield novel insights into the molecular mechanisms of CF pathology and should lead to new improved therapeutic approaches. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR BIOPHYSICS OF CFTR CHLORIDE CHANNELS Principal Investigator & Institution: Bompadre, Silvia G.; Medical Pharmacology and Physiology; University of Missouri Columbia 310 Jesse Hall Columbia, MO 65211 Timing: Fiscal Year 2002; Project Start 01-APR-2003 Summary: (provided by applicant): CFTR (Cystic Fibrosis Transmembrane conductance Regulator) is a small conductance Cl channel that is regulated by phosphorylation and gated by ATP hydrolysis. Mutations in the gene coding for CFTR result in the genetic disease cystic fibrosis. Our long-term research goals are to investigate how mutations in CFTR cause its defective functions at the single molecule level and to examine how pharmacological interventions circumvent dysfunction of the mutant protein. The current proposal is aimed to explore the biophysical and biochemical mecanisms of the R domain in CFTR. The specific aims of this proposal are: Aim1. To investigate the mechanism of glibenclamide effect in CFTR-dR gating. Specifically we will investigate how the absence of the R domain reveals another binding site for glibenclamide. We will also test other sulphonylurea drugs. Aim 2. To investigate the role of the R domain in the functional defect of dF508, the most common mutation associated with cystic fibrosis disease. Specifically, we will investigate whether the deletion of the R domain can restore CFTR-dF508 channel function. We will combine electrophysiology methods with molecular biology methods to achieve these aims. Results from this work will not only shed light on the function of the R domain in CFTR, but will also provide invaluable information to help the understanding of the most commom disease associated mutation of the CFTR channel. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR GENETICS OF CYSTIC FIBROSIS Principal Investigator & Institution: Cutting, Garry R.; Professor; Pediatrics; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001; Project Start 01-MAY-1991; Project End 30-APR-2003 Summary: (Applicant's abstract): Study of the autosomal recessive disorder cystic fibrosis (CF) has produced novel insights into the process of epithelia electrolyte movement at a molecular level. Patients with this disorder have altered viscosity and anti-bacterial properties of secretions in the lungs and pancreas due to defective chloride and sodium transport across epithelial cell membranes. The protein defective in this disease, the CF transmembrane conductance regulator (CFTR), functions as a cAMPactivated chloride channel and, in airway epithelia, as a regulator of other ion channels in the same cell. The latter role of CFTR explains abnormal function of several different

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ion channels in cells from CF patients, and indicates that this molecule is a critical component of a pathway coordinating ion movement across apical membranes of airway cells. It also suggests that channels regulated by CFTR an the proteins involved in these regulatory pathways may be able to influence lung function independent of CFTR and could therefore be therapeutic targets for CF. The overall goal of this proposal is to determine the importance of th regulatory function of CFTR in pulmonary epithelial electrolyte transport. Thi will be achieved by pursuit of the following aims: 1) to determine whether preservation of the regulatory function of CFTR correlates with improved lung function in patients carrying mutations in each CFTR gene. CFTR mutations will be identified in patients with clinical evidence of CFTR dysfunction but absen lung disease and patients without evidence of CFTR dysfunction but with lung disease similar to CF using the denaturing gradient-gel electrophoresis (DGGE) technique. The consequence of missense mutations upon CFTR processing will be assessed by immunoprecipitation and sizing of mutant CFTR protein transiently expressed in HEK 293 cells. Alteration in the regulatory function will be determined by patch-clamp analysis of CFTR mutants transiently expressed in non-polarized human CF airway epithelial cells and Ussing chamber measurements of electrolyte movement across polarized epithelial cells stably expressing mutant CFTR. 2) To determine whether defects in proteins other than CFTR can give rise to pulmonary phenotype similar to CF. An extensive search for unusua CFTR mutations will be performed in CF patients that have no mutations identified by DGGE. CAMP-activated Cl- conduction will be assessed in patients without CFTR mutations by nasal potential difference testing and patch-clamp analysis of their nasal epithelial cells. Finally, epithelial cells from patients without CFTR mutations but with abnormal cAMP-activated Cl- conductio will be transfected with the wild-type CFTR cDNA to confirm that provision of normally functioning CFTR does not correct the defect in Cl- conduction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR MECHANISMS OF CFTR REGULATION Principal Investigator & Institution: Ladias, John A.; Beth Israel Deaconess Medical Center St 1005 Boston, MA 02215 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-regulated chloride channel that determines the rate of electrolyte and fluid transport in the apical membrane of epithelial cells. Abnormal CFTR function is associated with the pathogenesis of cystic fibrosis and secretory diarrhea. Our long-term objective is to understand the molecular mechanisms underlying the regulation of CFTR at the atomic level and develop novel strategies for modulating the activity of this channel and treating the CFTR-associated diseases. The CFTR topology consists of two membrane-spanning domains and five cytoplasmic domains: an N-terminal domain (NTD), two nucleotide-binding domains, a regulatory domain (R) and a C-terminal domain (CTD). The CFTR activity is modulated through phosphorylation of the R domain, ATP hydrolysis by the NBDs, and interactions of its NTD and CTD domains with syntaxin 1A and NHERF proteins, respectively. However the regulatory mechanisms remain unknown primarily because the three-dimensional structure of the CFTR domains and the structural basis of their interaction with intracellular regulatory proteins remain elusive. This proposal addresses these questions and focuses on the structural analysis of cytoplasmic CFTR domains and their complexes with regulatory proteins, using molecular biology techniques and X-ray crystallography. The specific aims are: 1. To dissect the structural basis of CFTR channel

Studies 75

gating mediated through the interaction of the CFTR CTD with the NHERF PDZ1 and PDZ2 domains. 2. To elucidate the molecular mechanisms underlying the regulation of CFTR channel activity through the interaction of the CFTR NTD with syntaxin 1A. 3. To determine the three-dimensional atomic structures of the CFTR NBD1 and NBD2 domains. These studies will provide the first high-resolution three-dimensional structures of four cytoplasmic CFTR domains and the structural basis of CFTR regulation by proteins syntaxin 1A and NHERF. This information is an essential step towards elucidating the basic molecular mechanisms that control the CFTR channel gating. Importantly, the atomic coordinates of these complexes could be used for structure-based rational design of drugs that would modify selectively the CFTR activity with clinical applications in the treatment of cystic fibrosis and secretory diarrhea. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR PATHOGENESIS OF P. AERUGINOSA IN CF Principal Investigator & Institution: Barbieri, Joseph T.; Professor; Microbiol & Molecular Genetics; Medical College of Wisconsin Po Box26509 Milwaukee, WI 532264801 Timing: Fiscal Year 2002; Project Start 15-JUL-2002; Project End 30-JUN-2006 Summary: (provided by applicant): The morbidity and mortality for most cystic fibrosis (CF) patients is caused by Pseudomonas aeruginosa, however its pathogenesis during early stages of infection of children with CF is poorly understood. P. aeruginosa possesses several virulence factors, which contribute to its pathogenesis. A relatively new class of virulence factor is the type Ill cytotoxins, which are delivered into eukaryotic cells upon the direct binding of the bacterium to the eukaryotic cell membrane. These cytotoxins subvert the host innate immune system, allowing establishment of initial foci of infection. This proposal represents a consortium among researchers at the Medical College of Wisconsin, the National Institutes of Health (NHBLI and NCI) and the Wisconsin CF Neonatal Screening Project and will provide insight into the pathogenesis of P. aeruginosa in children with CF. Recent studies have shown that components of the type-Ill apparatus are commonly expressed in adult CF patients who are infected by P. aeruginosa and that sera from children with CF contain antibodies against the type-Ill apparatus and the type III cytotoxin, ExoS. Two hypotheses will be tested: (i) stable colonization of the lung of children with CF requires expression of the type-Ill system of P. aeruginosa and (ii) the immune response to antigens of the type-Ill system is an early and accurate measurement of infection of the lung of children with CF by P. aeruginosa. This proposal will conduct retrospective and prospective longitudinal studies to determine the expression of the type-Ill system of P. aeruginosa in children with CF and to correlate this data with stable infection by P. aeruginosa, clinical outcome, the child's genotype for host modifier genes. There are three specific aims: measure the immune response to the type-Ill system of P. aeruginosa in children with CF; identify type-III antigens and immunogens of P. aeruginosa isolated from children with CF, and characterize the biological and biochemical properties of type-Ill cytotoxins from P. aeruginosa isolates from children with CF and antibodies to type-Ill cytotoxins. Completion of these studies will define the molecular properties of P. aeruginosa during early infections of children with CF and develop strategies to accurately detect P. aeruginosa infections, as well as, provide insight towards the identification of vaccine candidates to delay or prevent infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR PATHOPHYSIOLOGY OF CYSTIC FIBROSIS Principal Investigator & Institution: Hwang, Tzyh-Chang; Associate Professor; Dalton Research Center; University of Missouri Columbia 310 Jesse Hall Columbia, MO 65211 Timing: Fiscal Year 2003; Project Start 30-SEP-1999; Project End 31-AUG-2007 Summary: (provided by applicant): Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is a protein kinase A (PKA)-activated, ATP-gated chloride channel. Defective function of this channel in the apical membrane of epithelial cells is responsible for the debilitating symptoms in patients with cystic fibrosis. Although PKA-dependent phosphorylation of the regulatory (R) domain of CFTR is critical for CFTR function, the molecular mechanism of how phosphorylation of the R domain activates CFTR remains unclear. How many serine residues need to be phosphorylated to activate CFTR? Which residues are essential? Are those phosphorylation sites functionally degenerate or distinct? Biophysical studies of CFTR modulation by pharmacological reagents have led to the conclusion that membrane bilayer properties play a critical role in CFTR function. Pilot studies show that cholesterol, a key lipid component in cell membranes, has a major impact on CFTR function and its response to pharmacological reagents. How does cholesterol affect CFTR? Does it bind to the CFTR protein? Is the effect of cholesterol on CFTR gating secondary to an alteration of membrane fluidity? Is the choleserol-rich microdomain of the cell membrane involved? A multi-disciplinary team with biochemist, biophysicist, bioengineer and molecular biologist has been assembled to tackle these important questions. A variety of techniques will be used including site-directed mutagenesis, cell-attached, excised inside-out and whole-cell configurations of the patch-clamp technique, rapid photorelease of caged cAMP and membrane fluidity measurements with novel molecular rotors. The proposal is aimed to 1) study the molecular basis for phosphorylation-dependent regulation of CFTR function, and 2) investigate the biophysical and biochemical mechanisms for CFTR modulation by cholesterol. A clear picture of how CFTR is regulated by phosphorylation machinery and lipid environment will emerge from our studies. The information obtained will not only facilitate a fundamental understanding of how CFTR functions, but also aid in the development of novel therapeutics for patients with cystic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR STUDIES OF ABC TRANSPORTERS Principal Investigator & Institution: Li, Min; Associate Professor; Physiology; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2002; Project Start 15-JUL-2002; Project End 31-MAY-2005 Summary: (provided by applicant): The ATP-binding cassette (ABC) superfamily proteins are important functional transporters in both prokaryotes and eukaryotes, playing the primary roles in mediating the entry and exit of a variety of molecules, which is essential for growth and regulation. Increasing evidence has shown that the native forms of these membrane-bound proteins are highly organized macromolecular complexes where the molecular composition and functional stoichiometry confer the native biology of these proteins and are dynamically regulated.The long-term objective of the proposed research is aimed at investigating the molecular organization and function of ABC transporting by focusing on cystic fibrosis transmembrane conductance regulator (CFTR). In particular, we will focus on biochemical and functional interactions between the CFTR and its associated proteins. The proposed experiments in this application focus on a group of four previously unknown CFTR-

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Associated proteins (CAPs) that have been purified on the basis of high affinity association with the CFTR protein. The genes encoding these four CAPs have been isolated in our laboratory. The proposed experiments are designed to address their potential molecular and functional roles in the CFTR activities. Through a combination of proposed biochemical, cellular, molecular, and electrophysiological experiments, we wish to obtain important information about the mechanism by which CAPs interact with CFTR as well as the potential functional roles of CAPs in modulation of the CFTR activity. Cystic Fibrosis (CF) is an autosomal recessive disorder caused primarily by mutations of a membrane channel protein known as cystic fibrosis transmembrane conductance regulator (CFTR). The mutations found in CF patients cause changes of both channel activity and subcellular location of the CFTR protein. Interactions between CFTR and other structural and regulatory proteins are essential for its proper function in human. Thus, the knowledge about these various interactions is essential for the full understanding of human diseases caused by the mutated CFTR Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MUC4 MUCIN AND AIRWAY EPITHELIAL REGENERATION IN COPD Principal Investigator & Institution: Voynow, Judith A.; Assistant Prof. of Pediatrics; Pediatrics; Duke University Durham, NC 27706 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): In chronic obstructive pulmonary diseases such as chronic bronchitis, and in cystic fibrosis, the airway epithelium is constantly exposed to neutrophil elastase (NE), an inflammatory protease. The cellular response to NE dictates the balance between epithelial injury and repair. A critical factor in this balance is the activation of the epidermal growth factor receptor (EGFR), a member of the ErbB receptor tyrosine kinase family. Activation of EGFR requires homo- or heterodimerization of the receptor. A major EGFR heterodimerization partner in airway epithelial cells is ErbB2. To date, the only ligand known to activate ErbB2 is MUC4. MUC4 is a major membrane-tethered, respiratory tract mucin with epidermal growth factor (EGF)-like domains. We have made four key observations supporting a critical role for MUC4 in activating the airway epithelial response to NE: (1) NE acts on airway epithelial cells to enhance MUC4 mRNA stability and increase MUC4 protein levels. (2) NE induces tyrosine phosphorylation of EGFR. (3) NE stimulates proliferation of normal human bronchial epithelial cells in serum-free and EGF-free media. 4. MUC4, ErbB2 and EGFR colocalize in injured superficial airway epithelial cells in vivo. These observations support the hypotheses that NE triggers a molecular cascade of events in airway epithelial cells by inducing the production of MUC4, a key regulatory molecule in the cascade, activating ErbB2, and thereby promoting the heterodimerization/activation of EGFR. EGFR activation is a critical prerequisite for epithelial proliferation. The Specific Aims to be tested in this proposal are: (1) To determine whether NE induces MUC4activation of the ErbB2/EGFR receptor tyrosine kinase cascade, resulting in epithelial cell proliferation. (2) To identify the RNA stability domains and RNA-binding proteins regulating NE-induced expression of MUC4, a key molecule in this signaling cascade. (3) To determine the relevance of these signaling pathways in mediating epithelial proliferation in vivo in chronic bronchitis and cystic fibrosis. Our ultimate goal is to use information from this project to identify new biologic targets for rational therapies to induce normal airway epithelial proliferation and differentiation following injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MUCIN SECRETION IN COLUMNAR EPITHELIAL CELLS Principal Investigator & Institution: Kuver, Rahul P.; Medicine; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001; Project Start 15-APR-1999; Project End 31-DEC-2003 Summary: Mucins are high molecular weight glycoproteins which form a viscous gel lining epithelial surfaces forming a physical barrier between the host and the environment. All columnar epithelial cells secrete mucins, as do specialized goblet cells lining the gastrointestinal tract. A mechanistic understanding of mucin secretion has clinical relevance for a number of diseases including cystic fibrosis (CF), inflammatory bowel disease and peptic ulcer disease. Prior work on mucin secretion has been performed in neoplastic cells. Furthermore, much of the knowledge in this field is derived from the study of goblet cells. Whether the same processes apply to nonneoplastic columnar epithelial cells is not known. We propose to employ cystic fibrosis as a disease model to probe structural and functional aspects of mucin secretion in columnar epithelial cells. Thick mucus is a phenotypic hallmark and causes much of the morbidity of CF. Studies by our group and others show a complex relationship between CFTR, the chloride channel defective in CF patients, and the processes by which mucin glyproteins are secreted by columnar epithelial cells. We hypothesize that in CF columnar epithelial cells, post-translational processing of mucin glycoproteins and mucin granule exocytosis are altered. The specific aims are to: 1. Characterize the signal transduction pathways involved in mucin secretion in columnar epithelial cells, and determine whether mucin secretion is dependent on chloride ion movements. 2. Investigate mucin post-translational processing in columnar epithelial cells. 3. Determine whether CFTR is functionally involved in mucous granule exocytosis in columnar epithelial cells. 4. Determine whether isolated mucous granules contain functional CFTR This proposal will provide a structured framework of research training for the candidate. The sponsor's group's expertise in biliary cell biology will ensure a supportive and stimulating environment for the candidate. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MUCOSAL DYSFUNCTION IN REFRACTORY RHINOSINUSITIS Principal Investigator & Institution: Togias, Alkis G.; Associate Professor of Medicine; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001 Summary: Our extensive evaluation of the airways of patients with refractory chronic rhinosinusitis during the previous funding period of this project resulted in an unexpected finding: in comparison to healthy controls, patients with this condition exhibited nasal mucosal secretory hyporesponsiveness upon localized provocation with histamine. The importance of this phenomenon is accentuated by the concomitant observation that the same patients had excessive mucosal inflammation documented in nasal fluid cytology. In the case of perennial allergic rhinitis, anther chronic inflammatory condition, nasal mucosal inflammation would be associated with mucosal hyperreponsiveness. We now propose that secretory mucosal hyporesponsiveness plays a central pathophysiologic role in patients with refractory rhinosinusitis as it may lead to diminished homeostatic and protective mechanisms against environmental insults such as allergens, irritants and infections. The competitive renewal of this project is, thus, designed to identify the functional elements of the mucosa that contribute to reduced secretory responsiveness and to investigate the pathophysiologic importance of this phenomenon. Using the technique of nasal provocation with stimulants that have

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specific actions on various mucosal structures, our first aim is to test the hypothesis that the glandular apparatus is mainly responsible for the observed mucosal dysfunction. In our second aim, we will test whether secretory mucosal hyporesponsiveness is a risk factor for worse outcomes after exposure to inducers of allergic, viral and neurogenic inflammation under experimental conditions, as well as a risk factor for poor treatment outcomes. Our third aim will address the hypothesis that secretory mucosal hyporesponsiveness exhibits familial predisposition. This will be tested by comparing the mucosal responsiveness of the siblings of patients with refractory rhinosinusitis to (a) the siblings of our health control group (b) patients with cystic fibrosis, who invariably suffer from refractory rhinosinusitis and have a well characterized genetic defect, and (c) the patients of patients with cystic fibrosis who are obligate carriers of CFTR mutations. This project is an integral part of the overall Program Project Grant the main hypothesis of which remains that epithelial cell/mucosal dysfunction play a central role in the pathogenesis of chronic rhinosinusitis. This project offers a novel hypothesis on the pathophysiologic mechanism of this condition by focusing around an identified secretory mucosal dysfunction. Establishing such a mechanism may lead to new approaches for the treatment of this major, yet poorly managed, health problem. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NASAL ELECTRIC POTENTIAL DIFFERENCE IN NORMAL AND CYSTIC FIBROSIS PATIENTS Principal Investigator & Institution: Welsh, Michael J.; Professor; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2001; Project Start 01-DEC-2000; Project End 30-NOV-2001 Summary: The goal of this study is to evaluate the significance of the transepithelial voltage across the nasal epithelium in normal subjects, patients with cystic fibrosis (CF), and non-CF patients with bronchiectasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEW INFLAMMATION

THERAPY

FOR

CYSTIC

FIBROSIS

DNA-INDUCED

Principal Investigator & Institution: Mccoy, Sharon L.; Targeted Gene Delivery, Inc. 2611 Sw 3Rd Ave, Ste 200 Portland, OR 97201 Timing: Fiscal Year 2001; Project Start 20-APR-2001; Project End 19-OCT-2001 Summary: (Adapted from the Investigator's Abstract): Cystic fibrosis (CF) is the most common lethal genetic disease in North America, affecting one in every 2500 individuals. Most of the morbidity and over 90 percent of the mortality results from chronic progressive inflammation of the lungs. Current therapies have proven unsuccessful at preventing the ultimate respiratory failure seen in these patients. When instilled into mouse lungs, DNA isolated from the sputum of patients with CF, has recently been shown to induce neutrophil migration, suggesting that CF DNA contributes to inflammation. Targeted Gene Delivery, Inc. has developed a proprietary recombinant protein that binds both bacterial and mammalian DNA. This SBIR Phase I proposal will test in an animal model, the feasibility of using this soluble protein as a treatment strategy to safely and effectively eliminate or reduce CF DAN-induced airway inflammation. The investigators speculate that this proprietary protein will bind to extracellular CF DNA in the airway, preventing CF DNA from binding to immune lung cells, and prevent subsequent induction of an inflammatory response. The company speculates this new treatment strategy, in combination with current anti-inflammatory

80 Cystic Fibrosis

strategies, may in the future prove effective in eliminating the chronic inflammation seen in patients with cystic fibrosis. PROPOSED COMMERCIAL APPLICATION: Targeted Gene Delivery, Inc. holds the exclusive rights to the sequence for a unique DNA binding protein (DNA-R) and for the use of this protein as a soluble receptor molecule to block DNA-induced inflammation. The DNA-R protein offers the opportunity for develoment of a specific product with therapeutic application to reduce or eliminate chronic and progressive DNA-induced lung inflammation seen in patients with cystic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NONINVASIVE VENTILATION IN CHILDREN WITH CYSTIC FIBROSIS Principal Investigator & Institution: Marcus, Carole L.; Professor of Pediatrics; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, PA 19104 Timing: Fiscal Year 2003; Project Start 09-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Cystic fibrosis (CF) is the most common, lifeshortening genetic disease in Caucasians. The vast majority of patients die from cardiorespiratory failure. Although most patients now live into early adulthood, a third will die before their 21st birthday. Noninvasive positive pressure ventilation (NIPPV) has been used effectively to treat respiratory failure in adults with chronic lung disease. However, there have been no controlled, prospective studies of the use of NIPPV in delaying the onset or progression of chronic respiratory failure in children with CF. We hypothesize that early intervention with noninvasive positive pressure ventilation improves daily function and quality of life, and delays the onset of respiratory failure, in patients with cystic fibrosis. Specifically, in children and adolescents with severe CFrelated lung disease treated with NIPPV, compared to matched controls, we predict (1) An improvement in respiratory function, as evidenced by a slower rate of decline of pulmonary function tests, better exercise tolerance, improved ventilatory muscle endurance and improved gas exchange during wakefulness and sleep; (2) An improvement in nutritional and metabolic status, as evidenced by weight gain and a decreased resting energy expenditure; and (3) Improved quality of life, better quality of sleep and a decreased number of pulmonary exacerbations. This study will be the first to use a prospective, randomized, double-blinded design to comprehensively evaluate the effects of NIPPV in pediatric patients with CF. In keeping with the mission of the RFA, this study will use a multidisciplinary approach to improve management and enhance the quality of life in children with chronic respiratory failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NONPARASITIC DRUG DISCOVERY AND DEVELOPMENT Principal Investigator & Institution: Schuster, Brian G.; U.S. Walter Reed Army Inst of Research 503 Robert Grant Ave Silver Spring, MD 20910 Timing: Fiscal Year 2001 Summary: This associate program will provide evaluation of plant extracts and isolated pure compounds for antiviral, anti-cancer, antibacterial, and antifungal activities, CNS and cardiovascular activities, Cystic Fibrosis, Opportunistic infections, Antituberculosis and biochemical and secondary enzyme based evaluation. The AP will also undertake studies and development of Phytomedicines as well as training in host countries. The antiviral assays will be conducted at Southern Research Institute (SRI), Alabama; anti-tumor evaluation at the University of Utah; CNS activity assays will be

Studies 81

based at University of Miami and the Cystic Fibrosis screen at Florida State University. The National Institute of Allergy and Infectious Disease will screen samples for Opportunistic infections while MDS Panlabs will conduct biochemical and enzyme induced assays. Phytomedicine development will be conducted in ICBG laboratories in source countries. The high-volume antiviral pre-screen available at SRI will accommodate the evaluation of approximately 100-200 submitted test materials (natural product extracts/chemical compounds) per year for five years. The anti- tumor test system will include an activity screen using Chinese hamster ovary cell lines as secondary assay for extracts and active fractions. The assays will include a line that is sensitive to killing by agents that produce DNA double strand breaks of topoisomerase II inhibitors and tubulin inhibitors, another line that is sensitive to killing by some alkylating agents, and the third line will be from those that are sensitive to killing by some alkylating agents, and the third line will be from those that are sensitive to bulky DNA adducts such as melphalan or mitomycin C. Enhanced toxicity of an unknown drug towards any of these lines, therefore, will not only suggest a DNA directed mechanism, but suggest the mechanism by which that DNA damage is produced. The third assay under this Associate Program will be the neurochemical and radio- receptor assays which is suitable for high throughput screening for drug discovery and rapid biological profiling of natural products. Research developments in basic preclinical and clinical Neuroscience have catalyzed unprecedented efforts towards the discovery and development of novel CNS drugs which should prove effective for the treatment of neuropsychiatric diseases. The Cystic Fibrosis assays will screen plant material for compounds active in increasing the function of chimeric cystic fibrosis transmembrane conductance regulator (CFTR) reporter gene in yeast. The MDS Panlab will conduct various biochemical and enzyme mechanism based assays aimed at identifying isolated compounds from plant extracts that were found active in the automated receptorbinding assay. The International Centre for Ethnomedicine and Drug Development (Inter-CEED) will coordinate the development and standardization of Phytomedicines and Nigeria in collaboration with select pharmaceutical companies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL PROTEASE FORMULATION BASED ON CROSSLINKED CRYSTALS Principal Investigator & Institution: Shenoy, Bhami C.; Altus Biologics, Inc. 625 Putnam Ave Cambridge, MA 021394807 Timing: Fiscal Year 2003; Project Start 01-JUL-2000; Project End 31-MAR-2005 Summary: (provided by applicant): Design of stable and efficient formulation of proteins for therapeutic use as drugs has been a major focus of biotechnology and pharmaceutical companies. In the Phase I grant, we developed a stable, active formulation of protease from Aspergillus melleus, TheraCLEC-Protease, for use in the treatment of chronic abdominal pain in chronic pancreatitis and also along with TheraCLEC-Lipase and amylase for the treatment of malabsorption as a result of pancreatic insufficiency in cystic fibrosis and chronic pancreatitis. TheraCLEC-Protease exhibited product characteristics superior to commercially available pancreatic enzyme products. TheraCLEC-Protease exhibited a very high level of activity against casein and stability under low pH and towards various proteases present in the intestine. Moreover, in the preliminary investigations, the TheraCLEC-Protease did not show any toxicity. Based on these results in Phase II, we will prepare a drug product prototype for use in the treatment of abdominal pain in chronic pancreatitis and along with TheraCLEC-Lipase for use in the treatment of pancreatic insufficiency, azotorrhea and

82 Cystic Fibrosis

steatorrhea in cystic fibrosis and chronic pancreatitis patients. As a first step, we will crystallize and crosslink the protease with methods developed in Phase I Subsequently, we will mix TheraCLEC-Protease with TheraCLEC-Lipase and amylase for use in a final formulation or alone depending on the disease and type of treatment. The final formulation will be tested for efficacy in digesting proteins and fats in dogs with ligated pancreatic ducts. Using radiolabeled TheraCLEC-Protease, we will follow the lack of absorption into the systemic circulation. In addition, we will test the subacute, subchronic and long-term effects of feeding TheraCLEC-Protease in two species. If successful, a TheraCLEC-Protease prototype will provide an efficient treatment for abdominal pain. TheraCLEC-Protease will be ready to enter clinical trials, and will provide a novel treatment for pancreatic insufficiency in chronic pancreatitis and cystic fibrosis along with TheraCLECLipase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ORAL MULTIDOSE CPX IN ADULT PATIENTS W/ CYSTIC FIBROSIS Principal Investigator & Institution: Ahrens, Richard C.; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2001 Summary: This study is evaluating the pharmacokinetics, safety and efficacy of multiple ascending oral doses of CPX, a new drug in the class of protein repair, in subjects with mild to moderate cystic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ORAL MULTIDOSE CPX IN ADULT PTS W/ MILD TO SEVERE CF Principal Investigator & Institution: Aitken, Moira L.; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001 Summary: Cystic Fibrosis (CF) is a fatal disease caused by a defective gene that encodes for CF transmembrane conductance regulator (CFTR), a glycoprotein important in chloride transport. Approximately 75% of CF patients carry a deletion of phenylalanine from position 508 of the coding sequence for CFTR. This mutant CFTR is incompletely processed within the endoplasmic reticulum with limited transport of nonfunctinal CFTR to the airway epithelial surface, thereby causing defective chloride secretion. "Protein assist" therapy, such as CPX is a new approach to activate chloride secretion via the mutant protein channels. CPX binds with high specificity and affinity to the first nucleotide binding domain of CFTR and restores function to mutant CFTR molecules in vitro. This Phase II study will evaluate the safety and efficacy of multiple ascending oral doses of oral CPX in adults with CF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ORAL MULTIDOSE CPX IN ADULTS WITH CYSTIC FIBROSIS Principal Investigator & Institution: Wohl, Mary E.; Children's Hospital (Boston) Boston, MA 021155737 Timing: Fiscal Year 2001 Summary: This study is a randomized, double-blind, placebo-controlled, ascending oral multi-dose study to evalute the efficacy, safety and pharmacokinetics of CPX administered to adult patients with mild to moderately severe cystic fibrosis.

Studies 83

Background: Cystic fibrosis is the most common, fatal, autosomal recessive disease affecting the Caucasian population. Overall, 5% of Caucasians in the U.S. are heterogeneous for the defective gene responsible for the disease. The disease is caused by a single defective gene or chromosome 7 that codes for a 1480 amino acid protein called cystic fibrosis transmembrane conductance regulator (CFTR). The manifestations of cystic fibrosis in the lung are characterized by thickened airway secretions that result from abnormal epithelial ion transport. The abnormality is based on defective cyclic adenosine monophosphate (cAMP) mediated C1- secretion, which is exacerbated by physiological Na absorption. Paracellular water transport in the airways is consequently reduced. The resulting lumenal dehydration is thought to be a damage signal to the pulmonary epithelium causing increased mucin secretion. The water-poor lumen environment itself induces an abnormal physical state of the secreted mucins. The result is a vicious cycle leading to an accumulation of excessively viscous mucus, bacterial overgowth, and infection. Although cystic fibrosis is a whole body disease manifesting in different ways throughout the body as a dysfunction of epithelial cells, it is usually the lung problem that is principally responsible for the invariably fatal outcome of this illness, for which there is currently no cure. Cystic fibrosis protein-repair therapy is a new approach using drugs to restore function to mutant CFTR molecules. The concept that it might be possible to activate mutant CFTR resident in the cystic fibrosis cell has rreceived support from a number of recent experiments. CPX is a new drug in the class of protein-repair therapeutics which may interact directly with the CFTR. CPX was discoverd by Harvey Pollard, M.D., Ph.D. and Kenneth Jacobson, Ph.D. of the National Institute of Diabetes and Digestive and Kidney Disorders (NIDDK) of the National Institutes of Health (NIH). CPX, an A1-receptor antagonist binds with high specificity and affinity to the nucleotide-binding fold (NBF) at position 508 in the first NBF domain (NBF-1) of F508 mutant CFTR, and activates outward chloride currents from primary cultures of cystic fibrosis human airway cells. Pollard et al hypothesized that compounds which bind to CFTR close to the F508 location should induce a local conformation that could affect protein-lipid interactions, and might affect the trafficking, maturation and overall level of CFTR in the cell. CPX is the only cystic fibrosis drug in clinical development that promotes CFTR trafficking and stimulates chloride ion transport. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OSMOTIC REGULATION OF MACROPHAGES IN CYSTIC FIBROSIS Principal Investigator & Institution: Riches, David Wh.; Professor and Division Head; National Jewish Medical & Res Ctr and Research Center Denver, CO 80206 Timing: Fiscal Year 2001; Project Start 15-SEP-2000; Project End 31-JUL-2004 Summary: (adapted from the application): It has been proposed that in cystic fibrosis, the defective cystic fibrosis transmembrane regulator (CFTR) gene is responsible for hypersecretion and/or malabsorption of NaCl in airway epithelia leading to marked elevations in NaCl in airway surface liquid (ASL). Previous studies from this investigative team have shown that the pro-inflammatory chemokine, IL-8, is produced by macrophages in CF at an early age thereby contributing to neutrophil accumulation in the airways. In this proposal, the investigator addresses the mechanism by which osmolality may regulate macrophage function in CF. In preliminary studies, he has shown that changes in osmolality greatly potentiate pro-inflammatory chemokine production by macrophages, as well as by potentiating monocyte apoptosis. The goals of this proposal are to investigate the mechanisms by which hyperosmolality changes monocyte and macrophage function. The investigator hypotheses that increased

84 Cystic Fibrosis

chemokine production will result in increased neutrophil presence in the airways, while increased monocyte apoptosis will remove an important vehicle of neutrophil clearance. These goals will be addressed by three specific aims. Specific Aim 1 will address the mechanism of potentiation of IL-8 production by modest hyperosmolality and test the hypothesis that the mechanism involves JNK activation, AP-1 transactivation, and a hyperosmolality responsive element in the IL-8 promoter. Specific Aim 2 will investigate the mechanism of increased apoptosis in the presence of modest hyperosmolality. Based on preliminary findings, the investigator hypothesizes that the mechanisms will involve concurrent activation of p38 MAP kinase and inhibition of pro-survival signals conferred by either p42 ERK and/or Akt. Specific Aim 3 will investigate the proinflammatory chemokine production and apoptosis in a relevant in vivo model of CF airways involving bronchial epithelial cell xenografts in nude mice using epithelial cells from normal and CF-lungs. These studies are expected to provide novel, important insights into the role of the defective CFTR in promoting pulmonary inflammation in cystic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FIBROSIS

OVERCOMING

NUTRIENT

MALABSORPTION

IN

CYSTIC

Principal Investigator & Institution: Clark, William A.; Yasoo Health, Inc. 2109 W Market St, Ste 122 Johnson City, TN 37602 Timing: Fiscal Year 2001; Project Start 25-SEP-2001; Project End 31-DEC-2002 Summary: In cystic fibrosis (CF), pancreatic insufficiency and a diminished bile acid pool cause malabsorption of vitamin E, carotenoids and other fat-soluble antioxidants, which contributes to resulting oxidative stress and poor nutritional status, both of which are associated with increased risk of disease, neurological dysfunction and reduced quality of life. The object of this study is to determine the feasibility of using an oral liquid formulation of micellar-like vehicles to overcome malabsorption of important nutrients and antioxidants and therefore improve oxidation and nutrition status. The researchers intend to study a unique generally regarded as safe (GRAS) molecule as the delivery vehicle for fat-soluble nutrients and antioxidants. The formulation will be optimized for physical and chemical stability, and for taste acceptable to children and young adults. Although tested first in cystic fibrosis patients, this technology could be useful to other fat malabsorbers. The technology is based on d-alpha-tocopheryl polyethylene glycol 1000 succinate or TPGS. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PAMIDRONATE ON BONE DENSITY IN PATIENTS WITH CYSTIC FIBROSIS Principal Investigator & Institution: Aris, Robert; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATHOGENEISIS OF CYSTIC FIBROSIS IN THE GI SYSTEM Principal Investigator & Institution: Delisle, Robert C.; Associate Professor; Anatomy and Cell Biology; University of Kansas Medical Center Msn 1039 Kansas City, KS 66160

Studies 85

Timing: Fiscal Year 2001; Project Start 01-MAR-2000; Project End 31-JAN-2004 Summary: The long-term objective is to understand how loss of functional CFTR (the cystic fibrosis transmembrane regulator) affects expression and post- translational processing of sulfated glycoconjugates and the role of these altered glycoproteins in the development of cystic fibrosis (CF). High levels of sulfated glycoconjugates with abnormal post-translational processing are believed to contribute to obstruction in the pancreas and intestines, and digestion and absorption of nutrients is abnormal in CF. The model mucin-like sulfated glycoprotein Muclin will be used to explore these issues. Muclin is over-expressed in the pancreas and small intestine of CFTR (-/-) mice, and immunolocalization of Muclin in these tissues shows that it is associated with protein plugs in the acinar lumen and mucin plugs in the intestinal crypt lumen. The hypothesis is that in the absence of functional CFTR, mucin-like glycoconjugates, such as Muclin, are over-expressed and have altered post-translational processing. They then contribute to the deleterious accumulation of protein aggregates in the lumina of the pancreatic acini and small intestinal crypts. The following specific aims will be addressed. 1. To test the hypothesis that post-translational processing of Muclin is altered in the absence of CFTR in epithelial cells which normally express CFTR, i.e., the intestinal crypt cell, and to determine the mechanism of this change. The carbohydrate structure and protein core size of Muclin in normal and CF intestine will be determined. 2. To test the hypothesis that excess Muclin alters the protein secretory pathway in gastrointestinal tissues of CF mice. Pancreatic secretions will be studied in vivo and in vitro in normal and CF mice, and the effect of pH on the interaction of Muclin with zymogens will be assessed. Also, the luminal pH of secretory compartments in CF and normal cells will be measured to test whether CFTR has a functional role in pH gradients in the cell. 3. To test the hypothesis that abnormal acidity in the intestine mediates CF pathogenesis and the over-expression of Muclin. Pathology and Muclin expression will be compared in CF mice, and CF mice crossed with gastrin deficient mice (lack gastric acid secretion) to normalize intestinal Ph. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHASE II STUDY TO EVALUATE DMP777 IN ADULTS WITH CYSTIC FIBROSIS Principal Investigator & Institution: Jain, Manu; Northwestern University Office of Sponsored Programs Chicago, IL 60611 Timing: Fiscal Year 2001 Summary: Cystic Fibrosis (CF) is a common inherited life-threatening disease affecting approximately 20,000 individuals in the United States. The defective gene in CF encodes for a protein termed the cystic fibrosis transmembrane regulator (CFTR). CFTR function results in ofrmation of thick adherent viscous mucus, which causes luminal obstruction in the lungs and eventual organ damage. The development of mucus stasis contributes to impaired bacterial clearance and creates a microenvironment conducive to bacterial proliferation. This provides stimulus to recruitment and activation of polymorphonuclear leuckocytes (PMNs) in the airways. The PMNs release massive quantities of of toxic substances onto the epithelial surface, which has dual effect of damaging the airway and recruiting additional PMNs. The most important PMN derived substance is felt to be neutrophil elastase. DMP 777 is a compound that inhibits neutrophil elastase within the intra and extracellularly. Phase 1 studies have indicated that the drug is well tolerated in normal patients. The goal of this study is to administer various doses of DMP777 to CF patients over the age of 18, and measure the

86 Cystic Fibrosis

pharmacokinetic and pharmacodynamic characteristics using timed serum samples. The drug will be administered for 9 days and patients will be monitored for signs of toxicity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHASE II TRIAL OF INS365 IN ADULT/PEDIATRIC CF PATIENTS Principal Investigator & Institution: Beck, Sue; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001 Summary: INS 365 is a new molecule under study as an inhaled medication to impreve chloride and water transport and lung mucus clearance. It may also increase mucus clearance by increasing the rate at which the cilia (little hair-like fibers lining the airways) beat to push the mucus out. The purpose of this study is to evaluate the safety of a single dose of INS365 delivered by inhalation from a nebulizer to adults and children with Cystic Fibrosis. The highest dose that can be tolerated will be determined. The effect of INS365 on the amount of sputum produced will also be measured. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHASE IIA MULTIPLE DOSE ESCALATION STUDY TO EVALUATE LUNG SPECIFIC/DMP 777 Principal Investigator & Institution: Sheils, Catherine; Children's Hospital (Boston) Boston, MA 021155737 Timing: Fiscal Year 2001 Summary: Multicenter, randomized, double-blind, placebo-controlled, dose-escalation study. Following a screening period, patients will begin a treatment period during which they will be entered into one of six cohors. Cystic fibrosis (CF) is a common inherited life-threatening disease affecting approximately 20,000 individuals in the U.S. and 50,000 worldwide. CF is inherited in a classic Mendelian autosomal recessive pattern with an estimated incidence of 1:2500 Caucasian births. The pharmacokinetic (PK) and pharmacodynamic (PD) attributes of DMP 777 as shown in animals may be beneficial in the treatment of CF lung disease. DMP 777 is a potent inhibitor of polymorphonuclear leukocytes elastase located both within he azurophilic granules of viable cells and extracellularly following release at tissue sites of activation. Specific Aims: 1) To evaluate safety and tolerability of multiple oral doses of DMP 777 administered at six different dose levels 2) To determine PK and PD characteristics of multiple oral doses of DMP 777 administered at six different dose levels and/or regimens 3) To define DMP 777 dosage levels necessary to achieve sustained high-level systemic neutrophil elastase inhibition as determined by measurements of circulating PMN-lysate AAPVase inhibition and whole blood urea fragment formation obtained at both peak and trough concentrations of parent compound, in a selectively defined cohort of patients with cystic fibrosis following oral administration of DMP 777 for 9 days duration (twice or thrice daily). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHENOTYPIC DETERMINANTS OF MURINE CHOLELITHIASIS Principal Investigator & Institution: Carey, Martin C.; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2002; Project Start 01-SEP-1998; Project End 31-JUL-2005

Studies 87

Summary: (provided by applicant): Progress in understanding cholesterol gallstone formation in inbred mice has led to new and continuing specific aims, which are mostly extensions of the previous grant. The principal experimental goals are to identify, characterize and quantify the molecular pathophysiologies and phenotypes involved in murine gallstone formation, particularly those caused by cholesterol gallstone (Lith) genes. Aim I proposes to determine the critical pathophysiological changes that are induced by genetic susceptibility within newly-identified quantitative trait loci (QTL) in genetically-diverse inbred mouse strains. This information will be crucial for identifying positional candidate genes for selected QTL's. Aim 2 will determine whether the proximal biliary tree plays a decisive role in bile lithogenicity and cholesterol gallstone susceptibility induced by the Lith1 locus and establish whether blocking cholehepatic shunting of bile salts prevents cholelithogenesis. Aim 3 will examine efflux transporters and their regulation at the enterocyte level as causes of the augmented cholesterol absorption from the intestine of gallstone-susceptible inbred mice. Aim 4 will investigate the pathogenesis of cholesterol cholelithogenesis in mice with targeted disruption of the cholecystokinin (CCK)-A receptor and carboxypeptidase E, the latter intracellular enzyme processing pro-CCK to CCK; it is anticipated that in addition to biliary dysmotility, there will be small intestinal hypomotility leading to augmented lumenal cholesterol absorption. Aim 5 will elucidate the pathogenesis of pigment gallstones in murine models of cystic fibrosis. The hypothesis predicts a less alkaline bile within the intrahepatic biliary tree and gallbladder with enterohepatic cycling of unconjugated bilirubin from bile salt malabsorption, the latter speculated to be secondary to apical sodium-bile salt co-transporter (ASBT) dysfunction. As a result of a more acidic bile, there will be increased endogenous ?-glucuronidase activity intrahepatically, as well as in the gallbladder, with augmented hydrolysis of bilirubin conjugates resulting in calcium bilirubinate precipitation, thereby leading to "black" pigment gallstones, as well as intrahepatic microprecipitates causing mechanical bile duct obstruction. Because of the close genetic correspondence between mammalian genomes, these pathophysiological studies should lead to more fundamental understanding of these common, as well as economically-significant digestive diseases in human beings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHENYLBUTRATE THERAPY FOR CYSTIC FIBROSIS Principal Investigator & Institution: Zeitlin, Pamela L.; Professor of Pediatrics; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001 Summary: Over 700 unique mutations have been found in the cystic fibrosis gene, and they can be classified in five general categories with respect to the cystic fibrosis transmembrane conductance regulator protein (CFTR). Therapy can now be addressed in a genotype-specific manner, and a new term has been coined to describe the novel concept- "protein-repair therapy." The goal of this project this project is to develop protein- therapy for CF using a unique class of short chain fatty acid compounds that regulate gene expression. The delta508 mutation is present in over 70% of CF chromosomes and is a prototype Class II mutation, a so-called trafficking mutation. Because delta508 is also a partial conduction mutation, correction of the trafficking arrest should lead to improvement in epithelial chloride transport because the mutant channel conducts chloride. The hypothesis of this grant is that the butyrate compounds, specifically 4-phenylbutyrate (4-PBA), will correct the biosynthetic arrest in delta508 expression by regulation of endogenous chaperone molecules in the endoplasmic. Preliminary data will be presented, supporting a role for 4-PBA in regulating an

88 Cystic Fibrosis

important chaperone protein gene (Hsc70), thereby significantly increasing trafficking of delta508 protein in vitro. Part I of this grant explores the physiologic events surrounding the transfer of the mutant protein from the protein synthetic to degradative pathway. Aim 1 is to study the interaction of 4-PBA and related butyrates with the biosynthesis and processing of delta508 in vitro in CF airway epithelial cell lines. Quantitative measurement of protein production, protein degradation (ubiquitinated ATP-dependent and independent degradation) and post- translation (molecular chaperoning) processing will be studied in the context of chaperone proteins. Part II examines the butyrate regulation of events at the level of gene regulation and mRNA production; Aim 2 is to study the molecular biology of butyrate regulation of trafficking. Butyrate-sensitive sequences in the human CFTR and Hsc 70 promoters will be identified by reporter gene assays, electrophoretic mobility shift assays and DNAS footprinting. Butyrate-sensitive inducers and inhibitors and histone acetylation will be examined in detail. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHENYLBUTYRATE THERAPY FOR CYSTIC FIBROSIS--DOSE EFFECTS Principal Investigator & Institution: Choo-Kang, Lee; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2001 Summary: This is a clinical trial to determine whether a new FDA-approved oral drug (approved for rare metabolic diseases) could be used to treat CF patients. This drug, phenylbutyrate, may be able to restore normal chloride ion movements in body organs and glands. We would like to see whether high doses of this drug would be safe and work by restoring normal levels of chloride ion transport in a dose-dependent manner. We also would like to see how the CF patient absorbs, breaks down, and excretes the drug from the body. This is a Phase I dose escalatoin and safety study which means that we will enroll patients in the lowest dose first and then enroll additional people at higher doses into dose-limiting toxicity (serious side effects) is uncovered. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHYSIOLOGIC MEMBRANE TRAFFIC REGULATION: INTESTINAL CFTR Principal Investigator & Institution: Ameen, Nadia A.; Pediatrics; University of Miami Box 016159 Miami, FL 33101 Timing: Fiscal Year 2002; Project Start 15-MAR-2002; Project End 30-JUN-2002 Summary: This proposal addresses critical issues that will directly influence the treatment of two important gastrointestinal diseases: cystic fibrosis (CF) and secretory diarrhea. Both diseases target the small intestine and are linked by the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Current information implicates up-regulation of CFTR in the pathogenesis of secretory diarrhea and downregulation in CF pathogenesis. Nonetheless, the mechanisms that regulate CFTR are still poorly understood. Though cAMP and cGMP- dependent phosphorylation regulates CFTR, membrane traffic also regulates CFTR and appears to be important to the pathogenesis of both secretory diarrhea and CF. However, the physiologic role of this potentially important mechanism remains unknown. Studies testing the role of CFTR membrane traffic and its role in the regulation of anion secretion using cultured cells are conflicting. Furthermore, little has been done to understand the role of this important protein using natural endogenously CFTR-expressing tissues. This proposal will employ

Studies 89

morphologic and biochemical cell biologic techniques in conjunction with electrophysiology and natural intestinal tissues to determine a role for membrane traffic in regulated CFTR and other potential alternate chloride channels and anion transport. Studies will primarily be performed in rat because of the similarity in intestinal distribution of CFTR to the human. These investigations will be complemented by studies in the normal and CF human intestine, and transgenic CFTR mouse intestinal tissues. Light and electron microscopic immunolocalzation techniques will identify the cell-specific sites of CFTR membrane traffic and chloride secretion. Functional biochemical techniques such biotinylation/immunoprecipitation will complement morphologic studied to investigate a role for membrane traffic. The studies and approaches outlined in this proposal are designed to achieve several goals: first to understand processes relevant to human physiology and disease pathogenesis, second to provide therapeutic avenues to correct defective traffic in CF and secretory diarrhea and third to use these skills to develop a career as an independent clinician scientist. This will be achieved by a comprehensive program to acquire both technical and intellectual skills from a cadre of distinguished and outstanding mentors and to draw on the scientific environments of various disciplines both in her home based institution and outside centers of excellence in related field of study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PILOT STUDY--SYNTHESIS TRANSMEMBRANE SEGMENTS

AND

ASSEMBLY

OF

CFTR

Principal Investigator & Institution: Deber, Charles M.; Hospital for Sick Chldrn (Toronto) 555 University Ave Toronto, Timing: Fiscal Year 2001 Summary: The Cystic fibrosis transmembrane conductance regulator (CFTR) is the membrane protein product of the gene known to be defective in cystic fibrosis patients. CFTR functions by transporting chloride ions through a transmembrane (TM) domain believed to consist of two sets of six tightly packed and assembled membrane spanning helical segments (TM1-6, TM7- 12, ca, 20 amino acids each). However, channel remain to be deduced in molecular terms. (1) Since packing of TM domains appears to be directed by specific recognition elements contained within the individual TM segments, and the N-terminal portion of CFTR (TM1-6) is known to form a functional channel, we propose to prepare a series of peptides based on the native sequences of the CFTR TM domain segments 1-6 by solid-phase synthesis, and to determine the affinities of the individual TM segments for each other. Individual TM segments will be combined in combinations (e.g., TM5-6, TM6-1, TM1-2, etc.).Affinities would be quantitated by fluorescence energy transfer, circular dichroism spectroscopy, and gel electrophoresis. These experiments will be supported by molecular modeling to identify favorably- packed helical dimers of CFTR helices, and by channel conductance measurements performed on CFTR TM peptides individually and in combinations. Pairs found to have affinity of dimerization would likely be in direct 3-D contact in the native channel. (2) An increasing number o missense mutations within the CFTR TM domain are now being associated with CF disease. We reason that certain 'high-information' residues impair channel function by interfering with helix-helix packing. Peptides prioritized to key TM-domain mutations observed in genotyped CF patients from the in-house database at the Hospital for Sick Children (e.g., G85E, R347H, R347W) ill be prepared and studied as above in combinations with wild type partners. From the combined information thus obtained, we will construct a working model for the molecular geometry of the CFTR channel, and use the epidemiological data to generate hypotheses concerning possible

90 Cystic Fibrosis

relationships between severity of CF disease and molecular defects in the corresponding mutant CFTR's. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PILOT--INDUCTION OF T CELL TOLERANCE TO ANTIVIRAL VECTOR Principal Investigator & Institution: Zhou, Tong; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2002 Summary: Description (adapted from the application): An unsolved problem in adenovirus-based gene therapy is the elicitation of an immune response that rapidly eliminates infected cells and ablates transgene expression. Although deletion of certain antigenic structure from the adenovirus improves the prolongation of transgene expression, the immune response and the subsequent tissue inflammation remain major problems in the application of adenovirus based gene therapy. Thus, it is both reasonable and desirable to design an immunointervention strategy to induce specific immune tolerance to the adenoviral vector. The overall goal of this application is to test an innovative strategy to induce specific tolerance by syngeneic antigen presenting cells (APCs) that express Fas ligand. The central hypothesis is that when the APCs present adenoviral antigens to the responding T cells, high levels of Fas ligand expression by these APCs would induce apoptosis of adenovirus specific T cells. Thus, exposure of host to adenoviral vector infected APCs expressing Fas ligand would lead to depletion of a specific T cell population, and therefore induce immune tolerance to the adenoviral vector. The decreased immune response to the adenoviral vectors would protect the transfected host cells from T cell attack and prolong transgene expression. Moreover, if transgenic products are immunogenic, then T cell tolerance can be induced in a similar manner. To test this hypothesis, we will first determine whether immune tolerance to adenoviral vectors can be specifically induced by adenoviral antigen presenting cells that express Fas ligand; and then determine whether treatment with adenoviral antigen presenting cells that express Fas ligand improves the efficacy of adenoviral gene therapy in an animal model of cystic fibrosis. The present application will introduce a novel and powerful immunointervention strategy into adenoviral vector based gene therapy designed to inhibit the inflammatory response and prolong transgene expression. The accomplishment of this application might improve adenoviral gene therapy in the treatment of cystic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PILOT--POTASSIUM CHANNEL PROPERTIES OF AIRWAY CELLS Principal Investigator & Institution: Devor, Daniel C.; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001 Summary: Cystic fibrosis (CF) is characterized by both a hyper-absorption of Na+ as well as a diminished or absent CI secretory response to cAMP-mediated agonists. Based on thee observations, three distinct pharmacological approaches have been explored. These include inhibitor of Na+ transport, activation of CFTR by direct pharmacological agonists and activation of alternative conductances that may circumvent the primary CF defect. Based upon the requirement for electrical coupling between apical and basolateral membranes to sustain either Na+ absorption of CI-secretion regulation of a basolateral membrane K+ conductance is a requisite to the maintenance of these ion

Studies 91

transport processes. The Na+ (EnaC) and Cl-(CFTR) channels involved in these processes have been cloned and studied extensively. However, the potassium channels critical to the maintenance of the electrochemical driving force for Na+ absorption and CI-secretion have not been identified at the single channel level nor he they been molecularly identified. An understanding of these potassium channels is critical to defining ion transport across the human airway. Our preliminary studies suggest that these K+ channels represent the resting conductances of the airway cells. We propose to characterize thee potassium channels in both primary cultures of human bronchial epithelial (HBE) and the serous cell line, calu-3 using whole-cell and single-channel patch-clamp techniques. We hypothesize that the recently cloned family of two pore domain K+ channels re responsible for these conductances. These channels have been shown to be constitutively active when heterologously expressed and are believed to present background or resting K+ conductances in cells. We will then use a RT-PCR based approach to amplify the two pore-domain class of potassium channels from HBE and calu-3 cells which we hypothesize are critical to these ion transport processes. Once these clones are identified we will use antisense oligonucleotides to selectively knockout these conductances and determine their effects on ion transport across HBE and calu-3 cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PILOT--PROLONGING GENE EXPRESSION BY RNA REPLICATION Principal Investigator & Institution: Ball, L A.; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2002 Summary: Description (adapted from the application): The goal of this pilot project is to explore the potential of RNA replication for prolonging the synthesis of messenger RNAs in the context of gene therapy for cystic fibrosis. RNA replication will be catalyzed by the RNA-dependent RNA polymerase that is encoded by one of the nodaviruses, a family of small, spherical, RNA viruses of insects, with bipartite singlestranded RNA genomes. The larger segment of the viral genome replicates autonomously when introduced into a wide variety of cells, and also supports the replication of other RNAs that carry appropriate cis-acting signals. In recent work, we used a hormone-inducible RNA polymerase II promoter to initiate vigorous RNA replication from the nuclei of cultured cells transfected with the RNA replicase cDNA. We have now designed self-contained DNA cassettes to launch replication of the mRNAs for several different reporter genes. The levels and duration of reporter gene expression will be compared with and without mRNA replication, in cultured cells and in the lungs of mice, thereby allowing us to determine the contribution of RNA replication to the abundance and longevity of gene expression in these two situations. Finally, we will attempt to achieve the replicative amplification of CFTR mRNA in this system and examine its expression in cultured cells, including primary airway cells from CF patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PILOT--SILENCING OF TRANSGENES BY HISTONE DEACETYLASE Principal Investigator & Institution: Townes, Tim M.; Professor and Chairman; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2002

92 Cystic Fibrosis

Summary: Description (adapted from the application): Approaches to cystic fibrosis gene therapy include the use of vectors derived from adeno-associated virus and murine or other retroviruses. These vectors are of particular interest because of their potential for long-term expression and/or integration in host chromosomes. Duration of expression from murine retroviral vectors is limited by host inactivation of transgenes carried by these viral constructs. The silencing of integrating viral DNA occurs over weeks to months in both epithelial and non-epithelial cells. We have determined that part of the mechanism underlying inactivation of adeno-associated viral vectors involves selective deacetylation of vector DNA. Not all integrating AAV vectors are silenced. In non-selected cells, approximately 80% of integrated viral genomes in HeLa cells, and 50% in K562 (erythroleukemia cells) were inactivated by this process. Treatment with Trichostatin A (3: M), a specific inhibitor of histone deacetylase, reactivated transgene expression in a fashion that did not appear to be either promoter or cell type specific. In this pilot project, we will examine the duration and efficiency of reporter gene transfer by AAV and MuLv to airway epithelial cell lines and primary airway epithelial cells taken from cystic fibrosis patients. We will evaluate the nature of integration events in unselected, AAV-infected cells and relate this data to the gene silencing that occurs. Integration with recombinant AAV vectors is not fully understood in human airway epithelial cells, but many studies are in progress to optimize integration and/or episomal persistence with this type of vector. By studying nonselected cells after AAV or MuLv gene transfer, we will examine the frequency and nature of AAV constructs that do integrate, and help characterize the mechanism by which integrated genomes are silenced in primary human lung cells. In addition, we will test the efficiency of gene transfer using AAV vectors in a mouse model, and determine whether histone deacetylases participate in transgene inactivation of AAV in mammalian airways in vivo. The reactivation of silenced, virally transduced genes has implications for gene therapy. Efficient gene transfer followed by drug treatment to relieve suppression may provide a powerful combination treatment for various genetic and infectious diseases. The purpose of this Pilot and Feasibility Project is to test the safety and efficacy of compounds capable of augmenting histone hyperacetylation for possible effects in the setting of gene transfer to airway epithelial cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PK OF LIQUID IBUPROFEN IN INFANTS, TODDLERS AND PRESCHOOLERS W/ CYSTIC FIBROSIS Principal Investigator & Institution: Cropp, Gerd; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PREDICTING DEATH IN CF PATIENTS AWAITING LUNG TRANSPLANT Principal Investigator & Institution: Belkin, Richard A.; Pediatrics; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2003; Project Start 23-JAN-2004 Summary: (provided by applicant) The traditional referral guidelines for lung transplant in CF are largely based on a FEV <30% predicted. The optimal timing for referral has not been determined. Other factors may be important in predicting the risk of death in these

Studies 93

patients. The presence of emerging infectious CF pathogens may be associated with a higher risk of death. These factors have not been tested in other studies. The identification of the above variables as risk factors for death may be used to modify the referral process or pre-transplantation therapy and improve survival of CF patients awaiting transplantation. We propose to perform a three-center retrospective cohort study, with the following aims: (1) determine the association of emerging CF pathogens (including Aspergillus spp. And MRSA) pretransplant with mortality while awaiting lung transplantation: before and after referral for lung transplantation, (2) determine the association of poor nutritional status (including shorter height) pretransplant with mortality while awaiting lung transplantation (3) determine the association of poor pulmonary function (including % predicted FEV1) pretransplant with mortality while awaiting lung transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROSPECTIVE DETERMINATION OF COMPUTED TOMOGRAPHY IN CYSTIC FIBROSIS Principal Investigator & Institution: Bowman, Michael; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, CA 90033 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MUCOIDY

PSEUDOMONAS

IN

CYSTIC

FIBROSIS--REGULATION

OF

Principal Investigator & Institution: Deretic, Vojo P.; Professor; Microbiology and Immunology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2001; Project Start 01-FEB-1992; Project End 04-SEP-2001 Summary: Pseudomonas aeruginosa conversion to mucoid phenotype plays a critical role in the establishment of chronic respiratory infections in cystic fibrosis (CF) which are responsible for the high morbidity and mortality in this disease. Conversion to mucoidy is controlled by the algU mucABCD locus. The algU gene is a positive regulator of mucoidy and encodes an equivalent of the extreme that shock sigma factor RpoE from enteric bacteria. This strongly suggests a connection between the extreme stress response and conversion of P. aeruginosa to mucoidy. The goal is of this proposal are: i) to delineate the molecular mechanism of conversion to mucoidy in P. aeruginosa; ii) to investigate the role of the stress system that controls mucoidy and possibly additional aspects of P. aeruginosa virulence; and iii) to assess the contributions of mucoidy and co-regulated systems to the pathogenic processes during chronic respiratory infections in CF. The following studies will be carried out: i) AlgUdependent transcription of the critical biosynthetic and regulatory genes necessary for the production of and oxidative stress response will be established; ii) MucA (or MucB) activity as an anti-IgMa factor or inhibitor of AlgU activity will be investigated and additional mutations and genes causing conversion to mucoidy will be characterized; iii) the proteins and genes that are controlled by AlgU and induced by stress or overexpressed in muc mutants will be analyzed by metabolic labeling, 2D gel analysis, and expression technology based on green fluorescent protein; iv) the role of AlgUdependent systems in P. aeruginosa pathogenesis in acute and chronic infections will be investigated by: (a) comparing the isogeneic algU+ and algU null strains for their

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susceptibility to killing with reactive oxygen intermediates and by phagocytic cells; (b) determining virulence of isogeneic exposed to P. aeruginosa aerosols; and (c) analyzing AlgU-dependent immunoreactive proteins using sera from CF patients. These studies will provide a complete model of the molecular mechanisms which govern conversion to mucoidy and develop a comprehensive view of the role that the extreme stress sigma factor AlgU plays in P. aeruginosa virulence and pathogenesis in CF with implications for pharmacological or immunological intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PSEUDOMONAS PRODUCTS, OXYGEN RADICALS, AND LUNG INJURY Principal Investigator & Institution: Britigan, Bradley E.; Professor; Internal Medicine; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2001; Project Start 01-DEC-1993; Project End 30-NOV-2003 Summary: Pseudomonas aeruginosa causes acute nosocomial pneumonia as well as chronic lung infections in cystic fibrosis patients. The mechanisms responsible for the resulting lung injury remain unclear. Formation of oxidant species such as superoxide and hydrogen peroxide are associated with many forms of lung injury. During the initial funding period of this program, we obtained evidence that three compounds actively secreted by P. aeruginosa damage pulmonary epithelial and endothelial cells via oxidant production. In the next funding period we will define the cellular mechanisms of action of redox cycling. This results in superoxide and hydrogen peroxide generation. Pyocyanin causes a host of deleterious effects on cellular functions both in vitro and in vivo. In spite of this, there is only limited data on the cellular events by cells. Furthermore, the site(s), mechanism(s), and nature of the oxidants produced by pyocyanin, as well as the cellular targets are also poorly understood. We hypothesize that the complex series of effects mediated by pyocyanin occur through its ability to induce site specific oxidant production which leads to the disruption of cellular energy generation and activation of oxidant sensitive signaling pathways. To test this hypothesis three specific aims will be accomplished. Aim 1 is to identify the mechanism(s) of epithelial cell acquisition, cellular trafficking, and metabolism of pyocyanin under in vitro conditions. Aim 2 is to determine how pyocyanin deplete epithelial cells of ATP and cAMP by defining the effects of pyocyanin on oxidative phosphorylation and glycolysis. This aim will also address if pyocyanin acts on oxidantregulated signaling pathways, IL-8 expression will serve as a model system. The first two aims will use an in vitro system of polarized epithelial cell monolayers using normal and CF cells. Aim 3 will examine the extent to which the in vitro effects of pyocyanin are observed occur under in vivo conditions. This work will focus on IL-8 release and utilize xenografts of human respiratory epithelial cells in SCID mice. These studies will use state of the art technique of cell biology and oxidant chemistry to define novel and previously unexplored mechanisms whereby P. aeruginosa may contribute to acute and/or chronic lung injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PULMONARY BENEFITS OF CYSTIC FIBROSIS NEONATAL SCREENING Principal Investigator & Institution: Farrell, Philip M.; Pediatrics; University of Wisconsin Madison 750 University Ave Madison, WI 53706 Timing: Fiscal Year 2001; Project Start 01-AUG-1985; Project End 31-MAR-2006

Studies 95

Summary: Although cystic fibrosis (CF) is the most common, life-threatening autosomal recessive genetic disorder of the white population, there are often delays in diagnosis and hence initiation of treatment. Advances of the past two decades have made CF screening feasible using routinely collected neonatal blood specimens and determining trypsinogen levels and CF mutations by DNA analyses. Our overall goal is to address the following hypothesis: Early diagnosis of CF through neonatal screening will be medically beneficial without major risks. "Medically beneficial" refers to better nutritional and/or pulmonary status, whereas "risks" include laboratory errors, potential iatrogenic medical sequelae, miscommunication or misunderstanding and adverse psychosocial consequences. Specific aims include assessment of the benefits, risks, costs, quality of life, and cognitive function associated with CF neonatal screening and delineation of the characteristic epidemiologic features of CF. A comprehensive, randomized clinical trial emphasizing early diagnosis as the key variable has been underway since 1985. Nutritional status has been assessed by anthropometric and biochemical methods, and the results have demonstrated significant benefits in the screened group. Answering the important questions about pulmonary outcome will require five more years of follow-up evaluation focused on lung function measures and quantitative chest radiology, including high resolution computerized tomography. If the questions underlying this study are answered favorably, it is likely that neonatal screening using a combination of trypsinogen and DNA tests will become the routine method for identifying new cases of CF and that diagnosis in early infancy will allow prevention of many clinically-significant problems such as malnutrition. If CF neonatal screening is implemented nationally, however, several epidemiologic gaps must be closed, and this will require more precise data on the course of this disease and determination of risk factors for pulmonary infections with Pseudomonas aeruginosa. This project will generate that important information, as well as essential data on the quality of life and cognitive function of children with CF who experience early or delayed diagnosis. We will also clarify the risks of screening and delineate for the first time the costs of diagnosis and treatment of CF throughout childhood as well as the cost-effectiveness of screening. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PULMONARY PATHOGEN DEFENSE MECHANISMS Principal Investigator & Institution: Boom, W Henry.; Professor of Medicine; Pediatrics; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2003; Project Start 01-JUL-1998; Project End 30-JUN-2008 Summary: (provided by applicant): This competitive renewal application for a postdoctoral training program in pulmonary host defenses to microbial pathogens (HL07889) at Case Western Reserve University (CWRU) seeks renewal funding for a research training program for M.D.,M.D.-Ph.D. and Ph.D. scientists. Funding for this novel training program was awarded in7/1998 on the strength of there search programs at CWRU in programmatic are as of tuberculosis, HIV and complications of cystic fibrosis. Research in pulmonary host defenses at CWRU has remained an institutional strength, with internationally recognized faculty with research programs on major pulmonary pathogens such as M. tuberculosis, HIV-1, Streptococcus pneumonia and Pseudomonas aeruginosa. Interdisciplinary approaches to study of host defenses to these bacterial and viral pulmonary pathogens involve faculty across basic and clinical departments and include immunology, molecular biology, biochemistry, genetics and cell biology. The interdisciplinary collaborations at CWRU in the area of pulmonary host defenses against microbial pathogens are greatly facilitated by the infrastructures of the

96 Cystic Fibrosis

Tuberculosis Research Unit (TBRU), the Center for AIDS Research (CFAR), the AIDS Clinical Trails Unit (ACTU), the Cystic Fibrosis Center and the NIH-funded Clinical Research Center (GCRC). In addition, strong basic research programs in the Departments of Pediatrics and Medicine in close proximity to and collaboration with clinical scientists has created a rich environment allowing trainees to learn how basic research translates into clinical investigation. The goals of the research training program are: 1. To provide rigorous training for promising M.D., M.D.-Ph.D. and Ph.D. postdoctoral fellows in the application of the tools of immunology, molecular biology or biochemistry to pulmonary host defenses to pathogens such as M. tuberculosis and HIV-I. 2. To assume an active role in career development by training and assisting trainees in securing funding either for additional postdoctoral training or for faculty development depending on their level of training at entree into the program and development in the training program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: QUALITY OF LIFE ASSESSMENT CYSTIC FIBROSIS Principal Investigator & Institution: Morris, Kimberly A.; Instructor of Pediatrics; Children's Hosp Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, PA 15213 Timing: Fiscal Year 2001; Project Start 04-MAY-1999; Project End 30-APR-2004 Summary: Dr. Kimberly Morris, a clinical psychologist, is a worthy candidate for the Mentored Research Scientist Development Award for Minority Faculty (K01). If she is given the award the award, her primary responsibility will be to explore the mechanisms by which chronic conditions, especially cystic fibrosis, affect life quality and to create a disease- specific quality of life measure. She will also continue her pursuit of scientific excellence by participating in research design and statistical courses and attending ethics seminars. Collectively, these activities will help Dr. Morris make the transition from a mentored scientist to an independent researcher in five years. She will then serve as a role model for African Americans in general, as well as for women of all races, while simultaneously contributing quality research to the scientific community. The environment at Children's Hospital of Pittsburgh (CHP) provides a wealth of opportunities for young professionals. CHP is a remarkable teaching and research institution and was ranked #6 out of 132 pediatric facilities by the U.S. News and World Report. The hospital is dedicated to research excellence and the institution makes a commitment to its health professionals by devoting the necessary facilities and resources to support research efforts. Furthermore, the Cystic Fibrosis Center at CHP is a are, teaching, and research institution which is accredited by the Cystic Fibrosis Foundation. Dr. David Orenstein, Professor of Pediatrics at the University of Pittsburgh, is a highly accomplished faculty member and research with a passion for developing the careers of junior faculty members. Dr. Orenstein is an influential investigator in the area of cystic fibrosis, exercise, and quality of life. He has authored two books, and more than 150 book chapters, abstracts, and journal articles. Similarly, Dr. Patricia A. Nixon, Associate Professor of Pediatrics at the University of Pittsburgh, is a well-respected and prolific researcher in the area of CF, exercise, lung transplantation, and quality of life. Together, they have obtained over $3 million in NIH funding. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: QUALITY OF LIFE IN PATIENTS WITH SEVERE CYSTIC FIBROSIS Principal Investigator & Institution: Goss, Christopher H.; Medicine; University of Washington Seattle, WA 98195

Studies 97

Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2008 Summary: (provided by the applicant):Cystic Fibrosis (CF) is one of the most common inherited fatal diseases. Over the past thirty years, the median age of survival has improved from 14 years in 1969 to 29.1 years (95% Cl's 27.5 to 31.6) in 1999 in the United States. With this improved survival, this disease has been transformed from a disease with very high infant mortality to a disease that must now be considered a chronic and progressive lung disease. Improving the survival in these patients has been the primary goal over the last 30 years, but now clinical researchers must broaden their assessment of outcome in this disease to include patient-oriented outcomes such as health-related quality of life. Unfortunately, there is very limited research on the utility and relative strengths of different methods to measure health-related quality of life in patients with CF, especially for that group with the most severe disease. A better understanding of the best instruments, the minimal clinically important difference of these instruments, and the course of quality of life in these patients is needed in order to assess the value of treatments and interventions and to counsel patients and their families about their prognosis and the morbidity associated with this disease. This application proposes a prospective cohort study of patients with severe CF. Four different health-related quality of life instruments will be assessed, including a recently developed CF specific quality of life instrument. Patients will be evaluated at 6 month intervals f or a total of three years. The overall object of this proposal is to advance the state of the art in the measurement of health-related quality of life in adolescent and adult patients with severe cystic fibrosis in order to facilitate development and assessment of treatments that improve the quality of patients' lives and help predict the best time for evaluation for a lung transplant. In addition, this application proposes to compare the baseline differences health-related quality of life in patients not listed for lung or heart lung transplant, listed for lung or heart lung transplant, and transplanted and how healthrelated quality of life changes through time in these patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: QUANTIFYING EFFECTS OF MALNUTRITION ON CYSTIC FIBROSIS Principal Investigator & Institution: Lai, Hui-Chuan; Pediatrics; University of Wisconsin Madison 750 University Ave Madison, WI 53706 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 30-JUN-2004 Summary: (provided by applicant) The project: Cystic fibrosis (CF) is the most common, life-threatening autosomal recessive genetic disorder with an incidence of 1 in 2900 white newborns in the US. Although malnutrition is common and has been shown to be an unfavorable prognostic factor in CF, the relationships between malnutrition and clinical outcomes have not been quantified. Such longstanding gap of knowledge can be attributed to lack of prospectively defined, long-term followed patient cohorts, as well as epidemiologists with combined expertise in CF nutrition and biostatistics. The overall objective of this proposal is to use modern statistical and epidemiological methods to quantify the relationships between malnutrition and determinants of long-term clinical outcome, which we define as lung function, progressive respiratory infection and survival. With the unique opportunity to utilize two rich ongoing longitudinal databases collected since 1985, namely, the CF Foundation Patient Registry and the Wisconsin CF Neonatal Screening Study database, we are enthusiastic to test the hypothesis that malnutrition predisposes CF patients to increased risks of pulmonary deterioration, with potentially greater effect on female than male patients. Specific aims are to develop: 1) baseline risk models, which predict outcomes based on nutritional

98 Cystic Fibrosis

status at the time of CF diagnosis, 2) short-term risk models, which predict outcomes based on nutritional deterioration in the preceding 2-4 years, and 3) long-term risk models, which utilize nutritional and pulmonary data from the entire patient history to predict survival. Accomplishing this project will generate important information regarding how nutrition affects pulmonary manifestations to impact CF survival. Such information is critical to developing new interventions to improve the life of patients with CF. The candidate: Dr. Lai is a postdoctoral fellow of Pediatrics and Biostatistics at UW-Madison. She has unique experiences combining basic nutrition research, clinical nutrition practice and biostatistics. This project will enable her to gain advanced training to enhance her career toward becoming an independent investigator with expertise in nutritional epidemiology of chronic diseases. The environment: This project will be performed in the Departments of Pediatrics and Biostatistics under the supervision of Dr. Philip Farrell, who is a well-recognized expert in CF research. The candidate will benefit from working with the multidisciplinary CF research team at the Madison CF center as well as from participation in the active and vigorous research community at UW-Madison. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: QUANTITATIVE TRANSPORTERS

STRUCTURE

&

FUNCTION

OF

ABC

Principal Investigator & Institution: Zou, Xiaoqin; Dalton Research Center; University of Missouri Columbia 310 Jesse Hall Columbia, MO 65211 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant) The ATP-binding cassette (ABC) superfamily is one of the largest and most highly conserved class of integral membrane proteins and is involved in the ATP-dependent transport of solutes across cellular membranes. Prominent members in this family include P-glycoprotein linked to multidrug resistance to chemotherapy for cancers and the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a chloride channel whose malfunction causes cystic fibrosis, the most common lethal genetic disease in Caucasians. One unique feature of CFTR is that it has two distinct nucleotide binding domains (NBDs) that play critical roles in the gating of CFTR channels. Our understanding of the molecular basis of the regulation mechanisms, however, remains primitive. Unresolved questions include: What is the functional role of the individual NBD? Which NBD opens the channel, and which NBD closes the channel? How do the two NBDs interact with each other? Do they form a dimeric structure? If yes, does this dimeric structure depend on the state of the channel? These are the fundamental questions that interest a broad spectrum of biologists. A quantitative, multi-disciplinary approach will be used to tackle the molecular mechanisms whereby CFTR gating is regulated. It is a combination of structural modeling, energetic studies, patch-clamp recordings, biochemical assays and chemical synthesis. We plan to investigate quantitatively the functional roles of NBDs in the gating of CFTR channels. The two parallel aims in this project are: Aim 1. To engineer the nucleotide-binding pockets of CFTR to distinguish the functional roles of the NBDs. Aim 2. To investigate the hetero-dimeric structure of the NBD complex. A clear understanding of the quantitative mechanisms of the functions of CFTR is essential to future therapeutic design for CFTR-related diseases such as cystic fibrosis and secretory diarrhea. The methods as well as the results are directly applicable; to quantitative structure-function studies on other ABC transporter proteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RAPID AND INEXPENSIVE MULTI-ALLELE CYSTIC FIBROSIS ASSAY Principal Investigator & Institution: Prudent, James R.; Chief Scientific Officer; Eragen Biosciences, Inc. 918 Deming Way, Ste 201 Madison, WI 53717 Timing: Fiscal Year 2002; Project Start 06-SEP-2002; Project End 28-FEB-2003 Summary: (provided by applicant): Cystic fibrosis is the most common autosomal recessive genetic disease in the United States. With the recent recommendation for multi-mutation CF screening by the ACMG/ACOG, more labs will be implementing multiplexed genotyping assays. Presently, DNA diagnostic tests for CF are expensive, complicated to run and limited to certain ethnic backgrounds. Using a powerful new technology called AEGIS we propose developing a fast, inexpensive, reliable and easy to run a multiplexed mutation detection system for clinical screening of mutations in the CFTR gene that cause CF in the majority of Americans. In Phase I, proof of concept studies will take place to show that the system is feasible for testing CF mutations on human genomic samples. In Phase Il, we intend to develop a clinical diagnostic assay multi-mutation carrier and newborn CF screening. PROPOSED COMMERCIAL APPLICATIONS: This project could result in an easy to run, low-cost, high-throughput, and ultrasensitive method for Cystic Fibrosis DNA mutation screening that minimizes PCR amplicon handling and is run on an inexpensive validated instrument platform. In addition, validation from this project will open the doors to other test kit development such as population carrier screening for other genetic diseases and research based chromosome mapping studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RAPID CYSTIC FIBROSIS DNA MUTATION SCREENING TEST Principal Investigator & Institution: Mandecki, Wlodek; Pharmaseq 11 Dear Park Dr, Ste 207 Monmouth Junction, NJ 08852 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JAN-2004 Summary: (provided by applicant): Cystic fibrosis (CF) is a highly morbid, autosomal recessive disease caused by one or more mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The CFTR protein is important in transporting sodium and chloride ions through the membranes of epithelial cells lining the lungs and other organs. In Caucasians, CF is the most lethal inherited disease of childhood (frequency of 1:3,300). In the U.S., about 25,000 people have CF and about 850 individuals are diagnosed with CF each year. CF affects all races and ethnic groups and it is underdiagnosed, especially in minorities. Present genetic screening assays are best suited for detecting CF in Caucasians and Ashkenazi Jews but, the mutations currently assayed for in the CF screening does not detect mutations specific for Black Americans and Hispanics. Electronic microtransponders will be used in a novel DNA detection system to quickly and accurately detect large numbers of CF DNA mutations in a single high-speed flow assay. Each microtransponder is an integrated circuit composed of photocells, memory and antenna. It stores information identifying the sequence of an attached oligonucleotide probe in its electronic memory. Complementary, dye-tagged target DNA sequences bind to probes on microtransponders and the results are read in a high-speed flow reader. The Specific Aims of Phase I are to prove feasibility of a novel, rapid and inexpensive microtransponder-based CFTR screening assay: 1) Select ten important cystic fibrosis (CF) mutations in Caucasians, Black Americans and Hispanics and prepare synthetic DNA probes to these mutations; 2) Prepare primers for all CFTR mutations tested for

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use in multiplex PCR reaction; 3) Covalently attach optimized DNA probes to microtransponders, perform a microtransponder-based DNA probe assay using cell lines containing CFTR gene mutations and match results to purchased cell line descriptions; 4) Perform the microtransponder CF assay on a small number of patient and control samples and compare results to standard methods used in a genetics laboratory in a major medical center in New Jersey. The microtransponder-based, multiplex assay proposed with extended mutation detection for domestic ethnic groups will significantly increase the utility of this important assay for more U.S. patients by adding important CFTR mutations observed in Blacks and Hispanics into a single, affordable, accurate, high-speed assay. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATED CIC CI CHANNELS IN CI SECRETION IN CF Principal Investigator & Institution: Cuppoletti, John; Professor; Molecular and Cellular Physio; University of Cincinnati 2624 Clifton Ave Cincinnati, OH 45221 Timing: Fiscal Year 2003; Project Start 20-JUL-1997; Project End 30-NOV-2006 Summary: (provided by applicant): The cystic fibrosis transmembrane regulator (CFTR) is a CI channel. In cystic fibrosis (CF), CI transport is reduced because the CFTR is mistrafficked, or has different maturation, stability, or unit conductance. Regulation of the function of other ion channels is also aberrant in CF, and airway cells have increased inflammation and bacterial infection. The long-term goal of this proposal is to reduce the severity of cystic fibrosis by activation of another chloride channel, CIC2. CIC2 CI channels are found in the same airway epithelia as CFTR, and activators of CIC2 that function in vivo, have been identified. CIC2 mRNA has not been shown to be upregulated in CF. However, in collaborative studies, the mRNA for the Kir4.2 K channel was found to be up-regulated in the lung of several murine models of CF using genomic approaches. The cloned and expressed channel is PKA-activated. This K channel may help promote CI transport by residual F508CFTR and other CI channels including CIC2. The key questions to be addressed in this proposal are whether activation of CI transport by activation of CIC2 directly (or indirectly through activation of this K channel) will be sufficient to compensate for loss of other functions observed in CF. The Specific Aims are to: 1) Establish whether CIC2 function can be separated from CFTR function by using pharmacological and molecular biological approaches; 2) Define the role of CIC2 in airway cell models cultured in conditions similar to the airway microenvironment by using pharmacological and molecular biological approaches. 3) Define whether correction of the CI transport defect by CIC2 activation affects other CFrelated changes in function. Na transport (ENaC) function, Ca-activated CI channel (CLCA2) function, and markers of inflammation and bacterial susceptibility will be studied; and 4) Define the role of up-regulation and activation of Kir4.2 K channel in CF. This will also be studied in terms of CI transport, Na transport, CLCA2 function, inflammation and bacterial susceptibility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF AIRWAY LACTOPEROXIDASE HOST DEFENSE Principal Investigator & Institution: Conner, Gregory E.; Cell Biology and Anatomy; University of Miami Box 016159 Miami, FL 33101 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 28-FEB-2005 Summary: (Applicant's Abstract): Respiratory infection is a major cause of human morbidity and mortality in infants, the elderly, the immune-compromised and those on

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mechanical ventilators. The airway epithelium and submucosal glands provide the first defense against such infection by secreting several antibiotic substances. However, little is known regarding the several identified non-immunologic mucosal defenses. More knowledge of airway anti-infection defense will be valuable for designing prophylactic therapy for individuals predisposed to airway infection, e.g., in cystic fibrosis and bronchiectasis. The long-term goal of the proposed studies is to gain information about lactoperoxidase (LPO)-mediated non-immunologic defense in the airway. Recent work in this lab has shown that a significant amount of LPO is present in airway mucus, that LPO's substrates, thiocyanate (SCN-) and hydrogen peroxide (H2O2), are also present in the airway, that LPO is the major in vitro H2O2 scavenging activity in mucus, and that, in vivo, LPO catalytic activity is important for clearance of inhaled bacteria. Based on the above observations, the proposed experiments will test hypotheses regarding the regulation of the airway LPO system. The studies will use both differentiated airway epithelia at an air-liquid interface and submucosal gland cells in submerged cultures. Studies outlined in Specific Aim 1 will test the hypothesis that LPO synthesis or secretion is regulated by infection-related inflammatory stimuli and will study LPO's biosynthetic pathway. Specific Aim 2 will test the hypothesis that SCN- is carried into the airway lumen by a basolateral active transporter coupled to an apical anion channel and test whether this anion transport may be defective in cystic fibrosis. Specific Aim 3 will test the hypothesis that levels of the LPO substrate, H2O2, are also regulated by infection-related inflammatory stimuli and will identify the enzymatic source of H2O2. Understanding the regulatory mechanism of the LPO system will provide an opportunity for development of new prophylactic and therapeutic anti-infective agents. In addition, the studies may provide important insight into the pathophysiology of airway diseases characterized by chronic airway infection such as cystic fibrosis and bronchiectasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF CFTR BY ADENOSINE, A2 RECEPTORS, AND PLA2 Principal Investigator & Institution: Clancy, John P.; Pediatrics; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2001; Project Start 03-MAY-2001; Project End 30-APR-2005 Summary: adapted from applicant's abstract): Cystic fibrosis is characterized by defective epithelial ion transport in the airways, bacterial infection, and intense, leukocyte-dominated inflammation. Together, these processes contribute to the progressive airway destruction characteristic of the disease. Mutations in CFTR initiate this cascade, creating an abnormal airway surface liquid microenvironment. While CFspecific abnormalities in ion transport and inflammation have been described and are currently under intense investigation, the factors within the airway microenvironment that modulate both fundamental aspects of CF airway disease are not clearly identified. Adenosine is an endogenous autocoid that is an attractive candidate molecule, activating C1- secretion across airway and other CFTR-expressing epithelia, and modulating many important aspects of leukocyte (neutrophil and macrophage) function. Evidence also suggests that both airway epithelia and inflammatory cells export adenosine nucleotides which are metabolized in the extracellular environment to adenosine. Cellular signaling is primarily through adenosine receptors, including A2 receptors. This proposal is intended to characterize how the inflammatory regulator adenosine, through A2 receptors, activates CFTR. Our preliminary results suggest that A2 receptors activate CFTR through phospholipase A2 (PLA2) and arachidonic acid.

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This signaling pathway represents a novel, previously undescribed mechanism to modulate CFTR activity. The studies outlined in this proposal will: (1) characterize A2 receptor activation of CFTR-dependent Cl transport in living cells and across airway epithelia in vivo, (2) determine whether adenosine is a predominant nucleotide in the airway microenvironment, and (3) help to develop and test strategies to improve the detection of wildtype CFTR activity, and to improve the function of mutant CFTRs in vitro and in vivo. Adenosine signaling provides a new framework in which to consider the interactions between the epithelia and immune system within the airway microenvironment, helping to bridge the gap between inflammation, CFTR, and Clsecretion. The experiments outlined also identify a new way to regulate CFTR, and therefore may help define new therapeutic targets in the disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF CFTR BY PROTEIN KINASE C Principal Investigator & Institution: Liedtke, Carol M.; Pediatrics; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001; Project Start 10-JUN-2001; Project End 31-MAY-2005 Summary: Cystic fibrosis is a disease of electrolyte transport abnormalities, which has, as its genetic basis, a mutation of the cystic fibrosis transmembrane regulator (CFTR), an apical secretory Cl channel. Correction of airway dysfunction in CF has centered on therapeutic approaches to activate apical Cl channels other than CFTR and genetic alteration of CFTR to correct abnormal Cl secretion and thus offset excess mucus accumulation. CFTR is regulated primarily by CAMP, however, the PI discovered that constitutive activity of PKC-epsilon is necessary for CAMP-dependent regulation of CFTR. Thus, regulation of CFTR function is more complicated than just cAMPdependent phosphorylation of CFTR. New pilot studies indicate an association between PKC-epsilon and CFTR that might represent direct or indirect binding. In addition to CFTR, other tracheal epithelial proteins associate with PKC-epsilon, including scaffold proteins which might form a multiprotein complex that tethers PKC-epsilon proximal to its target. The hypothesis of this grant proposal is that PKC-epsilon regulates CFTR function through phosphorylation. This will be studied in detail in the following specific aims: 1) To determine whether activity of PKC- epsilon regulates its interaction with CFTR. Activity will be manipulated using PKC inhibitors or, to also decrease mass, with antisense oligonucleotides to PKC-epsilon. Enzyme activity will be correlated with copurification of PKC-epsilon with CFTR and phosphorylation of wild type CFTR. Whether trafficking competent and incompetent mutant CFTR (G551D, deltaF508, respectively) alter CFTR interaction with PKC-epsilon and its phosphorylation of CFTR will be determined. 2) To determine whether activity of PKC-epsilon is regulated by association with a multiprotein complex. Binding of PKC-epsilon with recombinant or endogenous proteins (CFTR, RACK, actin) will be measured by direct binding or overlay assay and quantitated as a K-m for binding. Binding of activated and/or inactive enzyme and specificity for PKC isotype will be determined. Activity will be manipulated by omitting PKC activators or adding PKC inhibitor and by downregulating binding protein using an antisense approach. Whether rapid loss of CFTR function by PKC inhibitor is correlated to activity of serine/threonine protein phosphatase(s) and its association with PKC-epsilon finding partners will be determined. 3) To identify site(s) of interaction between PKC- epsilon and target/binding protein. Sequence motifs in specific domains of PKC-epsilon and/or binding will be predicted and tested using peptides to inhibit binding and cAMPdependent activation of CFTR.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF CFTR BY SYNTAXIN AND N-SEC 1 ISOFORMS Principal Investigator & Institution: Kirk, Kevin L.; Professor; Physiology and Biophysics; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2001; Project Start 30-SEP-1996; Project End 31-DEC-2005 Summary: (Adapted from the Applicant's Abstract): The broad goal of this renewal application is to define the nature and the functional relevance of the interactions between the CFTR chloride channel and SNAREs, the basic elements of the membrane fusion machinery. CFTR is an epithelial chloride channel that is implicated in two major diseases: cystic fibrosis (low CFTR activity) and secretory diarrhea (excessive CFTR activity). At present we know little about what molecules control CFTR function in epithelial cells, and how these intermolecular interactions integrate CFTR activity with other epithelial cell functions. We have observed that the macroscopic currents mediated by native CFTR and by disease-associated mutants in epithelial cells are tonically inhibited by syntaxin 1A, a plasma membrane-associated t-SNARE. We have also determined that syntaxin 1A inhibits CFTR currents by binding to the amino terminal tail of this ion channel (N-tail), and that this cytoplasmic tail plays a major role in controlling CFTR channel gating. In more recent preliminary studies we have observed that SNAP-23, a SNARE that forms heterodimers with syntaxin 1A, also appears to bind to the CFTR N-tail and regulate CFTR currents. On the basis of these results we will pursue three specific aims. First, we will test the hypothesis that SNAP23 directly binds to the CFTR N-tail and regulates macroscopic CFTR current (Aim 1). As part of this aim we will determine if SNAP-23 and syntaxin 1A form a ternary complex with the CFTR N-tail and cooperatively regulate CFTR currents. Second, we will test the hypothesis that syntaxin 1A and/or SNAP-23 inhibit the macroscopic currents mediated by wild type CFTR and disease-associated mutants by directly modulating the single channel gating properties of CFTR (Aim 2). Third, we will determine how interactions between CFTR channels and SNAREs help coordinate the processes of fluid and electrolyte transport, SNARE complex assembly and protein secretion in epithelial tissues (Aim 3). The results should provide new insights into how the functional activity of the CFTR chloride channel is modulated by intermolecular interactions, and how these interactions integrate CFTR activity with the other physiologie demands of an epithelial cell (e.g., protein secretion). Such information may lead to new strategies for manipulating CFTR function in cystic fibrosis and secretory diarrhea. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF CFTR GENE EXPRESSION Principal Investigator & Institution: Walsh, Martin J.; Pediatrics; Mount Sinai School of Medicine of Nyu of New York University New York, NY 10029 Timing: Fiscal Year 2001; Project Start 05-JUL-2001; Project End 30-APR-2005 Summary: Cystic fibrosis (CF), an autosomal recessive disorder, is caused by a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) gene product. The CFTR gene (CFTR) is regulated by promoter sequences that give rise to low levels of tissue-specific gene transcription. The overall objective of this proposal is to determine the mechanisms that direct transcription of CFTR to learn how CFTR transcription is related to the pathophysiology of CF. The acetylation of core histones within the nucleosome is associated with the formation of "open" chromatin, necessary

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for transcriptional activation. Furthermore, histone deacetylation is associated with repressive, or "closed", chromatin structure. The alteration in chromatin is critical for the control of gene transcription in vivo. We have demonstrated that CFTR transcription is directly associated with histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity, but it is unclear how histone acetylation regulates CFTR transcription. We propose that histone acetylation direct the transcription of CFTR. Currently, the mechanisms that direct histone acetylation to a specific gene and that regulate gene transcription are not well understood. First, we wish to test the hypotheses that regulation of CFTR transcription in vivo is mediated through histone acetylation. Based on our previous work we will examine whether transcription factors ATF1 and CBF/NF-Y and the histone acetyltransferase coactivator proteins, p300/CREB-binding protein (p300/CBP) and p300/CBP-associated factor (PCAF) mediate histone acetylation of CFTR. We will determine the function of histone acetylation in the regulation of CFTR transcription. CFTR is a target of histone acetylation when the CFTR promoter contains an inverted CCAAT (Y-box) element in vivo. Both CFTR transcript initiation and cAMP-mediated CFTR transcription regulation require the Y-box element, suggesting that this element, by interacting with specific transcription factors, may be essential to the modification of chromatin in CFTR. Second, we will test the hypothesis that CCAAT displacement protein (CDP) recruits HDACs to CFTR in vivo and is regulated by acetylation. CDP, a critical trans-acting regulator of CFTR transcriptional repression, is directly associated with a co-repressor complex composed of specific HDAC activity. CDP interacts with the co-activator p300/CBP. Furthermore, CDP is regulated by acetyltransferase (FAT) activities of p300/CBP and PCAF. We plan to test the role of CDP as a substrate for acetyltransferase and deacetylase function and to determine whether the acetylation of CDP effect transcription of CFTR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF CFTR TRAFFIC Principal Investigator & Institution: Frizzell, Raymond A.; Professor; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001 Summary: Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Patch clamp and reconstitution studies have demonstrated that this gene encodes a protein kinase and nucleotide regulated Cl selective channel. The role of the CFTR in transepithelial sodium chloride absorption and secretion explains the CF phenotype: defective regulation of apical Cl conductance by cAMP signaling pathways. Yet, the manner in which this Cl channel defect causes airway disease is not yet clear. At the apical membranes of airway epithelia, the regulation of Cl conductance results from two phenomena: the trafficking and insertion of CFTR Cl channels into the apical membrane, and regulation of CFTR in the membrane. Both acute regulation of plasma membrane CFTR channel activity and membrane trafficking of vesicles containing CFTR have been demonstrated in different CFTR expression systems. Kinase regulation of both processes is impaired in cells expressing mutant CFTRs. The overall aim of our studies to identify the structural and regulatory features of CFTR that determine its insertion and retrieval at the plasma membrane, and the way in which CFTR traffic influences the activity of other ion channels. The primary hypothesis underlying this proposal is that CFTR contains regulatory and structural information that determines its trafficking. A close correlation exists between CFTR insertion and retrieval an the regulation of CFTR Cl channel gating. Despite the wealth of our knowledge regarding the structural features of CFTR

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that determine channel gating, we know little of the molecular determinants of its trafficking and the way in which these events influence its interaction with other channels or cellular processes. Accordingly, we will use CFTR-expressing cells, human airway cell lines and primary airway cell cultures to identify the regulatory and structural features of CFTR that determine it sinser6tion and retrieval at the plasma membrane. The studies will be carried out using simultaneous measurements of Cl current and membrane capacitance, to assess the effects of phosphorylation and traffic regulatory proteins on these CFTR trafficking events. This knowledge is necessary for understand how the apical membrane content of wild type and mutant CFTRs is determined, for the understanding and treatment of CF lung disease, and to potentially modulate the plasma membrane content of CFTR subsequent to gene transfer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF CFTR TRAFFICKING Principal Investigator & Institution: Stanton, Bruce A.; Professor; Physiology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, NH 03755 Timing: Fiscal Year 2001; Project Start 30-SEP-1992; Project End 31-MAR-2003 Summary: Our long term objective is to understand the role of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in epithelial cell function. Approximately 70% of patients with Cystic Fibrosis (CF) are homozygous for deltaF508, a mutation that causes a defect in the trafficking of CFTR out of the endoplasmic reticulum. Thus, CF is a "trafficking" disease. However, little is known about the trafficking and polarized sorting of CFTR. Our central hypothesis is that the C-terminal amino acid motif T-R-L plays a key role in sorting or localizing CFTR to the apical membrane of epithelial cells. The T-R-L sequence matches the PDZ interacting domain consensus sequence S/T-X-L/V that binds to proteins containing PDZ domains. This interaction co-localizes proteins within specialized regions of cells including apical and basolateral membranes. In preliminary studies we found that deletion of T-R-L (CFTRdeltaTRL) caused CFTR to become non- polarized, whereas wild type (wt)-CFTR is localized to the apical membrane. Accordingly, our specific aims are to: (1) Test the hypothesis that the C-terminus of CFTR sorts or localizes CFTR to the apical plasma membrane; (2) Elucidate the sorting and trafficking pathways of CFTR; (3) Test the hypothesis that the C-terminus retains CFTR in the apical plasma membrane; and (4) Test the hypothesis that ezrin binding protein 50 (EBP50) and other proteins containing PDZ domains interact with and localized CFTR to the apical membrane. To these ends, several epithelial cell lines, including MDCK and human airway and sweat duct cell lines, will be transfected with green fluorescent protein (GFP)-CFTR expression vectors. Using confocal fluorescent microscopy we will localized GFP- CFTR and, in combination with pulse-chase and selective biotinylation of apical and basolateral membrane proteins, we will elucidate the sorting pathway of CFTR. We will also use a combination of cellular, molecular (i.e., yeast two hybrid interaction trap) and biochemical approaches to determine if CFTR and EBP50 interact, and if this interaction localizes CFTR to the apical membrane. Using the yeast two hybrid interaction trap, we will identify novel proteins that interact with the C-terminus of CFTR. Studies on CFTR trafficking are likely to provide important insights into why epithelial cell function is severely affected in CF and may lead to a treatment for CF. Because a number of other diseases result from defects in protein trafficking (i.e. polycystic kidney disease, Alzheimer's, Tay-Sachs, etc.), we anticipate that our work will be of general interest to investigators in a wide variety of fields. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF CHLORIDE ION CONDUCTANCE IN PANCREAS DUCT Principal Investigator & Institution: Cotton, Calvin U.; Associate Professor of Pediatrics,; Pediatrics; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001; Project Start 15-JUN-1999; Project End 30-APR-2003 Summary: Cystic Fibrosis (CE) is a multi-system disease caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein. Normally the protein functions as a cAMP-regulated C1-channel in the apical plasma membrane. The precise link between defective CFTR and the pathophysiology of CF is not known. It is generally assumed that CF results from abnormal ion and water movement across affected epithelia; however, other regulatory functions ascribed to CFTR may contribute to the disease. Genetic and pharmacologic restoration of apical membrane C1permeability in CF epithelia are often cited as a viable therapeutic strategies. One such approach is to activate "alternate" apical membrane, non-CFTR C1-channels. The rationale for this approach rests upon the observation that Ca2+-activated C1conductance (CACC) is preserved in human CF airway epithelia and that organ-specific disease severity in the CF knockout mouse is inversely related to the activity of CACC. Pancreatic duct epithelial cells express at least 4 types of plasma membrane C1conductances: cAMP-activated (CFTR), cAMP-activated (non-CFTR), CACC, and swelling activated (SACC). At least two, and perhaps as many as four, different plasma membrane anion channels underlie these four conductance pathways. The molecular identity of only one (CFTR) is known. Regulation of the CACC, cAMP-activated (nonCFTR), and SACC conductances has received little attention in pancreatic duct cells. Our previous studies revealed that the Ca2+-activated and the cAMP-activated (non-CFTR) conductances are present in the apical cell membrane of pancreatic duct cells and thereby represent potential pathways to circumvent the loss of functional CFTR. The goal of the work described in this proposal is to identify the single channel basis for these two conductances and to determine the regulatory pathways that control channel activity. Electrophysiological measurements of channel function in response to manipulation of signal transduction pathways will be used. The long term objective of the work is to develop pharmacologic approaches to control salt and water transport so as to compensate for loss of CFTR function in epithelia affected by cystic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF KIDNEY MEMBRANE ION CHANNELS Principal Investigator & Institution: Boulpaep, Emile L.; Yale University 47 College Street, Suite 203 New Haven, CT 065208047 Timing: Fiscal Year 2001 Summary: The proposed studies plan to characterize channels, in particular chloride channels, in cell membranes of proximal tubule cells, from kidneys of rabbit, salamander, or CFTR knockout mouse, using a combination of isolated perfused tubules, non-perfused renal tubules, and separated single cells that have preserved their epithelial polarity. Patch-clamp and optical techniques will be used. The specific aims are: 1. To test the hypothesis that the chloride channel in the basolateral membrane of the proximal tubule cells share many of the intrinsic properties of the cystic fibrosis transmembrane conductance regulator CI- channel, we will study the biophysics and kinetics of chloride channels in mammalian proximal tubule and the intracellular signal transduction pathways involved in their regulation. 2. To test whether the gating of the basolateral chloride channel in proximal tubule cells by hydrolytic and non-hydrolytic

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interactions of ATP is analogous to that of the CFTR CI-channel. 3. To test the hypothesis that the basolateral chloride channel in proximal tubule cells regulates transcellular chloride reabsorption by the proximal tubule, and that alterations of apical chloride uptake indirect modulate the function of the basolateral chloride channel. 4. To explore the alternative pathways for transcellular chloride movement in proximal tubules of a CFTR-knockout mouse. Although the kidney expresses CFTR, there appears to be no impaired ion transport in patients suffering from cystic fibrosis. We will use a CFTR-knockout mouse, in order to establish how chloride channels contribute to transcellular chloride movement, and whether there is a regulatory relationship between CFTR and other chloride pathways. 5. To test the hypothesis that epithelial polarity in dissociated cells is not maintained by intrinsic proteins associated with the tight junction, we will study a model of a proximal tubule cells, that maintains epithelial polarity for us to ten days, and examine the cytoskeletal interactions that are essential for preserving polarity. The overall scope of the project is to understand transepithelial solute movement by the kidney at the single cell membrane and single channel protein level and to contribute to the understanding of clinical disorders such as cystic fibrosis, hypertension, metabolic alkalosis, acidosis, and acute renal failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF PROINFLAMMATORY SIGNALING PATHWAYS BY CFTR Principal Investigator & Institution: Pollard, Harvey B.; Chair; Henry M. Jackson Fdn for the Adv Mil/Med Rockville, MD 20852 Timing: Fiscal Year 2002; Project Start 15-JUN-1998; Project End 31-JAN-2005 Summary: (provided by applicant): The principal goal of this proposal is to identify the intracellular signaling pathways in the lung that mediate the chronic processes of inflammation and infection associated with cystic fibrosis (CF). Preliminary data indicate that airway epithelial cell lines derived from CF trachea secrete massive levels of pro-inflammatory IL8. Consistently, gene therapy with CFTR, or drug therapy with CPX, suppresses baseline levels of IL8 secretion, while still allowing physiological IL8 secretion in response to the presence of bacteria. In normal epithelial cells, IL8 secretion is mediated by activation of the NFkB pathway, and pharmacogenomic studies indicate that a subset of NFkB pathway genes parallel the secretion of IL8 as a function of CFTR, CPX and exposure to P. aeruginosa. We have therefore hypothesized that the mechanism by which CFTR suppresses IL8 secretion from CF epithelial cells is by direct action on a pro-inflammatory intracellular signaling pathway. We wish to identify and study this pathway, and propose the following Specific Aims. Aim #1: To determine the signaling pathways by which CFTR and CPX suppress IL8 secretion from CF epithelial cells. We will use cDNA microarrays to identify genes whose expression is altered by CFTR, or by the presence of CPX. Aim #2: To identify the molecular mechanisms by which CFTR or CPX permit CF epithelial cells to respond physiologically to the presence of Pseudomonas aeruginosa. We will identify cis-acting elements within the IL8 promoter which mediate activation or suppression by CFTR, CPX and P. aeruginosa. Aim #3: To identify subdomains in CFTR that suppress IL8 secretion from CF epithelial cells. We will prepare viral vector constructs expressing CFTR from which different subdomains have been deleted, and identify the CFTR domain(s) required for suppression of IL8 secretion. Expectations, Innovation and Impact: Our expectations are that this research will generate valuable new knowledge that will be useful for the development of novel therapies for CF. The proposed hypothesis-driven research is innovative because biochemistry and hypothesis-driven pharmacogenomics have not

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previously been used in this way to investigate a single gene disease such as cystic fibrosis. The impact of this research will be to identify novel pathways by which CFTR affects the ability of lung epithelial cells to respond to bacterial assault. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REPEAT ADMIN OF REPLICATION DEFICIENT ADENOVIRUS VECTOR IN CYSTIC FIBROSI Principal Investigator & Institution: Crystal, Ronald G.; Chief; Rockefeller University New York, NY 100216399 Timing: Fiscal Year 2001 Summary: This proposal represents a renewal of an ongoing study, initiated in 1993, to evaluate the use of adenovirus (Ad) vectors to transfer and express the normal human cystic fibrosis transmembrane conductance regulator (CFTR) cDNA in the airway epithelium of individuals with cystic fibrosis (CF). The goal of these studies is to express the normal human CFTR cDNA in the airway epithelium of individuals with CF in sufficient amount, distribution, and persistence to compensate for the deficiency in normal CFTR gene expression that causes the respiratory manifestations of this disorder. Over the past 6 years, we have learned that: (1) Ad vectors are capable of transferring and expressing normal levels of CFTR mRNA in the airway epithelium of individuals with CF, but only transiently; and (2) although immune-mediated host defenses likely play a major role in limiting the duration of expression of Ad vectormediated gene transfer following intrabronchial administration, the human studies suggest that human anti-Ad host defenses are more complex than those of animals. The hypothesis underlying the proposed studies is that by understanding the pulmonary host immune and inflammatory responses to local administration of replication deficient Ad vectors, a strategy can be developed to use a "stealth" Ad vector, combined with transient immunosuppression, to circumvent these host responses to enable Admediated gene transfer to safely correct the biologic abnormalities of the airway epithelium of individuals with CF on a persistent basis. To evaluate this hypothesis, we propose to assess the persistence of the Ad vector genome, and the respiratory mucosal and systemic anti-Ad host defenses following intrabronchial administration of 2nd generation "stealth" Ad vectors (E4 or E3+), alone or together with transient systemic immunosuppression (corticosteroids or cyclosporine). Because the infected and inflamed respiratory epithelial surface in CF precludes evaluation of respiratory mucosal anti-Ad vector immune host defenses, we propose to carry out these studies in normal individuals, a study population in which we can investigate local (lung) anti-Ad responses to the Ad vectors in a fashion impossible in the CF population. The study will start with intrabronchial administration safety studies in normals with AdGVCD.10 (a 1st generation Ad vector that has already been administered by other routes to humans). Then, using airway epithelial vector genome persistence and anti-vector host responses to a 1st generation E1 E3 E4+ Null Ad vector as a baseline, the stealth Null vectors (E1 E3 E4 and E1 E3+ E4+) will be assessed alone, or with concomitant prednisone or cyclosporine administration. Should data be generated that demonstrate enhanced persistence of the Ad genome in the airway epithelium in normal individuals, the same vector design 1 immunosuppression will be used to evaluate the persistence of the vector genome, and CFTR expression following administration of an Ad vector containing normal human CFTR cDNA to individuals with CF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF ORDERED HELICAL SEGMENTS IN MEMBRANE PROTEINS Principal Investigator & Institution: Tomich, John M.; Professor; Biochemistry; Kansas State University 2 Fairchild Hall Manhattan, KS 665061103 Timing: Fiscal Year 2001; Project Start 01-DEC-1989; Project End 31-AUG-2003 Summary: (Verbatim from the Applicant's Abstract) Defective chloride transport in epithelial cells results from mutations in the cystic fibrosis transport regulator (CFTR). A potential approach for treatment of cystic fibrosis (CF) would be to restore chloride transport to airway epithelial cells. In this pursuit, a series of water-soluble anionconducting peptides capable of spontaneous insertion into epithelial cell membranes have been synthesized. This family of peptides is modeled after the pore-forming M2 transmembrane segment of a anion-selective channel, the brain glycine receptor (M2GlyR). To enhance the aqueous solubility of the hydrophobic M2GlyR sequence, various numbers of lysine residues have been added to either the C- or N- terminus. These peptides are able to increase short-circuit currents and water transport across epithelial cells. The specific aims of the proposed research are to further characterize, biophysically, the lead compound CK4-M2GlyR as well as variants of the M2GlyR sequence that are modified by: i) additions of various ionic groups to the C- or Nterminus; ii) replacement or rearrangement of transmembrane residues; iii) changing chirality by using all D amino acids. The resulting peptides will be evaluated in terms of properties essential for a potential therapeutic agent for CF including aqueous solubility, anion selectivity, membrane affinity, ability to enhance chloride transport in whole cells, long half-life and low cytotoxicity. The long-range goals of this project are to use molecular modeling to define the relationships between structure and function for the M2GlyR family of peptides and to design an optimized anion-conducting peptide. This compound will then be evaluated for its effects on the function of normal and CF airway epithelial cells from mouse and human sources. This in depth structure-activity study will also increase our knowledge about peptide-lipid interactions in general, an area of research that becomes increasingly important as more naturally occurring peptides are found to have channel-forming activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF PKC XI IN CYSTIC FIBROSIS AND OTHER DISEASES Principal Investigator & Institution: Traynor-Kaplan, Alexis E.; Inologic, Inc. 3005 1St Ave, Ste 300 Seattle, WA 98121 Timing: Fiscal Year 2001; Project Start 25-JUL-2001; Project End 24-JAN-2002 Summary: (Applicant's Abstract): A major complication of CF is prolonged lung inflammation in response to infections. Agents produced during infections exacerbate the underlying defect in cystic fibrosis, inadequate fluid secretion. The investigators hypothesize that two of these exacerbating agents, EGF and TGFalpha act through a PI-3 kinase-signaling pathway leading to phosphatidylinositol 3,4,5 trisphosphate (PIP3) production that triggers translocation of the protein kinase C isoform, PKC epsilon, from the cytosol to the membrane where it phosphorylates relevant substrates (i.e. ion channels). They will test whether other cellular responses contributing to CF pathophysiology such as mucin secretion, mucin gene expression and cell proliferation are also mediated by PIP3 -induced translocation of PKC epsilon. If so, then PKC epsilon activation may mediate many of the pathological consequences of inflammation in CF and perhaps other degenerative lung conditions such as asthma, chronic obstructive pulmonary disorder and idiopathic pulmonary fibrosis. PROPOSED COMMERCIAL

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APPLICATION: Agents that reverse the translocation of PKC epsilon could be useful in the treatment of cystic fibrosis and other inflammatory diseases of the airways. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF SURFACTANT PROTEIN B IN INNATE AIRWAY DEFENSE Principal Investigator & Institution: Baatz, John E.; Assistant Professor; Pediatrics; Medical University of South Carolina 171 Ashley Ave Charleston, SC 29425 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2005 Summary: (Applicant's Abstract): Surfactant protein B (SP-B) is essential for postnatal survival and normal surfactant function. SP-B is capable of reorganizing lipid bilayers and is fusigenic protein. Based on these characteristics and the similarity of SP-B's amino acid sequence to those of several antimicrobial peptides, we hypothesized that SP-B itself has antimicrobial properties. Preliminary data obtained by our laboratory have demonstrated he SP-B has in vitro antibacterial activity. The significance of this observation is three-fold. First SP-B is expressed solely in mammalian lungs where it is secreted into the airway lining fluid by bronchial, bronchiolar and alveolar epithelial cells at relatively high concentrations. For that reason, it may act as a component of local mucosal immunity to prevent bacterial infections in these and other regions of the lung. Second, surfactant replacement preparations containing SP-B are presently used for safe treatment of neonatal respiratory distress syndrome, and such preparations do not elicit immunological responses. Third, SP-B is easily isolated or synthesized. Thus, there is potential for safe therapeutic use of SP-B for treatment of pulmonary bacterial infections. Use of SP-B to prevent or eradicate bacterial growth in the airway would be of particular importance in cystic fibrosis (CF), where progressive lung damage occurs as a result of persistent bacterial infection. Moreover, we have found aberrant forms of SP-B in bronchoalveolar lavage (BAL) of adult CF patients and that mature SP-B may be degraded or modified. We will test the hypothesis that SP-B is a component of the innate pulmonary immune system, protecting the human airway against bacterial infection, and this activity may be compromised in the airways of CF patients. The aims of this proposal are 1) to determine molecular forms and activity of SP-B in BAL from CF patients vs. those of normal humans, 2) to delineate the sites in the airway where SPB is found and in which it may play a defensive role, 3) to characterize the antibacterial activity of SP-B in vitro, and 4) to develop preparations containing native or synthetic SP-B for use as antibacterial agents in vivo. Results from the proposed experiments will lay the foundation for therapeutic use of SP-B for eradication of bacterial lung infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SAFETY OF AEROSOLIZED TOBRAMYCIN IN YOUNG CHILDREN W/ CYSTIC FIBROSIS Principal Investigator & Institution: Wilmott, Robert W.; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, OH 45229 Timing: Fiscal Year 2001 Summary: Aerosolized tobramycin (TOBI) has been shown to be safe and efficacious in cystic fibrosis (CF) patients over six years of age in helping to control the chronic pseudomonas aeruginosa frequently associated with CF pulmonary disease. Phase III studies using 300 mg of aerosolized TOBI documented a mean peak serum concentration of 1.0 micrograms/mL in CF patients older than six years of age. While aerosolized aminoglycosides offer an attractive option for anti-pseudomonal therapy in young children, systemic absorption of an aerosol dose in young children cannot be

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predicted from data in older subjects. This multi-center study proposes to assess the peak serum tobramycin level after escalating doses of aerosolized TOBI in children less than six years of age. The first cohort of 10 subjects (ages 6 months to 6 years) received a single, 180 mg dose of TOBI. Based on a mean peak serum tobramycin concentration of 0.48 micrograms/mL and absence of significant side effects, a second cohort of 20 subjects was studied using a single 300 mg dose of TOBI. Results from this cohort are pending. There were only 9 subjects studied at this site (Children's Hospital, Cincinnati). The plan is to use information gained from this Phase I study as the basis for future multi-center studies evaluating safety and efficacy of TOBI in children with CF under six years of age. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SDZ RAD IN STABLE LUNG TRANSPLANT RECIPIENTS WITH CYSTIC FIBROSIS Principal Investigator & Institution: Loyd, James E.; Associate Professor; Vanderbilt University 3319 West End Ave. Nashville, TN 372036917 Timing: Fiscal Year 2001 Summary: The pharmacokinetics of SDZ RAD (a deivative of Rapamycin) may be different in lung transplant recipients w/pancreatic insufficient cystic fibrosis. SPECIFIC AIMS: 1) To compare the pharmacokinetics of two different single oral doses of SDZ RAD during steady state administration of Neoral in stable lung transplant receipients w/pancreatic insufficient cystic fibrosis. 2) To assess the effect of two different single oral doses of SDZ RAD on the steady state pharmacokinetics profile of Neoral. 3)To evaluate the safety and tolerability of two different single oral doses of SDZ RAD in stable lung transplant recipients w/pancreatic insufficient cystic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SEROUS CELL MALFUNCTION AND CYSTIC FIBROSIS LUNG DISEASE Principal Investigator & Institution: Wine, Jeffrey J.; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001 Summary: Most people with cystic fibrosis (CF) die from chronic lung infections, but it is unknown how CFTR mutations compromise mucosal defenses. The hypothesis to be tested is that CF lung disease begins because CFTR mutations disrupt serous cell secretion, thus depriving CF airways of the antibiotic-rich fluid secreted by serous cells, which express the highest levels of CFTR among airway cells. Preliminary data indicate that serous cells require CFTR for fluid secretion. The serous cell malfunction hypothesis will be directly tested by measuring antibiotic levels in secretions. This project is made possible by a model serous cell line (Calu-3 cells) and especially by improve human airway 1 degree cultures that retain a "pure" serous cell phenotype. Aim 1 test the hypothesis that serous cell 1 degree cultures and Calu-3 cells express abundant antimicrobials, including defensins and collectins. Semi-quantitative RT- PCR will be used to measure expression of mRNA for lysozyme, lactoferrin, secretory component, serum leukocyte protease inhibitor (SLPI), the human defensin molecules hBD-1 and hBD-2, and the collectin SP-A. Aim 2 will test the hypothesis that human airway serous cells do not secrete antibiotics in CF. ELISA will be used to quantify the release of antimicrobials from Calu-3 cells, from serous cell 1 degree cultures from control and CF subjects, and in nasal lavages from normal and CF subjects. Aim 3 tests the hypothesis

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that CF human airway serous cells do not secrete fluid. A double-sided capacitance probe method will be used to measure fluid secretion across the 1 degree serous cell monolayers from controls and CF individuals. Gland secretions will also be measured with constant bore capillaries in freshly excised trachea and bronchi from controls and CF individuals. Aim 4 will test the hypothesis that serous cells require CFTR to secrete in response to increase [Ca/2+]/i, and that they secrete a variable mixture of HCO/3 and Cl-. This will be tested by shot circuit current measurements, isotope fluxes and patch-clamping. The results expected for this project are that Ca/2+ dependent secretion of Cl and fluid by serous cells will be greatly diminished in CF, resulting in reduced volumes of antibiotics reaching the airway surface from the glands. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: S-NITROSOTHIOL BREAKDOWN BY AIRWAY EPITHELIAL CELLS Principal Investigator & Institution: Gaston, Benjamin M.; Associate Professor; Pediatrics; University of Virginia Charlottesville Box 400195 Charlottesville, VA 22904 Timing: Fiscal Year 2003; Project Start 01-JAN-1999; Project End 31-DEC-2006 Summary: (provided by applicant): S-Nitrosothiols are endogenous adducts of nitric oxide and cysteine thiols. Increasingly, it is appreciated that S-nitrosylation reactions may result in post-translational protein modifications. These modifications have been associated with cyclic GMP-independent bioactivities that may be regulated to physiological advantage. For example, proteins may be modified by transnitrosation reactions with S-nitrosylated peptides such as S-nitrosoglutathione, concentrations of which appear to be enzymatically regulated. Indeed, several enzymes are now appreciated to regulate the catabolism of S-nitrosoglutathione, including glutathionedependent formaldehyde dehydrogenase and gamma-glutamyl transpeptidase. Snitrosothiol biochemistry may be involved in the regulation of a broad spectrum of bioactivities in the airway, including ion channel conductivity, inflammatory cell apoptosis, and airway smooth muscle relaxation. Of note, we have recently observed that S-nitrosoglutathione increases the expression and maturation of the most common mutant form of cystic fibrosis transmembrane regulatory protein (CFTR), deltaF508. Levels of S-nitrosothiols appear to be low in the airways of patients with both cystic fibrosis and with asthma, in part because of increased activity of S-nitrosoglutathione catabolic enzymes. Indeed, if it was not for accelerated S-nitrosoglutathione catabolism, S-nitrosoglutathione replacement therapy could be envisioned as a novel therapy for both cystic fibrosis and asthma. In this project, we plan to 1) characterize the regulation of S-nitrosothiol catabolism in the cystic fibrosis and asthmatic airway epithelium; 2) define the mechanism by which S-nitrosoglutathione and other S-nitrosothiols may increase the maturation of kF508 CFTR; and 3) evaluate mechanisms by which Snitrosoglutathione catabolism might be circumvented to achieve salutary bioactivities in the airways, including increased CFTR maturation. We anticipate that this project will provide new tools for understanding the cell biology of cystic fibrosis and asthma, and that it may lead to the development of new therapies for both diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SOLUTION NMR STUDIES OF AN ATP-BINDING CASSETTE Principal Investigator & Institution: Wang, Chunyu; Biochem & Molecular Biophysics; Columbia University Health Sciences New York, NY 10032 Timing: Fiscal Year 2003; Project Start 01-DEC-2003; Project End 30-NOV-2004

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Summary: (provided by applicant): The ATP-binding cassette (ABC) is the signature module of the ABC transporter superfamily. ABC transporters comprise a significant percentage of all non-viral genomes and transport a variety of important cargos, including ions, amino acids, lipids, sugars and proteins, across cell and organelle membranes. The ABC transporters are associated with a number of diverse and critical pathologies, such as multi-drug resistance (MDR) and cystic fibrosis. ATP-binding cassettes are the energy generating motor domain of the ABC transporters but their mechanism of ATP hydrolysis and mechanochemical energy transduction is poorly understood. Recent crystallographic studies suggest that ATP-induced conformational changes in ABCs are likely to be the crucial coupling mechanism between ATP hydrolysis and solute translocation. The present fellowship proposal will apply a wide array of powerful solution nuclear magnetic resonance (NMR) techniques to delineate ATP-induced conformational and dynamic changes in the ABC domain (MJ1267) of the branched amino acid transporter from a hyperthermophilic archaebacterium. Similar studies will be carried out in a variety of mutants to establish the relationship between ATP-induced conformational changes, the mechanism of ATP-catalysis and molecular etiology of important diseases. Detailed structural and dynamic information gleaned from the proposed studies will broaden our fundamental understanding of ATPbinding cassette function and contribute essential knowledge and tools to the structurebased drug design for cystic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURAL STUDIES OF BACTERIAL QUORUM SENSING REGULATOR Principal Investigator & Institution: Churchill, Mair E.; Associate Professor; Pharmacology; University of Colorado Hlth Sciences Ctr Uchsc at Fitzsimons Aurora, CO 800450508 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 31-MAY-2006 Summary: (provided by applicant): Persistent bacterial infections are a major cause of death in cystic fibrosis patients and immune-compromised individuals. A number of gram-negative bacteria including Pseudomonas aeruginosa, a major pathogen in cystic fibrosis, cause infections that are difficult to treat because the bacteria form a "biofilm community" that renders them less sensitive to traditional antibiotics. Quorum sensing, mediated by acylhomoserine lactone (AHL) signaling molecules, regulates pathogenesis and biofilm formation in P. aeruginosa. Therefore, understanding the molecular basis of quorum sensing is a high priority in the development of novel anti-bacterial agents. The long term goal of this project is to extend the understanding of the quorum-sensing system to the atomic level to develop a detailed description of the mechanisms that control bacterial pathogenesis. The main focus of this proposal is the class of enzymes that produce the AHL signal, AHL-synthases, because bacteria lacking the AHL signal fail to become pathogenic or form stable biofilms. Although there are models of the mechanism of action of the AHL-synthases, there are currently no structures of any AHL synthase. High resolution structural information is absolutely essential for fully understanding the mechanism of AHL synthesis and will provide the basis for future structure-based inhibitor design for development of novel therapeutics. The specific aims for this project are: (I) determine the high resolution crystal structure of the Pantoea stewartii subsp. Stewartii AHL-synthase (EsaI) to understand its function, mechanism, and relationship to other enzymes that utilize similar substrates. Perform mutagenesis, binding and kinetics experiments with EsaI to better understand the catalytic mechanism and substrate specificity. (II) Study the P. aeruginosa AHL-

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synthase, LasI, using structural and biochemical techniques to understand how specificity of AHL production is determined. (III) Establish whether the AHL-synthase homologues in divergent organisms produce a homoserine lactone signal using mass spectrometry and activity assays. Study the structures and mechanisms to determine similarities to other AHL synthases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STUDIES OSTEOPOROSIS

IN

SCLERODERMA

AND

CYSTIC

FIBROSIS

Principal Investigator & Institution: Merkel, Peter A.; Assistant Professor; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, MA 02118 Timing: Fiscal Year 2001; Project Start 18-JUL-2001; Project End 30-JUN-2006 Summary: (provided by applicant): To provide support for research projects in the field of rheumatology that will form the basis of a structured mentoring program for young investigators pursuing careers in patient-oriented clinical research. This application has two major specific research aims: 1) Develop new outcome measures for skin assessment in scleroderma for use in clinical trials and 2) Determine the prevalence and progression of osteoporosis in patients with cystic fibrosis (CF). Both projects will have direct relevance to furthering the health of the populations under study. Clinical research in scleroderma, including therapeutic trials, is greatly hampered by a lack of reliable and precise outcome measurements of disease activity. Skin thickening and fibrosis are major causes of morbidity and dysfunction for patients with scleroderma. The great success in extending the life expectancy of patients with CF gained in the last 20 years has resulted in patients now experiencing diseases as adults not formerly encountered in this population. Among these diseases is osteoporosis. Patients with CF appear to be at high risk for osteoporosis due to nutritional, pharmacologic, and genetic factors but the pathophysiology and extent of the problem is not known. Patients with scleroderma will be followed prospectively and evaluated for skin disease activity by skin scoring, durometer readings (thickness), light-based technologies, skin biopsies, selfassessments, and functional status instruments. These data will be analyzed to determine a core set of outcome measures for scleroderma. and validated by an expert panel of national researchers in this disease. An observational cohort of patients with CF will be studied. Baseline and 2-year measurements of bone density, nutritional status, and biochemical markers of bone turnover will performed. A comprehensive program for training new clinical investigators by the principal investigator is proposed. This program includes trainees taking an active and integral role in the research studies described. Additionally, trainees will be enrolled in formal coursework in biostatistics, epidemiology, and clinical research techniques leading to a master degree. A unique seminar and a series of support services at the host institution will further complement the training program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SUBSTRATE UTILIZATION IN CYSTIC FIBROSIS Principal Investigator & Institution: Moran, Antoinette; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, MN 554552070 Timing: Fiscal Year 2001 Summary: In previous studies of clinically stable, non-diabetic adults with cystic fibrosis (CF), we made a unique observation. Although these patients had enhanced peripheral insulin sensitivity, they had hepatic insulin resistance as demonstrated by

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significantly elevated hepatic glucose production (HGP), both fasting and during insulin infusion. We postulate that increased HGP occurs in CF at the expense of body protein and fat stores, promoting an overall catabolic state. Our objective is to characterize the contributions of carbohydrate, protein and fat metabolism to abnormally elevated HGP in CF. We will use a combination of 13C NMR spectroscopy, stable and radioisotopes to accomplish this objective. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SYNTHETIC GENE CARRIERS TO TREAT CYSTIC FIBROSIS Principal Investigator & Institution: Szoka, Francis C.; Professor; Biopharmaceutical Sciences; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001; Project Start 30-SEP-1992; Project End 31-MAR-2003 Summary: Our scientific goal is to develop more potent non-viral gene delivery systems to treat genetic diseases of the lung such as cystic fibrosis (CF). Our hypothesis is that non-viral gene delivery systems must surmount multiple barriers in series and that modest improvements at overcoming each barrier can lead to substantial improvements on overall gene expression efficiency. The challenge is to correctly identify the barriers and to devise means to overcome them. We target the lung in this research because the morbidity and mortality associated with CF is due to pulmonary complications from alterations in the gene encoding the CF transmembrane conductance regulator (CFTR) in lung epithelial cells. Furthermore, gene therapy of CF has been documented with plasmid DNA containing the CFTR sequence complexed to cationic lipids (lipoplexes) or cationic polymers (polyplexes) in animals and lipoplexes have been used in human clinical trials to deliver CFTR to the airways. However lipoplex delivery efficiency is low, gene expression is transient, the current complexes have an acute toxicity and little is known concerning their mechanism of action. We propose three approaches to improve gene delivery to the lung by improving the current non-viral systems: Approach 1, involves improved cationic molecules and techniques for compacting DNA. Approach 2, involves improved membrane destabilizing formulations to increase DNA delivery into the cytoplasm of the cell. Approach 3, involves altered and improved surface properties for minimizing toxicity upon injection and increasing gene delivery to target cells. We also will examine ways to improve DNA persistence and distribution in the target cells using plasmids containing nuclear matrix attachment sites, in situ generation of defective viruses from plasmid systems and low molecular weight RNA/DNA hybrids for site-specific CFTR gene correction. The effects of novel molecules and methods of DNA complex assembly will be evaluated in mechanismbased studies using gene expression, radioisotopic, fluorescent, confocal microscopic and electron microscopic techniques to determine: 1. The location, extent and mechanism of DNA release and delivery in cell culture. 2. To determine the mechanism of DNA delivery in vivo via the intravenous and intratracheal routes of administration. A mechanistic understanding of the current systems will help us to significantly improve non-viral DNA delivery by biophysical and biochemical methods and to assess the role of non-viral DNA delivery in the gene therapy treatment of cystic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: T CELL CONTROL OF AIRWAY MUCUS PRODUCTION Principal Investigator & Institution: Cohn, Lauren E.; Associate Professor; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, CT 065208047

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Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: Mucus hyperproduction contributes to morbidity and mortality in patients with chronic airway diseases. In asthma, chronic bronchitis and cystic fibrosis, inflammation is believed to stimulate mucus production, despite their different characteristic airway pathologies. We have defined two inflammatory pathways that lead to mucus production, using a murine system we developed to study the inflammatory effects of Th1 and Th2 cells in the respiratory tract. Th2 cells activated in the airways of mice stimulate airway eosinophilia, airway hyperresponsiveness and mucus production; features found in asthmatic patients. We show that mucus induction by Th2 cells does not require IL-4, IL-5, eosinophils or mast cells, but depends on signaling through IL-4Ralpha, the common chain in IL-13 and IL-4 receptors. Thus, it appears that IL-13 stimulates mucus production induced by Th2 cells. We also show that mucus can be induced by a mechanism that is Th2-independent and associated with airway neutrophilia, suggesting some of the features in chronic bronchitis and cystic fibrosis. We present novel studies showing that Th1 cells, through the production of IFNgamma, inhibit mucus production induced by both Th1 and Th2 cells. Furthermore, IFNgamma produced by Th1 cells has the potential to reduce airway pathology in immunotherapy of asthma. Our goals in this proposal are to gain a more complete understanding of the cellular and molecular mechanisms that regulate mucus production. Our aims are to 1) determine the mechanism by which CD4 Th cells stimulate mucus production; 2) determine how airway epithelial mucus production is inhibited by IFNgamma 3) determine the extent of inhibitory effects of IFNgamma on mucus production. Using our established adoptive transfer system in which Th1 and Th2 cells and recipient mice can be independently genetically manipulated, the precise factors important in the control of mucus production will be determined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TARGETING THE APICAL SURFACE OF HUMAN AIRWAY EPITHELIA Principal Investigator & Institution: Drapkin, Paola T.; Internal Medicine; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 30-JUN-2004 Summary: (provided by applicant) Gene therapy offers hope of a cure for cystic fibrosis (CF) by correcting mutation of the cystic fibrosis transmembrane conductance regulator (CFTR). Though not yet a reality, the goals of this proposal are aimed at generating viral vectors that successfully target epithelial cells of the human airway. Presently, viral vectors are inefficient at infecting the airway epithelia due, in large part, to the absence of viral receptors at the apical surface. One approach to circumventing this limitation is to target viral vectors to receptors that are accessible from the apical surface. Identifying and characterizing these proteins is a first step towards utilizing them as targets for viral vectors. The urokinase plasminogen activator receptor (uPAR) is apically expressed by human airway epithelia. This proposal will further study uPAR's utility as a gene transfer-targeting molecule. Its expression in different epithelial cell types, association with potential co-receptors, ability to endocytose and mechanism of endocytosis will be examined. Additionally, a seven amino acid uPAR binding peptide (u7p) will be engineered into outer capsid proteins of two gene transfer vectors, adenovirus (Ad) and adeno-associated virus serotype 2 (AAV2). U7p-modified viral proteins will be analyzed for their ability to bind uPAR. Viral particles will then be tested on uPAR expressing cells. Moreover, another potential receptor system, erbB2 and 3, will be examined as potential targeting proteins. Both receptors are expressed by human airway epithelia.

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Their expression pattern, cell type specificity and ability to internalize will be analyzed for potential as targeting molecules for gene transfer vectors. Identifying other apically expressed proteins from human airway epithelia will generate more potential targeting molecules. A surface biotinylation approach will be used for their isolation. Proteins will be separated and identified by MALDI-MS. Of particular interest are those apical proteins that internalize because they allow for entry into the cell. The major goals of this proposal are to generate candidate-targeting molecules with the hope of increasing efficiency of gene transfer vectors to the airways. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF ALPHA-DEFENSINS IN CYSTIC FIBROSIS LUNG DISE Principal Investigator & Institution: Spencer, L T.; Pediatrics; University of Florida Gainesville, FL 32611 Timing: Fiscal Year 2001; Project Start 05-JAN-2000; Project End 31-DEC-2004 Summary: As the principal investigator of this K23 proposal, I will complete fellowship training in pediatric pulmonology at the University of Florida in June 1999. I have accepted a faculty position in the same division effective in July 1999. Having completed 3 years of full-time research in basic and applied sciences in addition to residency and accelerated clinical and research fellowship training, my immediate career goals are to pursue further training in methodology designed to translate investigative findings of biomedical research to clinically useful applications. The proposed training program consists of an early period of relevant didactic training and initiation of research efforts, and culminates in 3 years of mentored research at 80 percent effort. The skills and experience obtained during this 5 year training program will provide opportunities for further research and funding in an independent manner. The proposed research is designed to characterize the role of neutrophil or alpha-defensins in cystic fibrosis (CF) lung disease. Our preliminary data indicates that alpha-defensin levels are significantly elevated in the airways of CF patients compared to healthy volunteers. These peptides possess cytotoxic and inflammatory properties, and may play a role in chronic endobronchial infection in CF. Using bronchoscopic evaluation of the lungs and bronchoalveolar lavage, we plan to define the specific and net effect of alpha-defensins in CF lung disease. We also plan to explore the possibility of modulation of deleterious effects of alpha-defensin with aerosolized alpha1- antitypsin, a molecule that may possess a wide range of therapeutic properties in CF lung disease. The methodology of this project is diverse, consisting of patient selection and recruitment, research bronchoscopy and specimen processing, complimentary ex vivo assays and experiments, collection of clinical data, clinical trial design and administration, and a broad range of statistical analysis methods. Structured didactic training will complement this project in providing multidisciplinary training geared towards independence in the conductance of patient-oriented research. Following completion of this training and research, my long-term career interest will remain in the area of pathogenesis and applied clinical intervention of neutrophil-mediated pulmonary disease in pediatric patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE ROLE OF APOPTOSIS IN CF PSEUDOMONAL LUNG INFECTION Principal Investigator & Institution: Cannon, Carolyn L.; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115

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Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 30-JUN-2005 Summary: The clinical hallmark of the genetic disorder cystic fibrosis (CF) is chronic pulmonary infection, particularly with Pseudomonas aeruginosa. The global objective of the proposed project is to gain further insight into the link between defects in the CF gene product, the cystic fibrosis transmembrane conductance regulator (CFTR), and the pathogenesis of pulmonary infections with P. aeruginosa in CF patients. Preliminary studies in a CF cell culture model using the TUNEL assay indicates that P. aeruginosa induces apoptosis in normal, but not CF, lung cells. The specific objective of this project is to delineate the role of apoptosis in the interaction of P. aeruginosa with respiratory epithelium. The specific aims are twofold: 1) characterize the induction of apoptosis in cell culture and mouse models of CF following infection with P. aeruginosa, using TUNEL staining, FACS analysis and confocal microscopy of normal and CF lung cells, a. specifically, to detail the time-course of infection induced apoptosis, b. establish the role of internalization of P. aeruginosa in the induction of apoptosis, and c. determine the role of caspases in the infection-induced apoptosis, and 2) compare the expression of genes regulating apoptosis in lung cells expressing differing Cftr alleles, both before and after infection with P. aeruginosa, using DNA-microarray technology, a. specifically, to identify the expression levels of genes instrumental in orchestrating apoptosis in both wild-type and deltaF508 CFTR expressing lung cells after infection with P. aeruginosa, and b. determine the time course of expression of infection induced genes. This approach will allow simultaneous monitoring of the expression levels of hundreds of genes, potentially identifying and implicating cellular pathways previously unappreciated as participants in the process of respiratory cell-pseudomonal interaction. Thus, we propose to investigate the role of apoptosis in the pathogenesis of pseudomonal pulmonary infection in CF with the ultimate goal of perhaps formulating new treatment strategies based on the findings of these studies. Completion of this project promises to provide the experience necessary for the applicant to initiate a career as an independent investigator in the field of pseudomonal pathogensis, and to provide further insight in the pathogenesis of CF lung diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF SURFACTANT PROTEIN GENETIC VARIANTS IN CF Principal Investigator & Institution: Floros, Joanna; Associate Professor; Cellular/Molecular Physiology; Pennsylvania State Univ Hershey Med Ctr 500 University Dr Hershey, PA 17033 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Our long-term objectives are to study mechanisms by which modifier genes affect pulmonary disease severity in patients with cystic fibrosis (CF), with emphasis on the surfactant proteins (SP-), which are produced by lung epithelial cells. SP-A and SP-D play a role in the innate host defense and/or the regulation of inflammatory processes in the lung, and SP-B is essential for normal lung function. Preliminary findings indicate that SP-A genetic variants are associated with disease severity in CF. The overall rationale for the proposed studies is that significant heterogeneity exists in the severity of pulmonary disease in CF patients, even in those that are homozygous for the F508 mutation of the CF transmembrane conductance regulator gene (CFTR). This phenotypic diversity may be related to the genetic heterogeneity of the surfactant protein genes. Genetic variation in the SP-B gene may relate to differences in pulmonary function and genetic variation in SP-A and SP-D may relate to differences in innate host defense function in CF. The overall hypothesis states that SP-A, SP-B, and SP-D are modifiers of pulmonary disease severity in CF and that

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differences exist among SP-A genetic variants in their ability to modulate phagocytosis of Pseudomonas aeruginosa. In this proposal, we will carry out two major groups of experiments. First, we will study family-based associations by carrying out extended transmission disequilibrium test (ETDT) and/or TDT analyses, of the SP-A, SP-B, and SP-D marker loci, and CF, to determine whether these loci are linked to CF and identify susceptibility SP alleles for CF severity. The entire CF study group as well as a number of subgroups based on CFTR genotype, severity, or other criteria, will be studied. Logistic regression analysis will be used to identify factors that may be of particular significance in CF along with specific genotypes (Aim 1). In the second group of experiments, we will focus on SP-A genetic variants for which preliminary evidence of an association between SP-A alleles and CF severity exists. We will study differences in the ability of SP-A alleles to enhance phagocytosis, by a macrophage-like cell line, of laboratory strains of mucoid and non-mucoid P. aeruginosa grown under different environmental conditions that have been shown to reproduce certain biochemical and functional characteristics found in clinical isolates of P. aeruginosa (Aim 2) and of mucoid and non-mucoid isolates of P. aeruginosa from CF patients (Aim 3). The findings may help identify specific host defense mechanisms involving alleles associated with pulmonary disease severity in CF and develop a useful in vitro model to study the in vivo modifications of P. aeruginosa and its clearance, and provide the basis for further consideration of novel therapeutic strategies to treat CF-related lung disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANS-SPLICING TO REPAIR CYSTIC FIBROSIS MRNA Principal Investigator & Institution: Mitchell, Lloyd G.; President and Chief Scientific Officer; Intronn, Llc 9700 Great Seneca Hwy, Ste 264 Rockville, MD 20850 Timing: Fiscal Year 2001; Project Start 15-SEP-1999; Project End 31-AUG-2002 Summary: The ultimate objective of this proposal is to develop a new general mechanism to reprogram any human or eukaryotic gene at the pre- messenger RNA level. Specifically, this proposal will develop our patented technology, spliceosome mediated RNA trans-splicing (SMaRT[TM]), towards the production of a practical gene therapy for the treatment of Cystic Fibrosis. In Phase 1, we produced a series of pretherapeutic RNA molecules (PTMs) that are capable of initiating SMaRT reactions with mutant Cystic Fibrosis Transmembrane Regulator (CFTR) pre-mRNA, repairing the mRNA and expressing full length CFTR protein in cultured cells. The goal in Phase 2 is to identify an optimal PTM that can repair mutant CFTR mRNA, appropriately express normal CFTR protein, and restore chloride channel function in the most clinically relevant models of Cystic Fibrosis. This lead PTM therapeutic candidate will enter full preclinical testing in Phase 3 and ultimately, human clinical trials if results warrant. Many other genetic diseases may also be amenable to SMaRT[TM] therapeutics. Trans-splicing PTMs could improve many aspects of gene therapies by conferring intra-cellular specificity, decreasing the size of the delivered gene, and acquiring the regulated expression of the endogenous target gene. PROPOSED COMMERCIAL APPLICATIONS: Development of RNA molecules capable of repairing mutant CFTR by trans-splicing could lead to a therapeutic for Cystic Fibrosis that could slow or halt disease progression. There is a clinical need to serve and treat this market of approximately 30,000 affected individuals in the U.S. alone. Additionally, the development of effective spliceosome mediated RNA trans-splicing technology would be of utility in many gene transfer applications including the treatment of other genetic diseases, infections by splicing viruses ( HIV, EBV, papilloma, etc) and cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TWO DOSES STUDY TO COMPARE THE SAFETY OF SDZ RAD IN HEART/LUNG TRANSPLANT Principal Investigator & Institution: Morris, Randall E.; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2001 Summary: This study of SDZ RAD was a randomized, double-blind, stratified(to primary diagnosis of pancreatic insufficient cystic fibrosis and non cystic fibrosis), crossover trial designed to test the tolerability, safety, pharmacokinetics, pharmacodynamics, and metabolism of SDZ RAD in stable lung and heart/lung transplant recipients. Trial participants received two different single oral doses of SDZ RAD (0.035 and 0.1 mg/kg, up to a maximum of 2.5 and 7.5 mg respectively). There was a washout period of approximately 15 days between the two administrations of SDZ RAD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ULTRASE MT12 FOR STEATORRHEA IN CYSTIC FIBROSIS Principal Investigator & Institution: Stern, Robert C.; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001 Summary: Pancreatic replacement enzymes have been used for treatment of cystic fibrosis since shortly after the disease was first described in 1938. These enzymes were introduced into medical practice before the passage of the Food, Drug, and Cosmetics Act. In addition, because they were derived from "food" and were therefore thought to be intrinsically safe, no rigorous formal studies of efficacy and safety, such as would be needed now to fulfill the requirements of an FDA new drug application, were ever performed. The use of this class of therapeutic agents was governed by the Department of Agriculture rather than by the Food and Drug Administration. Over the first few decades of use, the only major toxicity reported was symptomatic allergy to inhaled powdered enzymes (almost always in caregivers [e.g., parents and nurses]) and a rise in serum uric acid in some patients who required high doses. Both of these problems were rare, and neither represented a clinically important threat to cause irreversible injury or death. Relatively unsupervised use of these drugs continued. In recent years, however, very high-dose enteric coated preparations were introduced. These drugs were much more effective for many patients. New technology allowed production of very high-dose capsules (each containing 25000 or more units of lipase, compared to the 4000 units in previous preparations; the amount of proteases was also increased). Some patients who took very high doses (usually >5000-10000 units/lipase per kg per meal) developed severe colonic strictures (with obstruction) and many required surgery, including some who underwent subtotal colectomy. Although the exact pathophysiology of this toxicity is not known with certainty, there is little doubt that it hss been associated with the introduction of the high-dose capsules (and usually with the consumption of large amounts of them). With this occurrence of a new major toxicity the FDA was compelled to review the status of these drugs, and ruled that the very high-dose preparation (i.e., any capsule containing more than 20000 units of lipase) be removed from the market immediately, and that all other pancreatic enzymes must be expeditiously processed as new drugs. The study proposed here is one of many which are not necessary to establish efficacy (to the standards of an FDA new drug application) of pancreatic enzymes for treatment of CF. The specific aim of the study is to compare fat and protein absorption (as determined by a 3-day stool fat and protein determination) in CF patients during a

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three day period of administration of pancreatic enzyme replacement (Ultrase MT12) with meals with the same patient's data during a three-day period of administration of a placebo preparation with meals. " Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VALIDATION PRODUCTS FOR CYSTIC FIBROSIS MOLECULAR TESTS Principal Investigator & Institution: Rundell, Clark A.; Maine Molecular Quality Controls, Inc. 81 Research Dr Scarborough, ME 04074 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2004 Summary: (provided by applicant): This Phase II project develops a novel, comprehensive set of control products for quality assurance of molecular-based cystic fibrosis (OF) diagnostic tests. Controls are tested alongside patient specimens, as required by Federal regulations, to ensure quality in medical testing. Adoption of molecular diagnostics technology is inhibited by lack of commercial quality controls. Patient-based materials are often used as controls, which presents issues of patient confidentiality, infection risk and limited supply. Phase I research demonstrated feasibility of an innovative system for production of stable, renewable, noninfectious controls. In Phase II, constructs will be engineered to contain 16 medically important CF gene segments that carry forty-seven common CF diagnostic mutations. A unique cassette scheme for assembly of segments will yield a construct easily modified to accommodate new molecular tests. The construct will be stabilized by a proprietary technology and suspended in a biological matrix to mimic patient samples. Our control set will validate CF diagnostic assays and will serve as a model system to produce quality assurance products for genetic tests designed to detect multiple mutations. The availability of these products is important to medical diagnostics and makes a significant contribution to patient care by ensuring quality of genetic testing results. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: WOMEN'S HEALTH IN CYSTIC FIBROSIS Principal Investigator & Institution: Billings, Joanne L.; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, MN 554552070 Timing: Fiscal Year 2001; Project Start 05-JUL-2001; Project End 30-JUN-2006 Summary: Dr. Billings is a fourth year pulmonary and critical care fellow at the University of Minnesota who will become an Instructor of Medicine on July 1, 2000. Her long term goal is to develop an independent academic career combining clinical research with clinical medicine. Her primary research and clinical field will be in cystic fibrosis (CF). The proposed career development plan combines an intense interdisciplinary patient-- oriented research experience in association with a comprehensive structured didactic curriculum. The candidate is particularly interested in the health of women with CF. Data from patients seen at the University of Minnesota CF Center demonstrate greater mortality in women compared to men which appears to increase near the time of puberty. Dr. Billings will explore the hypothesis that estrogen and progesterone may have a negative impact on CF lung disease. The present study will examine lung function during the follicular and luteal phases of the menstrual cycle in normally menstruating young women with CF. Lung function of women with CF on birth control pills will be compared to those who are not. Pilot information on the effect of menopause on lung function, bone health, lipid levels and cardiovascular disease will

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also be obtained. If there is evidence of hormonal influence on pulmonary function, there may be future therapeutic implications and the potential to improve survival in women with CF. The Mentored Patient-Oriented Development Award affords the opportunity for the PI to translate existing knowledge of cohort study design into the practical application of study conduct and implementation. The applicant will pursue additional courses in the School of Public Health in the areas of clinical research, biostatistics and ethics. She will have the opportunity to expand her knowledge of endocrinology and metabolism as well as research methodology with this study of women's health. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “cystic fibrosis” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for cystic fibrosis in the PubMed Central database: •

"Bronchial Artery Delivery of Viral Vectors for Gene delivery in Cystic Fibrosis; Superior to Airway Delivery?". by Bakhai A Dr, MRCP, Sheridan DJ Professor, FRCP, Coutelle CC Professor, Drscmed. 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107842

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A conditional probability analysis of cystic fibrosis transmembrane conductance regulator gating indicates that ATP has multiple effects during the gating cycle. by Hennager DJ, Ikuma M, Hoshi T, Welsh MJ. 2001 Mar 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30698

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A C-terminal motif found in the [beta]2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na + /H + exchanger regulatory factor family of PDZ proteins. by Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, Welsh MJ, Lefkowitz RJ. 1998 Jul 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21104

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A Cystic Fibrosis Pancreatic Adenocarcinoma Cell Line. by Schoumacher RA, Ram J, Iannuzzi MC, Bradbury NA, Wallace RW, Hon CT, Kelly DR, Schmid SM, Gelder FB, Rado TA, Frizzell RA. 1990 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54034

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Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.

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A functional R domain from cystic fibrosis transmembrane conductance regulator is predominantly unstructured in solution. by Ostedgaard LS, Baldursson O, Vermeer DW, Welsh MJ, Robertson AD. 2000 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25884

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A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr [minus sign] /[minus sign] mice. by Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY, Alvarez JG. 1999 Nov 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24179

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A1 Adenosine-Receptor Antagonists Activate Chloride Efflux from Cystic Fibrosis Cells. by Eidelman O, Guay-Broder C, van Galen PJ, Jacobson KA, Fox C, Turner RJ, Cabantchik ZI, Pollard HB. 1992 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49332

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Abnormal passive chloride absorption in cystic fibrosis jejunum functionally opposes the classic chloride secretory defect. by Russo MA, Hogenauer C, Coates SW Jr, Santa Ana CA, Porter JL, Rosenblatt RL, Emmett M, Fordtran JS. 2003 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=162286

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Abnormal Secretagogue-Induced Intracellular Free Ca2+ Regulation in Cystic Fibrosis Nasal Epithelial Cells. by Reinlib L, Jefferson DJ, Marini FC, Donowitz M. 1992 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48782

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Activities of Tobramycin and Six Other Antibiotics against Pseudomonas aeruginosa Isolates from Patients with Cystic Fibrosis. by Shawar RM, MacLeod DL, Garber RL, Burns JL, Stapp JR, Clausen CR, Tanaka SK. 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89580

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Adenovirus-Mediated Persistent Cystic Fibrosis Transmembrane Conductance Regulator Expression in Mouse Airway Epithelium. by Scaria A, St. George JA, Jiang C, Kaplan JM, Wadsworth SC, Gregory RJ. 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=109954

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Altered cytokine production by cystic fibrosis tracheal gland serous cells.. by Kammouni W, Figarella C, Marchand S, Merten M. 1997 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=175746

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An Approach for Treating the Hepatobiliary Disease of Cystic Fibrosis by Somatic Gene Transfer. by Yang Y, Raper SE, Cohn JA, Engelhardt JF, Wilson JM. 1993 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46560

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Analysis of ClC-2 channels as an alternative pathway for chloride conduction in cystic fibrosis airway cells. by Schwiebert EM, Cid-Soto LP, Stafford D, Carter M, Blaisdell CJ, Zeitlin PL, Guggino WB, Cutting GR. 1998 Mar 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19931

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Antimicrobial Susceptibility of Haemophilus influenzae in the Respiratory Tracts of Patients with Cystic Fibrosis. by Moller LV, Regelink AG, Grasselier H, van Alphen L, Dankert J. 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=105407

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Antisense Oligodeoxynucleotide to the Cystic Fibrosis Gene Inhibits Anion Transport in Normal Cultured Sweat Duct Cells. by Sorscher EJ, Kirk KL, Weaver ML, Jilling T, Blalock JE, LeBoeuf RD. 1991 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52382

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Antisense Oligodeoxynucleotides to the Cystic Fibrosis Transmembrane Conductance Regulator Inhibit cAMP-Activated but not Calcium-Activated Chloride Currents. by Wagner JA, McDonald TV, Nghiem PT, Lowe AW, Schulman H, Gruenert DC, Stryer L, Gardner P. 1992 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49588

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Association of variant alleles of mannose binding lectin with severity of pulmonary disease in cystic fibrosis: cohort study. by Gabolde M, Guilloud-Bataille M, Feingold J, Besmond C. 1999 Oct 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28266

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Basal Expression of the Cystic Fibrosis Transmembrane Conductance Regulator Gene is Dependent on Protein Kinase A Activity. by McDonald RA, Matthews RP, Idzerda RL, McKnight GS. 1995 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41379

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Bicarbonate Conductance and pH Regulatory Capability of Cystic Fibrosis Transmembrane Conductance Regulator. by Poulsen JH, Fischer H, Illek B, Machen TE. 1994 Jun 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43990

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Bioactive tumor necrosis factor in the sputa of cystic fibrosis patients.. by Kelly N, Clee S, Nakielna B. 1995 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=170189

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Bronchoalveolar Fluid Is Not a Major Hindrance to Virus-Mediated Gene Therapy in Cystic Fibrosis. by Rooney CP, Denning GM, Davis BP, Flaherty DM, Chiorini JA, Zabner J. 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=136549

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Burkholderia cepacia Complex Infection in Italian Patients with Cystic Fibrosis: Prevalence, Epidemiology, and Genomovar Status. by Agodi A, Mahenthiralingam E, Barchitta M, Giannino V, Sciacca A, Stefani S. 2001 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88256

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Calcium and cAMP Activate Different Chloride Channels in the Apical Membrane of Normal and Cystic Fibrosis Epithelia. by Anderson MP, Welsh MJ. 1991 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52010

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cAMP-Inducible Chloride Conductance in Mouse Fibroblast Lines Stably Expressing the Human Cystic Fibrosis Transmembrane Conductance Regulator. by Rommens JM, Dho S, Bear CE, Kartner N, Kennedy D, Riordan JR, Tsui L, Foskett JK. 1991 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52328

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Capillary Electrophoresis --Single-Strand Conformation Polymorphism Analysis for Rapid Identification of Pseudomonas aeruginosa and Other Gram-Negative Nonfermenting Bacilli Recovered from Patients with Cystic Fibrosis. by Ghozzi R, Morand P, Ferroni A, Beretti JL, Bingen E, Segonds C, Husson MO, Izard D, Berche P, Gaillard JL. 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85573

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Cathelicidin Peptides Inhibit Multiply Antibiotic-Resistant Pathogens from Patients with Cystic Fibrosis. by Saiman L, Tabibi S, Starner TD, San Gabriel P, Winokur PL, Jia HP, McCray PB Jr, Tack BF. 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=90740

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Cell Death of Human Polymorphonuclear Neutrophils Induced by a Pseudomonas aeruginosa Cystic Fibrosis Isolate Requires a Functional Type III Secretion System. by Dacheux D, Attree I, Schneider C, Toussaint B. 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97008

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CFTR with a partially deleted R domain corrects the cystic fibrosis chloride transport defect in human airway epithelia in vitro and in mouse nasal mucosa in vivo. by Ostedgaard LS, Zabner J, Vermeer DW, Rokhlina T, Karp PH, Stecenko AA, Randak C, Welsh MJ. 2002 Mar 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122478

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'CFTR-opathies': disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations. by Noone PG, Knowles MR. 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64805

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Characterization of Immortal Cystic Fibrosis Tracheobronchial Gland Epithelial Cells. by Cozens AL, Yezzi MJ, Chin L, Simon EM, Finkbeiner WE, Wagner JA, Gruenert DC. 1992 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49251

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Characterization of the Cystic Fibrosis Transmembrane Conductance Regulator in a Colonocyte Cell Line. by Cohn JA, Nairn AC, Marino CR, Melhus O, Kole J. 1992 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48653

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Characterization of Unusual Bacteria Isolated from Respiratory Secretions of Cystic Fibrosis Patients and Description of Inquilinus limosus gen. nov., sp. nov.. by Coenye T, Goris J, Spilker T, Vandamme P, LiPuma JJ. 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130740

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Chloride channel and chloride conductance regulator domains of CFTR, the cystic fibrosis transmembrane conductance regulator. by Schwiebert EM, Morales MM, Devidas S, Egan ME, Guggino WB. 1998 Mar 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19458

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Chronic Melioidosis in a Patient with Cystic Fibrosis. by Schulin T, Steinmetz I. 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88000

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Clinical outcome in relation to care in centres specialising in cystic fibrosis: cross sectional study. by Mahadeva R, Webb K, Westerbeek RC, Carroll NR, Dodd ME, Bilton D, Lomas DA. 1998 Jun 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28574

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Cloning and Expression of a Human P2U Nucleotide Receptor, a Target for Cystic Fibrosis Pharmacotherapy. by Parr CE, Sullivan DM, Paradiso AM, Lazarowski ER, Burch LH, Olsen JC, Erb L, Weisman GA, Boucher RC, Turner JT. 1994 Apr 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43559

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Comparative genomic sequence analysis of the human and mouse cystic fibrosis transmembrane conductance regulator genes. by Ellsworth RE, Jamison DC, Touchman JW, Chissoe SL, Braden Maduro VV, Bouffard GG, Dietrich NL, Beckstrom-Sternberg SM, Iyer LM, Weintraub LA, Cotton M, Courtney L, Edwards J, Maupin R, Ozersky P, Rohlfing T, Wohldmann P, Miner T, Kemp K, Kramer J, Korf I, Pepin K, AntonacciFulton L, Fulton RS, Minx P, Hillier LW, Wilson RK, Waterston RH, Miller W, Green ED. 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15558

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Comparative In Vitro Activities of Meropenem, Imipenem, Temocillin, Piperacillin, and Ceftazidime in Combination with Tobramycin, Rifampin, or Ciprofloxacin against Burkholderia cepacia Isolates from Patients with Cystic Fibrosis. by Bonacorsi S, Fitoussi F, Lhopital S, Bingen E. 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89053

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Comparative Stability Studies of Antipseudomonal [beta]-Lactams for Potential Administration through Portable Elastomeric Pumps (Home Therapy for Cystic Fibrosis Patients) and Motor-Operated Syringes (Intensive Care Units). by Viaene E, Chanteux H, Servais H, Mingeot-Leclercq MP, Tulkens PM. 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=127357

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Comparison of Agar Diffusion Methodologies for Antimicrobial Susceptibility Testing of Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients. by Burns JL, Saiman L, Whittier S, Larone D, Krzewinski J, Liu Z, Marshall SA, Jones RN. 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86597

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Comparison of Culture and PCR for Detection of Burkholderia cepacia in Sputum Samples of Patients with Cystic Fibrosis. by Whitby PW, Dick HL, Campbell PW III, Tullis DE, Matlow A, Stull TL. 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=104893

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Comparison of Immunogenicity and Safety of a Virosome Influenza Vaccine with Those of a Subunit Influenza Vaccine in Pediatric Patients with Cystic Fibrosis. by Schaad UB, Buhlmann U, Burger R, Ruedeberg A, Wilder-Smith A, Rutishauser M, Sennhauser F, Herzog C, Zellmeyer M, Gluck R. 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89839

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Comparison of Isolation Media for Recovery of Burkholderia cepacia Complex from Respiratory Secretions of Patients with Cystic Fibrosis. by Henry D, Campbell M, McGimpsey C, Clarke A, Louden L, Burns JL, Roe MH, Vandamme P, Speert D. 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88640

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Comparison of Two Culture Methods for Detection of Tobramycin-Resistant GramNegative Organisms in the Sputum of Patients with Cystic Fibrosis. by Van Dalfsen JM, Stapp JR, Phelps C, Stewart P, Burns JL. 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=120123

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Compartmentalized autocrine signaling to cystic fibrosis transmembrane conductance regulator at the apical membrane of airway epithelial cells. by Huang P, Lazarowski ER, Tarran R, Milgram SL, Boucher RC, Stutts MJ. 2001 Nov 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=61178

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Cystic Fibrosis Epithelial Cells have a Receptor for Pathogenic Bacteria on their Apical Surface. by Imundo L, Barasch J, Prince A, Al-Awqati Q. 1995 Mar 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42350

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Cystic Fibrosis Gene Encodes a cAMP-Dependent Chloride Channel in Heart. by Hart P, Warth JD, Levesque PC, Collier ML, Geary Y, Horowitz B, Hume JR. 1996 Jun 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39024

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Cystic Fibrosis Gene Expression is not Correlated with Rectifying Cl- Channels. by Ward CL, Krouse ME, Gruenert DC, Kopito RR, Wine JJ. 1991 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51855

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Cystic Fibrosis Transmembrane Conductance Regulator Activation Stimulates Endosome Fusion in vivo. by Biwersi J, Emans N, Verkman AS. 1996 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38018

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Cystic fibrosis transmembrane conductance regulator is an epithelial cell receptor for clearance of Pseudomonas aeruginosa from the lung. by Pier GB, Grout M, Zaidi TS. 1997 Oct 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23711

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Cystic Fibrosis Transmembrane Conductance Regulator-Mediated Corneal Epithelial Cell Ingestion of Pseudomonas aeruginosa Is a Key Component in the Pathogenesis of Experimental Murine Keratitis. by Zaidi TS, Lyczak J, Preston M, Pier GB. 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96484

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Cytokines and Inflammatory Mediators Do Not Indicate Acute Infection in Cystic Fibrosis. by Wolter JM, Rodwell RL, Bowler SD, McCormack JG. 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95697

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Defective regulatory volume decrease in human cystic fibrosis tracheal cells because of altered regulation of intermediate conductance Ca2 +-dependent potassium channels. by Vazquez E, Nobles M, Valverde MA. 2001 Apr 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33209

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Development of rRNA-Based PCR Assays for Identification of Burkholderia cepacia Complex Isolates Recovered from Cystic Fibrosis Patients. by LiPuma JJ, Dulaney BJ, McMenamin JD, Whitby PW, Stull TL, Coenye T, Vandamme P. 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85518

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Differences in the Concentrations of Small, Anionic, Antimicrobial Peptides in Bronchoalveolar Lavage Fluid and in Respiratory Epithelia of Patients with and without Cystic Fibrosis. by Brogden KA, Ackermann MR, McCray PB Jr, Huttner KM. 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96733

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Differentiation of Burkholderia Species by PCR-Restriction Fragment Length Polymorphism Analysis of the 16S rRNA Gene and Application to Cystic Fibrosis Isolates. by Segonds C, Heulin T, Marty N, Chabanon G. 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85118

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Discrimination of Burkholderia gladioli from Other Burkholderia Species Detectable in Cystic Fibrosis Patients by PCR. by Bauernfeind A, Schneider I, Jungwirth R, Roller C. 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=105199

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Distribution of Genes Encoding Putative Transmissibility Factors among Epidemic and Nonepidemic Strains of Burkholderia cepacia from Cystic Fibrosis Patients in the United Kingdom. by Clode FE, Kaufmann ME, Malnick H, Pitt TL. 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86581

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Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. by Worlitzsch D, Tarran R, Ulrich M, Schwab U, Cekici A, Meyer KC, Birrer P, Bellon G, Berger J, Weiss T, Botzenhart K, Yankaskas JR, Randell S, Boucher RC, Doring G. 2002 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150856

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Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. by Vandivier RW, Fadok VA, Hoffmann PR, Bratton DL, Penvari C, Brown KK, Brain JD, Accurso FJ, Henson PM. 2002 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150889

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Engineering Actin-Resistant Human DNase I for Treatment of Cystic Fibrosis. by Ulmer JS, Herzka A, Toy KJ, Baker DL, Dodge AH, Sinicropi D, Shak S, Lazarus RA. 1996 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38651

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Epidemiological Analysis of Sequential Pseudomonas aeruginosa Isolates from Chronic Bronchiectasis Patients without Cystic Fibrosis. by Pujana I, Gallego L, Martin G, Lopez F, Canduela J, Cisterna R. 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85036

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Evaluation of MicroScan Autoscan for Identification of Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients. by Saiman L, Burns JL, Larone D, Chen Y, Garber E, Whittier S. 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=149561

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Evaluation of Reference Dilution Test Methods for Antimicrobial Susceptibility Testing of Pseudomonas aeruginosa Strains Isolated from Patients with Cystic Fibrosis. by Saiman L, Burns JL, Whittier S, Krzewinski J, Marshall SA, Jones RN. 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85429

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Expression of ExsA in trans Confers Type III Secretion System-Dependent Cytotoxicity on Noncytotoxic Pseudomonas aeruginosa Cystic Fibrosis Isolates. by Dacheux D, Attree I, Toussaint B. 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97914

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Expression of the Cystic Fibrosis Transmembrane Conductance Regulator Gene in the Respiratory Tract of Normal Individuals and Individuals with Cystic Fibrosis. by Trapnell BC, Chu C, Paakko PK, Banks TC, Yoshimura K, Ferrans VJ, Chernick MS, Crystal RG. 1991 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52127

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Factors Influencing Adeno-Associated Virus-Mediated Gene Transfer to Human Cystic Fibrosis Airway Epithelial Cells: Comparison with Adenovirus Vectors. by Teramoto S, Bartlett JS, McCarty D, Xiao X, Samulski RJ, Boucher RC. 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=110307

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Fatal Pulmonary Infection Due to Multidrug-Resistant Mycobacterium abscessus in a Patient with Cystic Fibrosis. by Sanguinetti M, Ardito F, Fiscarelli E, La Sorda M, D'Argenio P, Ricciotti G, Fadda G. 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87830

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Functional Roles of the Nucleotide-Binding Folds in the Activation of the Cystic Fibrosis Transmembrane Conductance Regulator. by Smit LS, Wilkinson DJ, Mansoura MK, Collins FS, Dawson DC. 1993 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47693

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Genetic Analysis of Pseudomonas aeruginosa Isolates from the Sputa of Australian Adult Cystic Fibrosis Patients. by Anthony M, Rose B, Pegler MB, Elkins M, Service H, Thamotharampillai K, Watson J, Robinson M, Bye P, Merlino J, Harbour C. 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=120616

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Genotyping Study of Scedosporium apiospermum Isolates from Patients with Cystic Fibrosis. by Defontaine A, Zouhair R, Cimon B, Carrere J, Bailly E, Symoens F, Diouri M, Hallet JN, Bouchara JP. 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130776

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Global Genomic Analysis of AlgU ([final sigma]sgr;E)-Dependent Promoters (Sigmulon) in Pseudomonas aeruginosa and Implications for Inflammatory Processes in Cystic Fibrosis. by Firoved AM, Boucher JC, Deretic V. 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=134789

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Glycosylation and the cystic fibrosis transmembrane conductance regulator. by Scanlin TF, Glick MC. 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59516

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GTP-Binding Proteins Inhibit cAMP Activation of Chloride Channels in Cystic Fibrosis Airway Epithelial Cells. by Schwiebert EM, Kizer N, Gruenert DC, Stanton BA. 1992 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50393

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Heterogeneity of Pseudomonas aeruginosa in Brazilian Cystic Fibrosis Patients. by Silbert S, Barth AL, Sader HS. 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88474

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Hsp70 Molecular Chaperone Facilitates Endoplasmic Reticulum-associated Protein Degradation of Cystic Fibrosis Transmembrane Conductance Regulator in Yeast. by Zhang Y, Nijbroek G, Sullivan ML, McCracken AA, Watkins SC, Michaelis S, Brodsky JL. 2001 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34585

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Identification and Antimicrobial Susceptibility of Alcaligenes xylosoxidans Isolated from Patients with Cystic Fibrosis. by Saiman L, Chen Y, Tabibi S, San Gabriel P, Zhou J, Liu Z, Lai L, Whittier S. 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88468

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Identification of a Protein that Confers Calcitonin Gene-Related Peptide Responsiveness to Oocytes by Using a Cystic Fibrosis Transmembrane Conductance Regulator Assay. by Luebke AE, Dahl GP, Roos BA, Dickerson IM. 1996 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39630

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Identification of an Ion Channel-Forming Motif in the Primary Structure of CFTR, the Cystic Fibrosis Chloride Channel. by Oblatt-Montal M, Reddy GL, Iwamoto T, Tomich JM, Montal M. 1994 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43186

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Identification of Mutations in Regions Corresponding to the Two Putative Nucleotide (ATP)-Binding Folds of the Cystic Fibrosis Gene. by Kerem B, Zielenski J, Markiewicz D, Bozon D, Gazit E, Yahav J, Kennedy D, Riordan JR, Collins FS, Rommens JM, Tsui L. 1990 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54973

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Immunocytochemical Localization of the Cystic Fibrosis Gene Product CFTR. by Crawford I, Maloney PC, Zeitlin PL, Guggino WB, Hyde SC, Turley H, Gatter KC, Harris A, Higgins CF. 1991 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52694

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Impact of Heterogeneity within Cultured Cells on Bacterial Invasion: Analysis of Pseudomonas aeruginosa and Salmonella enterica Serovar Typhi Entry into MDCK cells by Using a Green Fluorescent Protein-Labelled Cystic Fibrosis Transmembrane Conductance Regulator Receptor. by Gerceker AA, Zaidi T, Marks P, Golan DE, Pier GB. 2000 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97215

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Impact of Microbiology Practice on Cumulative Prevalence of Respiratory Tract Bacteria in Patients with Cystic Fibrosis. by Shreve MR, Butler S, Kaplowitz HJ, Rabin HR, Stokes D, Light M, Regelmann WE. 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=84543

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Impaired Cell Volume Regulation in Intestinal Crypt Epithelia of Cystic Fibrosis Mice. by Valverde MA, O'Brien JA, Sepulveda FV, Ratcliff RA, Evans MJ, Colledge WH. 1995 Sep 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40919

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In Vitro Activities of Designed Antimicrobial Peptides against Multidrug-Resistant Cystic Fibrosis Pathogens. by Schwab U, Gilligan P, Jaynes J, Henke D. 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89292

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In vitro correction of cystic fibrosis epithelial cell lines by small fragment homologous replacement (SFHR) technique. by Sangiuolo F, Bruscia E, Serafino A, Nardone AM, Bonifazi E, Lais M, Gruenert DC, Novelli G. 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130050

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In Vitro Pharmacodynamic Properties of Colistin and Colistin Methanesulfonate against Pseudomonas aeruginosa Isolates from Patients with Cystic Fibrosis. by Li J, Turnidge J, Milne R, Nation RL, Coulthard K. 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=90373

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In vitro pharmacodynamics of ceftazidime against Pseudomonas aeruginosa isolates from cystic fibrosis patients.. by Manduru M, Mihm LB, White RL, Friedrich LV, Flume PA, Bosso JA. 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=164067

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In vitro susceptibilities to amphotericin B, itraconazole, and miconazole of filamentous fungi isolated from patients with cystic fibrosis.. by Hennequin C, Benailly N, Silly C, Sorin M, Scheinmann P, Lenoir G, Gaillard JL, Berche P. 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=164071

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In vivo activation of the cystic fibrosis transmembrane conductance regulator mutant [Delta]F508 in murine nasal epithelium. by Kelley TJ, Thomas K, Milgram LJ, Drumm ML. 1997 Mar 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20135

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Innate Lung Defenses and Compromised Pseudomonas aeruginosa Clearance in the Malnourished Mouse Model of Respiratory Infections in Cystic Fibrosis. by Yu H, Nasr SZ, Deretic V. 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97396

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Intrinsic Anion Channel Activity of the Recombinant First Nucleotide Binding Fold Domain of the Cystic Fibrosis Transmembrane Regulator Protein. by Arispe N, Rojas E, Hartman J, Sorscher EJ, Pollard HB. 1992 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48487

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Ketoconazole Activates Cl- Conductance and Blocks Cl- and Fluid Absorption by Cultured Cystic Fibrosis (CFPAC-1) Cells. by Kersting U, Kersting D, Spring KR. 1993 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46443

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Lung Infections Associated with Cystic Fibrosis. by Lyczak JB, Cannon CL, Pier GB. 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=118069

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Mechanism of Conversion to Mucoidy in Pseudomonas aeruginosa Infecting Cystic Fibrosis Patients. by Martin DW, Schurr MJ, Mudd MH, Govan JR, Holloway BW, Deretic V. 1993 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47359

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Membrane targeting of cGMP-dependent protein kinase is required for cystic fibrosis transmembrane conductance regulator Cl[minus sign] channel activation. by Vaandrager AB, Smolenski A, Tilly BC, Houtsmuller AB, Ehlert EM, Bot AG, Edixhoven M, Boomaars WE, Lohmann SM, de Jonge HR. 1998 Feb 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19047

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Microbial Pathogenesis in Cystic Fibrosis: Pulmonary Clearance of Mucoid Pseudomonas aeruginosa and Inflammation in a Mouse Model of Repeated Respiratory Challenge. by Yu H, Hanes M, Chrisp CE, Boucher JC, Deretic V. 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=107888

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Molecular Analysis of the Ovine Cystic Fibrosis Transmembrane Conductanvce Regulator Gene. by Tebbutt SJ, Wardle CJ, Hill DF, Harris A. 1995 Mar 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42470

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Molecular basis for defective glycosylation and Pseudomonas pathogenesis in cystic fibrosis lung. by Poschet JF, Boucher JC, Tatterson L, Skidmore J, Van Dyke RW, Deretic V. 2001 Nov 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=61151

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Molecular Epidemiology of Stenotrophomonas maltophilia Isolated from Clinical Specimens from Patients with Cystic Fibrosis and Associated Environmental Samples. by Denton M, Todd NJ, Kerr KG, Hawkey PM, Littlewood JM. 1998 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=104959

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Molecular Epidemiology of Stenotrophomonas maltophilia Isolated from Cystic Fibrosis Patients. by Denton M, Kerr KG. 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130651

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Molecular Mechanisms of Fluoroquinolone Resistance in Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients. by Jalal S, Ciofu O, Hoiby N, Gotoh N, Wretlind B. 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89751

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Molecular Typing and Exopolysaccharide Biosynthesis of Burkholderia cepacia Isolates from a Portuguese Cystic Fibrosis Center. by Richau JA, Leitao JH, Correia M, Lito L, Salgado MJ, Barreto C, Cescutti P, Sa-Correia I. 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86514

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Mucoid Pseudomonas aeruginosa in cystic fibrosis: characterization of muc mutations in clinical isolates and analysis of clearance in a mouse model of respiratory infection.. by Boucher JC, Yu H, Mudd MH, Deretic V. 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=175548

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Mutant Cystic Fibrosis Transmembrane Conductance Regulator Inhibits Acidification and Apoptosis in C127 Cells: Possible Relevance to Cystic Fibrosis. by Gottlieb RA, Dosanjh A. 1996 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39654

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Mutation Detection by Mismatch Binding Protein, MutS, in Amplified DNA: Application to the Cystic Fibrosis Gene. by Lishanski A, Ostrander EA, Rine J. 1994 Mar 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43432

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Novel Bacterium Isolated from a Lung Transplant Patient with Cystic Fibrosis. by Pitulle C, Citron DM, Bochner B, Barbers R, Appleman MD. 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85827

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Occurrence and Risk of Cochleotoxicity in Cystic Fibrosis Patients Receiving Repeated High-Dose Aminoglycoside Therapy. by Mulheran M, Degg C, Burr S, Morgan DW, Stableforth DE. 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=90684

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P-113d, an Antimicrobial Peptide Active against Pseudomonas aeruginosa, Retains Activity in the Presence of Sputum from Cystic Fibrosis Patients. by Sajjan US, Tran LT, Sole N, Rovaldi C, Akiyama A, Friden PM, Forstner JF, Rothstein DM. 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=90850

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P2Z-Independent and P2Z Receptor-Mediated Macrophage Killing by Pseudomonas aeruginosa Isolated from Cystic Fibrosis Patients. by Zaborina O, Misra N, Kostal J, Kamath S, Kapatral V, El-Idrissi ME, Prabhakar BS, Chakrabarty AM. 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96875

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PCR-Based Detection and Identification of Burkholderia cepacia Complex Pathogens in Sputum from Cystic Fibrosis Patients. by McDowell A, Mahenthiralingam E, Moore JE, Dunbar KE, Webb AK, Dodd ME, Martin SL, Millar BC, Scott CJ, Crowe M, Elborn JS. 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88532

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Pharmacokinetics of aerosolized tobramycin in adult patients with cystic fibrosis.. by Touw DJ, Jacobs FA, Brimicombe RW, Heijerman HG, Bakker W, Briemer DD. 1997 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=163682

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Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients.. by Schaefer HG, Stass H, Wedgwood J, Hampel B, Fischer C, Kuhlmann J, Schaad UB. 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=163051

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Pharmacokinetics of Tobramycin in Adults with Cystic Fibrosis: Implications for Once-Daily Administration. by Beringer PM, Vinks AA, Jelliffe RW, Shapiro BJ. 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89775

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Pharmacokinetics of vancomycin in adult cystic fibrosis patients.. by Pleasants RA, Michalets EL, Williams DM, Samuelson WM, Rehm JR, Knowles MR. 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=163080

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Photosensitivity associated with ciprofloxacin use in adult patients with cystic fibrosis.. by Burdge DR, Nakielna EM, Rabin HR. 1995 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=162630

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Pneumocystis carinii Carriage among Cystic Fibrosis Patients, as Detected by Nested PCR. by Sing A, Geiger AM, Hogardt M, Heesemann J. 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88220

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Pneumonia Due to Bordetella bronchiseptica in a Cystic Fibrosis Patient: 16S rRNA Sequencing for Diagnosis Confirmation. by Wallet F, Perez T, Armand S, Wallaert B, Courcol RJ. 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130795

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Population Pharmacokinetic Analysis of Nonlinear Behavior of Piperacillin during Intermittent or Continuous Infusion in Patients with Cystic Fibrosis. by Vinks AA, den Hollander JG, Overbeek SE, Jelliffe RW, Mouton JW. 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=151777

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Population Pharmacokinetics and Use of Monte Carlo Simulation To Evaluate Currently Recommended Dosing Regimens of Ciprofloxacin in Adult Patients with Cystic Fibrosis. by Montgomery MJ, Beringer PM, Aminimanizani A, Louie SG, Shapiro BJ, Jelliffe R, Gill MA. 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=90855

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Population pharmacokinetics of ceftazidime in cystic fibrosis patients analyzed by using a nonparametric algorithm and optimal sampling strategy.. by Vinks AA, Mouton JW, Touw DJ, Heijerman HG, Danhof M, Bakker W. 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=163271

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Positive correlation of algD transcription to lasB and lasA transcription by populations of Pseudomonas aeruginosa in the lungs of patients with cystic fibrosis.. by Storey DG, Ujack EE, Mitchell I, Rabin HR. 1997 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=175584

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Protein phosphatase 2C dephosphorylates and inactivates cystic fibrosis transmembrane conductance regulator. by Travis SM, Berger HA, Welsh MJ. 1997 Sep 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23594

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Pseudomonas aeruginosa Cystic Fibrosis Isolates Induce Rapid, Type III SecretionDependent, but ExoU-Independent, Oncosis of Macrophages and Polymorphonuclear Neutrophils. by Dacheux D, Toussaint B, Richard M, Brochier G, Croize J, Attree I. 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=97504

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Pseudomonas aeruginosa isolates from patients with cystic fibrosis have different beta-lactamase expression phenotypes but are homogeneous in the ampC-ampR genetic region.. by Campbell JI, Ciofu O, Hoiby N. 1997 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=163920

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Pseudomonas aeruginosa lasR Transcription Correlates with the Transcription of lasA, lasB, and toxA in Chronic Lung Infections Associated with Cystic Fibrosis. by Storey DG, Ujack EE, Rabin HR, Mitchell I. 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=108233

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Pseudomonas aeruginosa Quorum-Sensing Signal Molecule N-(3-Oxododecanoyl)-lHomoserine Lactone Inhibits Expression of P2Y Receptors in Cystic Fibrosis Tracheal Gland Cells. by Saleh A, Figarella C, Kammouni W, Marchand-Pinatel S, Lazdunski A, Tubul A, Brun P, Merten MD. 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96855

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Pseudomonas aeruginosa Quorum-Sensing Systems May Control Virulence Factor Expression in the Lungs of Patients with Cystic Fibrosis. by Erickson DL, Endersby R, Kirkham A, Stuber K, Vollman DD, Rabin HR, Mitchell I, Storey DG. 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=127834

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Pulmonary Outcome in Cystic Fibrosis Is Influenced Primarily by Mucoid Pseudomonas aeruginosa Infection and Immune Status and Only Modestly by Genotype. by Parad RB, Gerard CJ, Zurakowski D, Nichols DP, Pier GB. 1999 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96804

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Questionnaire survey of urinary incontinence in women with cystic fibrosis. by Orr A, McVean RJ, Webb AK, Dodd ME. 2001 Jun 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33391

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Rapid Endocytosis of the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel. by Prince LS, Workman RB Jr, Marchase RB. 1994 May 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43958

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Recombinant Human DNase I Reduces the Viscosity of Cystic Fibrosis Sputum. by Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL. 1990 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=55129

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Recovery of Mycobacteria from Patients with Cystic Fibrosis. by Bange FC, Kirschner P, Bottger EC. 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=85755

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Red-Pigmented Candida albicans in Patients with Cystic Fibrosis. by Kerkmann ML, Schuppler M, Paul KD. 1999 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=84240

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Regulation of Cl- Channels in Normal and Cystic Fibrosis Airway Epithelial Cells by Extracellular ATP. by Stutts MJ, Chinet TC, Mason SJ, Fullton JM, Clarke LL, Boucher RC. 1992 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48504

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Regulation of cystic fibrosis transmembrane conductance regulator single-channel gating by bivalent PDZ-domain-mediated interaction. by Raghuram V, Mak DO, Foskett JK. 2001 Jan 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14749

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Regulation of the Gating of Cystic Fibrosis Transmembrane Conductance Regulator C1 Channels by Phosphorylation and ATP Hydrolysis. by Hwang T, Nagel G, Nairn AC, Gadsby DC. 1994 May 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43855

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Relationship of a Non-Cystic Fibrosis Transmembrane Conductance RegulatorMediated Chloride Conductance to Organ-Level Disease in Cftr(-/-) Mice. by Clarke LL, Grubb BR, Yankaskas JR, Cotton CU, McKenzie A, Boucher RC. 1994 Jan 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42972

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Rescuing protein conformation: prospects for pharmacological therapy in cystic fibrosis. by Gelman MS, Kopito RR. 2002 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151638

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Ribosomal DNA-Directed PCR for Identification of Achromobacter (Alcaligenes) xylosoxidans Recovered from Sputum Samples from Cystic Fibrosis Patients. by Liu L, Coenye T, Burns JL, Whitby PW, Stull TL, LiPuma JJ. 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=140369

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Role of the cystic fibrosis transmembrane conductance regulator in innate immunity to Pseudomonas aeruginosa infections. by Pier GB. 2000 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34018

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Routine susceptibility testing of four antibiotic combinations for improvement of laboratory guide to therapy of cystic fibrosis infections caused by Pseudomonas aeruginosa.. by Weiss K, Lapointe JR. 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=162957

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Salmonella enterica Serovar Typhi Modulates Cell Surface Expression of Its Receptor, the Cystic Fibrosis Transmembrane Conductance Regulator, on the Intestinal Epithelium. by Lyczak JB, Pier GB. 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130400

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Sensitivity of a Renal K+ Channel (ROMK2) to the Inhibitory Sulfonylurea Compound Glibenclamide is Enhanced by Coexpression with the ATP-Binding Cassette Transporter Cystic Fibrosis Transmembrane Regulator. by McNicholas CM, Guggino WB, Schwiebert EM, Hebert SC, Giebisch G, Egan ME. 1996 Jul 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38879

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Sera from Adult Patients with Cystic Fibrosis Contain Antibodies to Pseudomonas aeruginosa Type III Apparatus. by Moss J, Ehrmantraut ME, Banwart BD, Frank DW, Barbieri JT. 2001 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=98003

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Siderophore Production by Cystic Fibrosis Isolates of Burkholderia cepacia. by Darling P, Chan M, Cox AD, Sokol PA. 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=107988

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Single and Combination Antibiotic Susceptibilities of Planktonic, Adherent, and Biofilm-Grown Pseudomonas aeruginosa Isolates Cultured from Sputa of Adults with Cystic Fibrosis. by Aaron SD, Ferris W, Ramotar K, Vandemheen K, Chan F, Saginur R. 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=139693

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Single Nucleotide Primer Extension to Detect Genetic Diseases: Experimental Application to Hemophilia B (Factor IX) and Cystic Fibrosis Genes. by Kuppuswamy MN, Hoffman JW, Kasper CK, Spitzer SG, Groce SL, Bajaj SP. 1991 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50973

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Six-Year Molecular Analysis of Burkholderia cepacia Complex Isolates among Cystic Fibrosis Patients at a Referral Center for Lung Transplantation. by Heath DG, Hohneker K, Carriker C, Smith K, Routh J, LiPuma JJ, Aris RM, Weber D, Gilligan PH. 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=140335

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Specific and Rapid Detection by Fluorescent In Situ Hybridization of Bacteria in Clinical Samples Obtained from Cystic Fibrosis Patients. by Hogardt M, Trebesius K, Geiger AM, Hornef M, Rosenecker J, Heesemann J. 2000 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86213

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Sputum Itraconazole Concentrations in Cystic Fibrosis Patients. by Sermet-Gaudelus I, Lesne-Hulin A, Lenoir G, Singlas E, Berche P, Hennequin C. 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=90579

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Stable in vivo Expression of the Cystic Fibrosis Transmembrane Conductance Regulator with an Adeno-Associated Virus Vector. by Flotte TR, Afione SA, Conrad C, McGarth SA, Solow R, Oka H, Zeitlin PL, Guggino WB, Carter BJ. 1993 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47827

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Submucosal gland secretions in airways from cystic fibrosis patients have normal [Na +] and pH but elevated viscosity. by Jayaraman S, Joo NS, Reitz B, Wine JJ, Verkman AS. 2001 Jul 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=35477

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Superantigens and Cystic Fibrosis: Resistance of Presenting Cells to Dexamethasone. by Ben-Ari J, Gozal D, Dorio RJ, Bowman CM, Reiff A, Walker SM. 2000 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=95912

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Synergistic Activities of Macrolide Antibiotics against Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, and Alcaligenes xylosoxidans Isolated from Patients with Cystic Fibrosis. by Saiman L, Chen Y, San Gabriel P, Knirsch C. 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=127106

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Taking stock of gene therapy for cystic fibrosis. by Stern M, Geddes DM, Alton EW. 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59546

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The Common Variant of Cystic Fibrosis Transmembrane Conductance Regulator is Recognized by hsp70 and Degraded in a Pre-Golgi Nonlysosomal Compartment. by Yang Y, Janich S, Cohn JA, Wilson JM. 1993 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47592

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The Gene for Congenital Chloride Diarrhea Maps Close to but is Distinct from the Gene for Cystic Fibrosis Transmembrane Conductance Regulator. by Kere J, Sistonen P, Holmberg C, Chapelle AD. 1993 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47842

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The PEST sequence does not contribute to the stability of the cystic fibrosis transmembrane conductance regulator. by Chen EY, Clarke DM. 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130031

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The Pseudomonas aeruginosa Secretory Product Pyocyanin Inactivates [alpha]1 Protease Inhibitor: Implications for the Pathogenesis of Cystic Fibrosis Lung Disease. by Britigan BE, Railsback MA, Cox CD. 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96448

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Toward an Animal Model of Cystic Fibrosis: Targeted Interruption of Exon 10 of the Cystic Fibrosis Transmembrane Regulator Gene in Embryonic Stem Cells. by Koller BH, Kim H, Latour AM, Brigman K, Boucher RC Jr, Scambler P, Wainwright B, Smithies O. 1991 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=53004

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Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. by Li JD, Dohrman AF, Gallup M, Miyata S, Gum JR, Kim YS, Nadel JA, Prince A, Basbaum CB. 1997 Feb 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19623

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Two Cystic Fibrosis Transmembrane Conductance Regulator Mutations Have Different Effects on Both Pulmonary Phenotype and Regulation of Outwardly Rectified Chloride Currents. by Fulmer SB, Schwiebert EM, Morales MM, Guggino WB, Cutting GR. 1995 Jul 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41423

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Unique presentations and chronic complications in adult cystic fibrosis: do they teach us anything about CFTR? by Boyle MP. 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59552

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Uptake of Fluorescent Dyes Associated with the Functional Expression of the Cystic Fibrosis Transmembrane Conductance Regulator in Epithelial Cells. by Wersto RP, Rosenthal ER, Crystal RG, Spring KR. 1996 Feb 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40050

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Use of 16S rRNA Gene Sequencing for Identification of Nonfermenting GramNegative Bacilli Recovered from Patients Attending a Single Cystic Fibrosis Center. by Ferroni A, Sermet-Gaudelus I, Abachin E, Quesne G, Lenoir G, Berche P, Gaillard JL. 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=130867

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Use of Random Amplified Polymorphic DNA PCR To Examine Epidemiology of Stenotrophomonas maltophilia and Achromobacter (Alcaligenes) xylosoxidans from Patients with Cystic Fibrosis. by Krzewinski JW, Nguyen CD, Foster JM, Burns JL. 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=88395

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Use of Subtractive Hybridization To Identify a Diagnostic Probe for a Cystic Fibrosis Epidemic Strain of Pseudomonas aeruginosa. by Parsons YN, Panagea S, Smart CH, Walshaw MJ, Hart CA, Winstanley C. 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=154653

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Utility of Commercial Systems for Identification of Burkholderia cepacia Complex from Cystic Fibrosis Sputum Culture. by Shelly DB, Spilker T, Gracely EJ, Coenye T, Vandamme P, LiPuma JJ. 2000 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=87204

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Utility of Gram Staining for Evaluation of the Quality of Cystic Fibrosis Sputum Samples. by Nair B, Stapp J, Stapp L, Bugni L, Van Dalfsen J, Burns JL. 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=120690

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Variation in the Composition and Pore Function of Major Outer Membrane Pore Protein P2 of Haemophilus influenzae from Cystic Fibrosis Patients. by Regelink AG, Dahan D, Moller LV, Coulton JW, Eijk P, Van Ulsen P, Dankert J, Van Alphen L. 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=89055

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with cystic fibrosis, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “cystic fibrosis” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for cystic fibrosis (hyperlinks lead to article summaries): •

A bacterial cell to cell signal in the lungs of cystic fibrosis patients. Author(s): Collier DN, Anderson L, McKnight SL, Noah TL, Knowles M, Boucher R, Schwab U, Gilligan P, Pesci EC. Source: Fems Microbiology Letters. 2002 September 24; 215(1): 41-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12393198&dopt=Abstract

6 PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

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A clinical perspective of cystic fibrosis and new genetic findings: relationship of CFTR mutations to genotype-phenotype manifestations. Author(s): Kulczycki LL, Kostuch M, Bellanti JA. Source: American Journal of Medical Genetics. 2003 January 30; 116A(3): 262-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12503104&dopt=Abstract

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A comparative study of hypertonic saline, daily and alternate-day rhDNase in children with cystic fibrosis. Author(s): Suri R, Wallis C, Bush A, Thompson S, Normand C, Flather M, Grieve R, Metcalfe C, Lees B. Source: Health Technology Assessment (Winchester, England). 2002; 6(34): Iii, 1-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12583821&dopt=Abstract

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A comparison of pulmonary exacerbations with single and multiple organisms in patients with cystic fibrosis and chronic Burkholderia cepacia infection. Author(s): Mc Manus TE, Moore JE, Crowe M, Dunbar K, Elborn JS. Source: The Journal of Infection. 2003 January; 46(1): 56-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12504610&dopt=Abstract

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A comparison of the therapeutic effectiveness of and preference for postural drainage and percussion, intrapulmonary percussive ventilation, and high-frequency chest wall compression in hospitalized cystic fibrosis patients. Author(s): Varekojis SM, Douce FH, Flucke RL, Filbrun DA, Tice JS, McCoy KS, Castile RG. Source: Respiratory Care. 2003 January; 48(1): 24-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12556258&dopt=Abstract

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A cost-effectiveness analysis of rhDNase in children with cystic fibrosis. Author(s): Grieve R, Thompson S, Normand C, Suri R, Bush A, Wallis C. Source: International Journal of Technology Assessment in Health Care. 2003 Winter; 19(1): 71-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701940&dopt=Abstract

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A genetic screening programme for Tay-Sachs disease and cystic fibrosis for Australian Jewish high school students. Author(s): Barlow-Stewart K, Burnett L, Proos A, Howell V, Huq F, Lazarus R, Aizenberg H. Source: Journal of Medical Genetics. 2003 April; 40(4): E45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12676918&dopt=Abstract

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A girl with cystic fibrosis and failure to thrive. Author(s): Kamath BM, Bhargava S, Markowitz JE, Ruchelli E, Scanlin TF, Mascarenhas M. Source: The Journal of Pediatrics. 2003 July; 143(1): 115-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915836&dopt=Abstract

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A liposome model to treat pseudomonas in lungs of cystic fibrosis and immune compromised patients. Author(s): Yatvin MB. Source: Cellular & Molecular Biology Letters. 2002; 7(2): 304. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12097974&dopt=Abstract

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A model for transition from pediatric to adult care in cystic fibrosis. Author(s): Madge S, Bryon M. Source: Journal of Pediatric Nursing. 2002 August; 17(4): 283-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12219328&dopt=Abstract

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A mutation in the cystic fibrosis transmembrane conductance regulator generates a novel internalization sequence and enhances endocytic rates. Author(s): Silvis MR, Picciano JA, Bertrand C, Weixel K, Bridges RJ, Bradbury NA. Source: The Journal of Biological Chemistry. 2003 March 28; 278(13): 11554-60. Epub 2003 January 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12529365&dopt=Abstract

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A new age for childhood diseases. Cystic fibrosis. Author(s): Ellmers K, Criddle LM. Source: Rn. 2002 September; 65(9): 60-6; Quiz 70. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12365153&dopt=Abstract

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A possible antiinflammatory treatment for cystic fibrosis. Author(s): Derleth DP. Source: American Journal of Respiratory and Critical Care Medicine. 2003 January 15; 167(2): 278-9; Author Reply 279. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12524259&dopt=Abstract

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A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Author(s): Hodson ME, Gallagher CG, Govan JR. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 September; 20(3): 658-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12358344&dopt=Abstract

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A review of nutritional problems and the cystic fibrosis lung transplant patient. Author(s): Dosanjh A. Source: Pediatric Transplantation. 2002 October; 6(5): 388-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12390424&dopt=Abstract

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A scientific koan: what is the cause of cystic fibrosis? Author(s): Rubin BK. Source: Chest. 2003 June; 123(6): 1792-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12796151&dopt=Abstract

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A simple alfalfa seedling infection model for Pseudomonas aeruginosa strains associated with cystic fibrosis shows AlgT (sigma-22) and RhlR contribute to pathogenesis. Author(s): Silo-Suh L, Suh SJ, Sokol PA, Ohman DE. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 November 26; 99(24): 15699-704. Epub 2002 Nov 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12426404&dopt=Abstract

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A widely available method for the assessment of aerosol delivery in cystic fibrosis. Author(s): Kastelik JA, Wright GA, Aziz I, Davies M, Avery GR, Paddon AJ, Howey S, Morice AH. Source: Pulmonary Pharmacology & Therapeutics. 2002; 15(6): 513-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12493338&dopt=Abstract

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Abnormal glucose tolerance in cystic fibrosis: why should patients be screened? Author(s): Moran A, Milla C. Source: The Journal of Pediatrics. 2003 February; 142(2): 97-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12584525&dopt=Abstract

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Abnormal passive chloride absorption in cystic fibrosis jejunum functionally opposes the classic chloride secretory defect. Author(s): Russo MA, Hogenauer C, Coates SW Jr, Santa Ana CA, Porter JL, Rosenblatt RL, Emmett M, Fordtran JS. Source: The Journal of Clinical Investigation. 2003 July; 112(1): 118-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12840066&dopt=Abstract

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Abnormalities of the PTH-vitamin D axis and bone turnover markers in children, adolescents and adults with cystic fibrosis: comparison with healthy controls. Author(s): Greer RM, Buntain HM, Potter JM, Wainwright CE, Wong JC, O'Rourke PK, Francis PW, Bell SC, Batch JA. Source: Osteoporosis International : a Journal Established As Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the Usa. 2003 June; 14(5): 404-11. Epub 2003 April 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12730764&dopt=Abstract

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Absent secretion to vasoactive intestinal peptide in cystic fibrosis airway glands. Author(s): Joo NS, Irokawa T, Wu JV, Robbins RC, Whyte RI, Wine JJ. Source: The Journal of Biological Chemistry. 2002 December 27; 277(52): 50710-5. Epub 2002 October 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12368280&dopt=Abstract

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Acrodermatitis enteropathica-like eruption: a sign of malabsorption in cystic fibrosis. Author(s): Patrizi A, Bianchi F, Neri I, Specchia F. Source: Pediatric Dermatology. 2003 March-April; 20(2): 187-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12657028&dopt=Abstract

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Activity of disinfectants against Gram-negative bacilli isolated from patients undergoing lung transplantation for cystic fibrosis. Author(s): Perry JD, Riley G, Johnston S, Dark JH, Gould FK. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2002 November; 21(11): 1230-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12431498&dopt=Abstract

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Acute neurological deficits in a young adult with cystic fibrosis. Author(s): Sritippayawan S, MacLaughlin EF, Woo MS. Source: Pediatric Pulmonology. 2003 February; 35(2): 147-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12526078&dopt=Abstract

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Acute renal failure and cystic fibrosis. Author(s): Drew J, Watson AR, Smyth A. Source: Archives of Disease in Childhood. 2003 July; 88(7): 646. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818927&dopt=Abstract

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Acute renal failure in cystic fibrosis: association with inhaled tobramycin therapy. Author(s): Hoffmann IM, Rubin BK, Iskandar SS, Schechter MS, Nagaraj SK, Bitzan MM. Source: Pediatric Pulmonology. 2002 November; 34(5): 375-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12357482&dopt=Abstract

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Additive effect of dornase alfa and Nacystelyn on transportability and viscoelasticity of cystic fibrosis sputum. Author(s): Sun F, Tai S, Lim T, Baumann U, King M. Source: Can Respir J. 2002 November-December; 9(6): 401-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12522485&dopt=Abstract

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Adrenal insufficiency and testicular failure secondary to megestrol acetate therapy in a patient with cystic fibrosis. Author(s): McKone EF, Tonelli MR, Aitken ML. Source: Pediatric Pulmonology. 2002 November; 34(5): 381-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12357484&dopt=Abstract

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Age of diagnosis of cystic fibrosis. Author(s): Smith AD, Moffat CJ, Wilkinson JR. Source: Lancet. 2003 July 12; 362(9378): 171. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12867125&dopt=Abstract

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Airway clearance in cystic fibrosis. Author(s): Goss CH. Source: Respiratory Care. 2003 January; 48(1): 20-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12556256&dopt=Abstract

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Airway glycoconjugates and cystic fibrosis. Author(s): Roussel P. Source: Glycoconjugate Journal. 2001 September; 18(9): 645-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12386451&dopt=Abstract

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Airway mucus in cystic fibrosis. Author(s): Puchelle E, Bajolet O, Abely M. Source: Paediatric Respiratory Reviews. 2002 June; 3(2): 115-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12297057&dopt=Abstract

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Airway surface pH in subjects with cystic fibrosis. Author(s): McShane D, Davies JC, Davies MG, Bush A, Geddes DM, Alton EW. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 January; 21(1): 37-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12570106&dopt=Abstract

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Alcaligenes infection in cystic fibrosis. Author(s): Tan K, Conway SP, Brownlee KG, Etherington C, Peckham DG. Source: Pediatric Pulmonology. 2002 August; 34(2): 101-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12112775&dopt=Abstract

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Aminoglycoside prescribing and surveillance in cystic fibrosis. Author(s): Tan KH, Mulheran M, Knox AJ, Smyth AR. Source: American Journal of Respiratory and Critical Care Medicine. 2003 March 15; 167(6): 819-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12623858&dopt=Abstract

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An automated approach to quantitative air trapping measurements in mild cystic fibrosis. Author(s): Goris ML, Zhu HJ, Blankenberg F, Chan F, Robinson TE. Source: Chest. 2003 May; 123(5): 1655-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12740287&dopt=Abstract

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An evidence-based pilot study exploring relationships between psychologic and physiologic factors in post-lung-transplant adolescents with cystic fibrosis. Author(s): Sredl D, Werner T, Springhart D, Watkins D, Shaner M, McBride G. Source: Journal of Pediatric Nursing. 2003 June; 18(3): 216-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12796866&dopt=Abstract

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An overview of the pathogenesis of cystic fibrosis lung disease. Author(s): Boucher RC. Source: Advanced Drug Delivery Reviews. 2002 December 5; 54(11): 1359-71. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458149&dopt=Abstract

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An unusual case of pulmonary invasive aspergillosis and aspergilloma cured with voriconazole in a patient with cystic fibrosis. Author(s): Chow L, Brown NE, Kunimoto D. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 November 1; 35(9): E106-10. Epub 2002 October 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12384856&dopt=Abstract

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Anaerobic biofilm infections in cystic fibrosis. Author(s): Costerton JW. Source: Molecular Cell. 2002 October; 10(4): 699-700. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12419212&dopt=Abstract

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Anaerobic metabolism and quorum sensing by Pseudomonas aeruginosa biofilms in chronically infected cystic fibrosis airways: rethinking antibiotic treatment strategies and drug targets. Author(s): Hassett DJ, Cuppoletti J, Trapnell B, Lymar SV, Rowe JJ, Yoon SS, Hilliard GM, Parvatiyar K, Kamani MC, Wozniak DJ, Hwang SH, McDermott TR, Ochsner UA. Source: Advanced Drug Delivery Reviews. 2002 December 5; 54(11): 1425-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458153&dopt=Abstract

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Analysis of sequential aliquots of hypertonic saline solution-induced sputum from clinically stable patients with cystic fibrosis. Author(s): Aitken ML, Greene KE, Tonelli MR, Burns JL, Emerson JC, Goss CH, Gibson RL. Source: Chest. 2003 March; 123(3): 792-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628880&dopt=Abstract

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Analysis of the costs of diagnosing cystic fibrosis with a newborn screening program. Author(s): Lee DS, Rosenberg MA, Peterson A, Makholm L, Hoffman G, Laessig RH, Farrell PM. Source: The Journal of Pediatrics. 2003 June; 142(6): 617-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12838188&dopt=Abstract

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Analysis of the two common alpha-1-antitrypsin deficiency alleles PiMS and PiMZ as modifiers of Pseudomonas aeruginosa susceptibility in cystic fibrosis. Author(s): Meyer P, Braun A, Roscher AA. Source: Clinical Genetics. 2002 October; 62(4): 325-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12372062&dopt=Abstract

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Analytic validity of cystic fibrosis testing: a preliminary estimate. Author(s): Palomaki GE, Bradley LA, Richards CS, Haddow JE. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2003 January-February; 5(1): 15-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544471&dopt=Abstract

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Antibiotic treatment and renal stone formation in cystic fibrosis. Author(s): Alon US. Source: The Journal of Pediatrics. 2002 October; 141(4): 598; Author Reply 598. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12378210&dopt=Abstract

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Anti-inflammatory effects of montelukast in mild cystic fibrosis. Author(s): Schmitt-Grohe S, Eickmeier O, Schubert R, Bez C, Zielen S. Source: Annals of Allergy, Asthma & Immunology : Official Publication of the American College of Allergy, Asthma, & Immunology. 2002 December; 89(6): 599-605. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12487226&dopt=Abstract

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Antimicrobial susceptibility profile of molecular typed cystic fibrosis Stenotrophomonas maltophilia isolates and differences with noncystic fibrosis isolates. Author(s): Canton R, Valdezate S, Vindel A, Sanchez Del Saz B, Maiz L, Baquero F. Source: Pediatric Pulmonology. 2003 February; 35(2): 99-107. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12526070&dopt=Abstract

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Antineutrophil cytoplasmic antibodies directed against bactericidal/permeabilityincreasing protein detected in children with cystic fibrosis inhibit neutrophilmediated killing of Pseudomonas aeruginosa. Author(s): Sediva A, Bartunkova J, Bartosova J, Jennette C, Falk RJ, Jethwa HS. Source: Microbes and Infection / Institut Pasteur. 2003 January; 5(1): 27-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12593970&dopt=Abstract

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Anti-neutrophil-cytoplasmic auto-antibodies (ANCA) in 105 patients (56 adults and 49 children) suffering from cystic fibrosis, attending a Spanish hospital. Author(s): Carmona E, Perez-Aguilar F, Lopez JA, Ferrer-Calvete J, Sanchez-Cuenca JM. Source: Journal of Internal Medicine. 2002 September; 252(3): 281-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12270011&dopt=Abstract

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Applying CFTR molecular genetics to facilitate the diagnosis of cystic fibrosis through screening. Author(s): Bobadilla JL, Farrell MH, Farrell PM. Source: Adv Pediatr. 2002; 49: 131-90. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12214770&dopt=Abstract

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Are annual blood tests in preschool cystic fibrosis patients worthwhile? Author(s): Jaffe A, Buchdahl R, Bush A, Balfour-Lynn IM. Source: Archives of Disease in Childhood. 2002 December; 87(6): 518-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12456552&dopt=Abstract

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Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients. Author(s): Helmi M, Love RB, Welter D, Cornwell RD, Meyer KC. Source: Chest. 2003 March; 123(3): 800-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628881&dopt=Abstract

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Aspergillus terreus in a cystic fibrosis clinic: environmental distribution and patient colonization pattern. Author(s): Cimon B, Zouhair R, Symoens F, Carrere J, Chabasse D, Bouchara JP. Source: The Journal of Hospital Infection. 2003 January; 53(1): 81-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495692&dopt=Abstract

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Asthma in cystic fibrosis. Author(s): Balfour-Lynn IM. Source: Journal of the Royal Society of Medicine. 2003; 96 Suppl 43: 30-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906323&dopt=Abstract

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Atypical cystic fibrosis--diagnostic and management dilemmas. Author(s): Wallis C. Source: Journal of the Royal Society of Medicine. 2003; 96 Suppl 43: 2-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906319&dopt=Abstract

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Autonomic dysfunction in cystic fibrosis. Author(s): Mirakhur A, Walshaw MJ. Source: Journal of the Royal Society of Medicine. 2003; 96 Suppl 43: 11-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906320&dopt=Abstract

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Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. Author(s): Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, Coquillette S, Fieberg AY, Accurso FJ, Campbell PW 3rd; Macrolide Study Group. Source: Jama : the Journal of the American Medical Association. 2003 October 1; 290(13): 1749-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14519709&dopt=Abstract

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Bacterial infections and inflammation in the lungs of cystic fibrosis patients. Author(s): Conese M, Assael BM. Source: The Pediatric Infectious Disease Journal. 2001 February; 20(2): 207-13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11224844&dopt=Abstract

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Barriers to and new approaches for gene therapy and gene delivery in cystic fibrosis. Author(s): Ferrari S, Geddes DM, Alton EW. Source: Advanced Drug Delivery Reviews. 2002 December 5; 54(11): 1373-93. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458150&dopt=Abstract

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Basal nucleotide levels, release, and metabolism in normal and cystic fibrosis airways. Author(s): Donaldson SH, Lazarowski ER, Picher M, Knowles MR, Stutts MJ, Boucher RC. Source: Molecular Medicine (Cambridge, Mass.). 2000 November; 6(11): 969-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11147574&dopt=Abstract

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Bayesian forecasting of oral cyclosporin pharmacokinetics in stable lung transplant recipients with and without cystic fibrosis. Author(s): Rousseau A, Monchaud C, Debord J, Vervier I, Estenne M, Thiry P, Marquet P. Source: Therapeutic Drug Monitoring. 2003 February; 25(1): 28-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12548141&dopt=Abstract

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Beclomethasone diproprionate reduced airway inflammation without adrenal suppression in young children with cystic fibrosis: a pilot study. Author(s): Wojtczak HA, Kerby GS, Wagener JS, Copenhaver SC, Gotlin RW, Riches DW, Accurso FJ. Source: Pediatric Pulmonology. 2001 October; 32(4): 293-302. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11568990&dopt=Abstract

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Benzimidazolone activators of chloride secretion: potential therapeutics for cystic fibrosis and chronic obstructive pulmonary disease. Author(s): Singh S, Syme CA, Singh AK, Devor DC, Bridges RJ. Source: The Journal of Pharmacology and Experimental Therapeutics. 2001 February; 296(2): 600-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11160649&dopt=Abstract

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beta2 adrenoceptor gene polymorphisms in cystic fibrosis lung disease. Author(s): Buscher R, Eilmes KJ, Grasemann H, Torres B, Knauer N, Sroka K, Insel PA, Ratjen F. Source: Pharmacogenetics. 2002 July; 12(5): 347-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12142724&dopt=Abstract

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Bicarbonate secretion in the murine gallbladder--lessons for the treatment of cystic fibrosis. Author(s): Cuthbert AW. Source: Jop [electronic Resource] : Journal of the Pancreas. 2001 July; 2(4 Suppl): 257-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11875268&dopt=Abstract

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Bilateral ethmoidal mucocele in cystic fibrosis: report of a case. Author(s): Thome DC, Voegels RL, Cataldo de la Cortina RA, Butugan O. Source: International Journal of Pediatric Otorhinolaryngology. 2000 September 29; 55(2): 143-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11006454&dopt=Abstract

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Biochemical implications of sequence comparisons of the cystic fibrosis transmembrane conductance regulator. Author(s): Tan AL, Ong SA, Venkatesh B. Source: Archives of Biochemistry and Biophysics. 2002 May 15; 401(2): 215-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12054472&dopt=Abstract

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Biofilm studies yield targets against cystic fibrosis. Author(s): Flores G. Source: Drug Discovery Today. 2002 December 1; 7(23): 1147-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12547008&dopt=Abstract

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Biosensor technology for real-time detection of the cystic fibrosis W1282X mutation in CFTR. Author(s): Feriotto G, Ferlini A, Ravani A, Calzolari E, Mischiati C, Bianchi N, Gambari R. Source: Human Mutation. 2001; 18(1): 70-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11438995&dopt=Abstract

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Birth of healthy female twins after preimplantation genetic diagnosis of cystic fibrosis combined with gender determination. Author(s): Ray PF, Frydman N, Attie T, Hamamah S, Kerbrat V, Tachdjian G, Romana S, Vekemans M, Frydman R, Munnich A. Source: Molecular Human Reproduction. 2002 July; 8(7): 688-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12087085&dopt=Abstract

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Bisphosphonates for osteoporosis in people with cystic fibrosis. Author(s): Brenckmann C, Papaioannou A. Source: Cochrane Database Syst Rev. 2001; (4): Cd002010. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11687132&dopt=Abstract

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Body image and dieting behavior in cystic fibrosis. Author(s): Truby H, Paxton AS. Source: Pediatrics. 2001 June; 107(6): E92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11389290&dopt=Abstract

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Body image in cystic fibrosis--development of a brief diagnostic scale. Author(s): Wenninger K, Weiss C, Wahn U, Staab D. Source: Journal of Behavioral Medicine. 2003 February; 26(1): 81-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12690948&dopt=Abstract

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Bolus inhalation of rhDNase with the AERx system in subjects with cystic fibrosis. Author(s): Geller D, Thipphawong J, Otulana B, Caplan D, Ericson D, Milgram L, Okikawa J, Quan J, Bowman CM. Source: Journal of Aerosol Medicine : the Official Journal of the International Society for Aerosols in Medicine. 2003 Summer; 16(2): 175-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823911&dopt=Abstract

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Bone density, body composition, and inflammatory status in cystic fibrosis. Author(s): Ionescu AA, Nixon LS, Evans WD, Stone MD, Lewis-Jenkins V, Chatham K, Shale DJ. Source: American Journal of Respiratory and Critical Care Medicine. 2000 September; 162(3 Pt 1): 789-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10988084&dopt=Abstract

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Bone histomorphometry in adult patients with cystic fibrosis. Author(s): Haworth CS, Webb AK, Egan JJ, Selby PL, Hasleton PS, Bishop PW, Freemont TJ. Source: Chest. 2000 August; 118(2): 434-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10936137&dopt=Abstract

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Bone mineral density and quantitative ultrasound in adults with cystic fibrosis. Author(s): Flohr F, Lutz A, App EM, Matthys H, Reincke M. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2002 April; 146(4): 531-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11916622&dopt=Abstract

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Bone status in cystic fibrosis. Author(s): Sood M, Hambleton G, Super M, Fraser WD, Adams JE, Mughal MZ. Source: Archives of Disease in Childhood. 2001 June; 84(6): 516-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11369574&dopt=Abstract

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Breath isoprene during acute respiratory exacerbation in cystic fibrosis. Author(s): McGrath LT, Patrick R, Mallon P, Dowey L, Silke B, Norwood W, Elborn S. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2000 December; 16(6): 1065-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11292107&dopt=Abstract

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Bronchial artery embolization for hemoptysis in young patients with cystic fibrosis. Author(s): Barben J, Robertson D, Olinsky A, Ditchfield M. Source: Radiology. 2002 July; 224(1): 124-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12091671&dopt=Abstract

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Bronchial artery embolization for the management of nonmassive hemoptysis in cystic fibrosis. Author(s): Antonelli M, Midulla F, Tancredi G, Salvatori FM, Bonci E, Cimino G, Flaishman I. Source: Chest. 2002 March; 121(3): 796-801. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11888962&dopt=Abstract

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Bronchial reactions to the inhalation of high-dose tobramycin in cystic fibrosis. Author(s): Nikolaizik WH, Trociewicz K, Ratjen F. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 July; 20(1): 122-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12166559&dopt=Abstract

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Bronchoalveolar fluid is not a major hindrance to virus-mediated gene therapy in cystic fibrosis. Author(s): Rooney CP, Denning GM, Davis BP, Flaherty DM, Chiorini JA, Zabner J. Source: Journal of Virology. 2002 October; 76(20): 10437-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12239320&dopt=Abstract

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Bronchoalveolar lavage fluid surfactant protein-A and surfactant protein-D are inversely related to inflammation in early cystic fibrosis. Author(s): Noah TL, Murphy PC, Alink JJ, Leigh MW, Hull WM, Stahlman MT, Whitsett JA. Source: American Journal of Respiratory and Critical Care Medicine. 2003 September 15; 168(6): 685-91. Epub 2003 June 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829455&dopt=Abstract

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Bronchoconstriction following nebulised colistin in cystic fibrosis. Author(s): Cunningham S, Prasad A, Collyer L, Carr S, Lynn IB, Wallis C. Source: Archives of Disease in Childhood. 2001 May; 84(5): 432-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11316693&dopt=Abstract

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Bronchodilators in cystic fibrosis. Author(s): Brand PL. Source: Journal of the Royal Society of Medicine. 2000; 93 Suppl 38: 37-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10911817&dopt=Abstract

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Bronchodilatory effects of salbutamol, ipratropium bromide, and their combination: double-blind, placebo-controlled crossover study in cystic fibrosis. Author(s): Ziebach R, Pietsch-Breitfeld B, Bichler M, Busch A, Riethmuller J, Stern M. Source: Pediatric Pulmonology. 2001 June; 31(6): 431-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11389575&dopt=Abstract

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Bronchoscopically administered recombinant human DNase for lobar atelectasis in cystic fibrosis. Author(s): Slattery DM, Waltz DA, Denham B, O'Mahony M, Greally P. Source: Pediatric Pulmonology. 2001 May; 31(5): 383-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11340685&dopt=Abstract

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Buccal adherence of Pseudomonas aeruginosa in patients with cystic fibrosis under long-term therapy with azithromycin. Author(s): Baumann U, Fischer JJ, Gudowius P, Lingner M, Herrmann S, Tummler B, von der Hardt H. Source: Infection. 2001 January-February; 29(1): 7-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11261763&dopt=Abstract

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Burkholderia ambifaria sp. nov., a novel member of the Burkholderia cepacia complex including biocontrol and cystic fibrosis-related isolates. Author(s): Coenye T, Mahenthiralingam E, Henry D, LiPuma JJ, Laevens S, Gillis M, Speert DP, Vandamme P. Source: International Journal of Systematic and Evolutionary Microbiology. 2001 July; 51(Pt 4): 1481-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11491349&dopt=Abstract

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Burkholderia cepacia and cystic fibrosis--50 years on. Author(s): Moore JE, Elborn JS. Source: Commun Dis Public Health. 2001 June; 4(2): 114-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11524998&dopt=Abstract

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Burkholderia cepacia complex genomovars and pulmonary transplantation outcomes in patients with cystic fibrosis. Author(s): De Soyza A, McDowell A, Archer L, Dark JH, Elborn SJ, Mahenthiralingam E, Gould K, Corris PA. Source: Lancet. 2001 November 24; 358(9295): 1780-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11734238&dopt=Abstract

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Burkholderia cepacia complex in cystic fibrosis and non-cystic fibrosis patients: identification of a cluster of epidemic lineages. Author(s): Agodi A, Barchitta M, Giannino V, Collura A, Pensabene T, Garlaschi ML, Pasquarella C, Luzzaro F, Sinatra F, Mahenthiralingam E, Stefani S. Source: The Journal of Hospital Infection. 2002 March; 50(3): 188-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11886194&dopt=Abstract

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Burkholderia cepacia complex infection in Italian patients with cystic fibrosis: prevalence, epidemiology, and genomovar status. Author(s): Agodi A, Mahenthiralingam E, Barchitta M, Giannino V, Sciacca A, Stefani S. Source: Journal of Clinical Microbiology. 2001 August; 39(8): 2891-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11474009&dopt=Abstract

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Burkholderia cepacia complex infection in patients with cystic fibrosis. Author(s): Mahenthiralingam E, Baldwin A, Vandamme P. Source: Journal of Medical Microbiology. 2002 July; 51(7): 533-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12132768&dopt=Abstract

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Burkholderia cepacia complex: a contraindication to lung transplantation in cystic fibrosis? Author(s): LiPuma JJ. Source: Transplant Infectious Disease : an Official Journal of the Transplantation Society. 2001 September; 3(3): 149-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11493397&dopt=Abstract

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Burkholderia cepacia genomovar VI, a new member of the Burkholderia cepacia complex isolated from cystic fibrosis patients. Author(s): Coenye T, LiPuma JJ, Henry D, Hoste B, Vandemeulebroecke K, Gillis M, Speert DP, Vandamme P. Source: International Journal of Systematic and Evolutionary Microbiology. 2001 March; 51(Pt 2): 271-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11321071&dopt=Abstract

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Burkholderia cepacia in cystic fibrosis: implications for nursing practice. Author(s): Henskens JE, VonNessen SK. Source: Pediatric Nursing. 2000 May-June; 26(3): 325-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12026400&dopt=Abstract

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Burkholderia cepacia in cystic fibrosis: novel Australian cluster strain without accelerated respiratory deterioration. Author(s): Fitzgerald DA, Cooper DM, Paul M, Tiley S, Kado J, Cordwell J, Collins C. Source: Journal of Paediatrics and Child Health. 2001 April; 37(2): 130-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11328466&dopt=Abstract

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Burkholderia cepacia--a transmissible cystic fibrosis pathogen. Author(s): Burns JL. Source: The Journal of Pediatrics. 2001 November; 139(5): 618-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11713434&dopt=Abstract

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Burkholderia gladioli: recurrent abscesses in a patient with cystic fibrosis. Author(s): Jones AM, Stanbridge TN, Isalska BJ, Dodd ME, Webb AK. Source: The Journal of Infection. 2001 January; 42(1): 69-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11243758&dopt=Abstract

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Can glutamine and growth hormone promote protein anabolism in children with cystic fibrosis? Author(s): Hayes V, Schaeffer D, Mauras N, Punati J, Darmaun D. Source: Hormone Research. 2002; 58 Suppl 1: 21-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12373009&dopt=Abstract

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Cancer risk in nontransplanted and transplanted cystic fibrosis patients: a 10-year study. Author(s): Maisonneuve P, FitzSimmons SC, Neglia JP, Campbell PW 3rd, Lowenfels AB. Source: Journal of the National Cancer Institute. 2003 March 5; 95(5): 381-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12618503&dopt=Abstract

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Changes in pulmonary mechanics with increasing disease severity in children and young adults with cystic fibrosis. Author(s): Hart N, Polkey MI, Clement A, Boule M, Moxham J, Lofaso F, Fauroux B. Source: American Journal of Respiratory and Critical Care Medicine. 2002 July 1; 166(1): 61-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12091172&dopt=Abstract

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Characteristics of EPI-hNE4 aerosol: a new elastase inhibitor for treatment of cystic fibrosis. Author(s): Grimbert D, Vecellio L, Delepine P, Attucci S, Boissinot E, Poncin A, Gauthier F, Valat C, Saudubray F, Antonioz P, Diot P. Source: Journal of Aerosol Medicine : the Official Journal of the International Society for Aerosols in Medicine. 2003 Summer; 16(2): 121-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823906&dopt=Abstract

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Characterization of a novel chemotactic factor for neutrophils in the bronchial secretions of patients with cystic fibrosis. Author(s): Dudez TS, Chanson M, Schlegel-Haueter SE, Suter S. Source: The Journal of Infectious Diseases. 2002 September 15; 186(6): 774-81. Epub 2002 August 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12198611&dopt=Abstract

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Chest physiotherapy in infants with cystic fibrosis: to tip or not? A five-year study. Author(s): Button BM, Heine RG, Catto-Smith AG, Olinsky A, Phelan PD, Ditchfield MR, Story I. Source: Pediatric Pulmonology. 2003 March; 35(3): 208-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12567389&dopt=Abstract

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Children with cystic fibrosis: who should visit the otorhinolaryngologist? Author(s): Slieker MG, Schilder AG, Uiterwaal CS, van der Ent CK. Source: Archives of Otolaryngology--Head & Neck Surgery. 2002 November; 128(11): 1245-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12431163&dopt=Abstract

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Chronic pancreatitis and cystic fibrosis. Author(s): Witt H. Source: Gut. 2003 May; 52 Suppl 2: Ii31-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12651880&dopt=Abstract

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Circadian rhythm of hunger sensation in patients affected by cystic fibrosis. Author(s): Cugini P, Bella S, Cilli M, De Rosa R, Pandolfi C, Lucidi V, Castro M. Source: Eat Weight Disord. 2003 June; 8(2): 124-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12880189&dopt=Abstract

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Clinical application of direct sputum sensitivity testing in a severe infective exacerbation of cystic fibrosis. Author(s): Serisier DJ, Jones G, Tuck A, Connett G, Carroll MP. Source: Pediatric Pulmonology. 2003 June; 35(6): 463-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746944&dopt=Abstract

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Clinical characteristics and genotype analysis of patients with cystic fibrosis and nasal polyposis. Author(s): Cimmino M, Cavaliere M, Nardone M, Plantulli A, Orefice A, Esposito V, Raia V. Source: Clinical Otolaryngology and Allied Sciences. 2003 April; 28(2): 125-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12680831&dopt=Abstract

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Clinical improvement in cystic fibrosis with early insulin treatment. Author(s): Dobson L, Hattersley AT, Tiley S, Elworthy S, Oades PJ, Sheldon CD. Source: Archives of Disease in Childhood. 2002 November; 87(5): 430-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12390923&dopt=Abstract

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Clinical profile and frequency of delta f508 mutation in Indian children with cystic fibrosis. Author(s): Kabra SK, Kabra M, Lodha R, Shastri S, Ghosh M, Pandey RM, Kapil A, Aggarwal G, Kapoor V. Source: Indian Pediatrics. 2003 July; 40(7): 612-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12881616&dopt=Abstract

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Commentary on bronchial artery embolization for hemoptysis in young patients with cystic fibrosis. Author(s): Yovichevich S. Source: Radiology. 2003 September; 228(3): 903; Author Reply 903-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12954908&dopt=Abstract

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Communicating a diagnosis of cystic fibrosis to an adult: what physicians need to know. Author(s): Widerman E. Source: Behavioral Medicine (Washington, D.C.). 2002 Summer; 28(2): 45-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12613285&dopt=Abstract

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Comparing the clinical evolution of cystic fibrosis screened neonatally to that of cystic fibrosis diagnosed from clinical symptoms: a 10-year retrospective study in a French region (Brittany). Author(s): Siret D, Bretaudeau G, Branger B, Dabadie A, Dagorne M, David V, de Braekeleer M, Moisan-Petit V, Picherot G, Rault G, Storni V, Roussey M. Source: Pediatric Pulmonology. 2003 May; 35(5): 342-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687590&dopt=Abstract

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Comparison of lung deposition of colomycin using the HaloLite and the Pari LC Plus nebulisers in patients with cystic fibrosis. Author(s): Byrne NM, Keavey PM, Perry JD, Gould FK, Spencer DA. Source: Archives of Disease in Childhood. 2003 August; 88(8): 715-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12876172&dopt=Abstract

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Comparison of steatocrit and fat absorption in persons with cystic fibrosis. Author(s): Wagner MH, Bowser EK, Sherman JM, Francisco MP, Theriaque D, Novak DA. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002 August; 35(2): 202-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12187298&dopt=Abstract

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Comparison of two different protocols of neonatal screening for cystic fibrosis. Author(s): Narzi L, Lucarelli M, Lelli A, Grandoni F, Lo Cicero S, Ferraro A, Matarazzo P, Delaroche I, Quattrucci S, Strom R, Antonelli M. Source: Clinical Genetics. 2002 September; 62(3): 245-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12220442&dopt=Abstract

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Congenital absence of vas deferens and cystic fibrosis. Author(s): Leonardi S, Bombace V, Rotolo N, Sciuto C, La Rosa M. Source: Minerva Pediatr. 2003 February; 55(1): 43-7, 47-50. English, Italian. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12660625&dopt=Abstract

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Consensus report on nutrition for pediatric patients with cystic fibrosis. Author(s): Borowitz D, Baker RD, Stallings V. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002 September; 35(3): 24659. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12352509&dopt=Abstract

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Coping with cystic fibrosis. Author(s): Abbott J. Source: Journal of the Royal Society of Medicine. 2003; 96 Suppl 43: 42-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906325&dopt=Abstract

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Correlation of six different cystic fibrosis chest radiograph scoring systems with clinical parameters. Author(s): Terheggen-Lagro S, Truijens N, van Poppel N, Gulmans V, van der Laag J, van der Ent C. Source: Pediatric Pulmonology. 2003 June; 35(6): 441-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746940&dopt=Abstract

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Cushing's syndrome due to pharmacological interaction in a cystic fibrosis patient. Author(s): Main KM, Skov M, Sillesen IB, Dige-Petersen H, Muller J, Koch C, Lanng S. Source: Acta Paediatrica (Oslo, Norway : 1992). 2002; 91(9): 1008-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12412882&dopt=Abstract

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Cyclosporine pharmacokinetics and dose monitoring after lung transplantation: comparison between cystic fibrosis and other conditions. Author(s): Knoop C, Vervier I, Thiry P, De Backer M, Kovarik JM, Rousseau A, Marquet P, Estenne M. Source: Transplantation. 2003 August 27; 76(4): 683-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12973109&dopt=Abstract

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Cystic Fibrosis and Burkholderia pseudomallei Infection: An Emerging Problem? Author(s): Holland DJ, Wesley A, Drinkovic D, Currie BJ. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 December 15; 35(12): E138-40. Epub 2002 November 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12471591&dopt=Abstract

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Cystic fibrosis and Chiari type I malformation: autopsy study of two infants with a rare association. Author(s): Rakheja D, Xu Y, Burns DK, Veltkamp DL, Margraf LR. Source: Pediatric and Developmental Pathology : the Official Journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. 2003 January-February; 6(1): 88-93. Epub 2002 November 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12415481&dopt=Abstract

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Cystic fibrosis and guidelines to assess significance of new colonisers? Author(s): Garske L, Moore JE, Crowe MJ, Elborn JS. Source: Ir J Med Sci. 2002 April-June; 171(2): 116-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12173884&dopt=Abstract

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Cystic fibrosis and pregnancy. Report from French data (1980-1999). Author(s): Gillet D, de Braekeleer M, Bellis G, Durieu I; French Cystic Fibrosis Registry. Source: Bjog : an International Journal of Obstetrics and Gynaecology. 2002 August; 109(8): 912-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12197372&dopt=Abstract

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Cystic fibrosis and renal disease. Author(s): Stephens SE, Rigden SP. Source: Paediatric Respiratory Reviews. 2002 June; 3(2): 135-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12297060&dopt=Abstract

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Cystic fibrosis and the transition to adulthood. Author(s): Palmer ML, Boisen LS. Source: Soc Work Health Care. 2002; 36(1): 45-58. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12506961&dopt=Abstract

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Cystic fibrosis and the use of pharmacogenomics to determine surrogate endpoints for drug discovery. Author(s): Eidelman O, Zhang J, Srivastava M, Pollard HB. Source: American Journal of Pharmacogenomics : Genomics-Related Research in Drug Development and Clinical Practice. 2001; 1(3): 223-38. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12083969&dopt=Abstract

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Cystic fibrosis carrier screening: issues in implementation. Author(s): Watson MS, Desnick RJ, Grody WW, Mennuti MT, Popovich BW, Richards CS. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2002 November-December; 4(6): 407-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12509709&dopt=Abstract

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Cystic fibrosis carrier testing in pregnancy in Canada. Author(s): Wilson RD, Davies G, Desilets V, Reid GJ, Shaw D, Summers A, Wyatt P, Young D, Crane J, Armson A, de la Ronde S, Farine D, Leduc L, Van Aerde J; Society of Obstetricians and Gynaecologists of Canada. Source: J Obstet Gynaecol Can. 2002 August; 24(8): 644-51. English, French. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12196844&dopt=Abstract

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Cystic fibrosis gene testing a challenge: experts say widespread use is creating unnecessary risks. Author(s): Vastag B. Source: Jama : the Journal of the American Medical Association. 2003 June 11; 289(22): 2923-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799389&dopt=Abstract

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Cystic fibrosis in adults: a changing scene. Author(s): Blau H, Livne M, Mussaffi H. Source: Isr Med Assoc J. 2003 July; 5(7): 491-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901245&dopt=Abstract

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Cystic fibrosis in North Indian children. Author(s): Singh M, Prasad R, Kumar L. Source: Indian J Pediatr. 2002 July; 69(7): 627-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12173705&dopt=Abstract

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Cystic fibrosis mutation I1234V in a Qatari lady. Author(s): Wahab AA. Source: Journal of Tropical Pediatrics. 2003 February; 49(1): 54-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12630722&dopt=Abstract

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Cystic fibrosis of the pancreas. Author(s): Hammerschmidt DE. Source: The Journal of Laboratory and Clinical Medicine. 2003 April; 141(4): 283. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12701591&dopt=Abstract

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Cystic fibrosis presenting as acute pancreatitis and obstructive azoospermia in a young adult male with a novel mutation in the CFTR gene. Author(s): Conway SP, Peckham DG, Chu CE, Ellis LA, Ahmed M, Taylor GR. Source: Pediatric Pulmonology. 2002 December; 34(6): 491-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12422349&dopt=Abstract

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Cystic fibrosis presenting as fetal anemia. A case report. Author(s): Rijhsinghani A, Hansen WF, Phan B. Source: J Reprod Med. 2002 August; 47(8): 686-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12216439&dopt=Abstract

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Cystic fibrosis presenting as kwashiorkor in a Sri Lankan infant. Author(s): Mei-Zahav M, Solomon M, Kawamura A, Coates A, Durie P. Source: Archives of Disease in Childhood. 2003 August; 88(8): 724-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12876174&dopt=Abstract

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Cystic fibrosis screening using the College panel: platform comparison and lessons learned from the first 20,000 samples. Author(s): Strom CM, Huang D, Buller A, Redman J, Crossley B, Anderson B, Entwistle T, Sun W. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2002 July-August; 4(4): 289-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12172395&dopt=Abstract

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Cystic fibrosis transmembrane conductance regulator (CFTR) activity in nasal epithelial cells from cystic fibrosis patients with severe genotypes. Author(s): Andersson C, Dragomir A, Hjelte L, Roomans GM. Source: Clinical Science (London, England : 1979). 2002 October; 103(4): 417-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12241542&dopt=Abstract

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Cystic fibrosis transmembrane conductance regulator modulates neurosecretory function in pulmonary neuroendocrine cell-related tumor cell line models. Author(s): Pan J, Bear C, Farragher S, Cutz E, Yeger H. Source: American Journal of Respiratory Cell and Molecular Biology. 2002 November; 27(5): 553-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12397014&dopt=Abstract

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Cystic fibrosis transmembrane conductance regulator: the NBF1+R (nucleotidebinding fold 1 and regulatory domain) segment acting alone catalyses a Co2+/Mn2+/Mg2+-ATPase activity markedly inhibited by both Cd2+ and the transition-state analogue orthovanadate. Author(s): Annereau JP, Ko YH, Pedersen PL. Source: The Biochemical Journal. 2003 April 15; 371(Pt 2): 451-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12523935&dopt=Abstract

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Cystic fibrosis transmembrane conductance regulators (CFTR) in biliary epithelium of patients with hepatolithiasis. Author(s): Kim HJ, Lee SK, Kim MH, Son JM, Lee SS, Park JS, Seo DW, Min YI. Source: Digestive Diseases and Sciences. 2002 August; 47(8): 1758-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12184527&dopt=Abstract

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Cystic fibrosis transmembrane regulator gene mutations in Bahrain. Author(s): Eskandarani HA. Source: Journal of Tropical Pediatrics. 2002 December; 48(6): 348-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12521276&dopt=Abstract

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Cystic fibrosis transport regulator and its mRNA are expressed in human epidermis. Author(s): Sato F, Soos G, Link C, Sato K. Source: The Journal of Investigative Dermatology. 2002 December; 119(6): 1224-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12485421&dopt=Abstract

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Cystic fibrosis, pregnancy, and recurrent, acute pancreatitis. Author(s): Virgilis D, Rivkin L, Samueloff A, Picard E, Goldberg S, Faber J, Kerem E, Wilschanski M. Source: Journal of Pediatric Gastroenterology and Nutrition. 2003 April; 36(4): 486-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12658041&dopt=Abstract

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Cystic fibrosis. Author(s): Ratjen F, Doring G. Source: Lancet. 2003 February 22; 361(9358): 681-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12606185&dopt=Abstract

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Cystic fibrosis: bench to bedside 2003. Author(s): Rubin BK. Source: Can Respir J. 2003 April; 10(3): 161-4. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12712228&dopt=Abstract

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Cystic fibrosis: current trends in respiratory care. Author(s): Wagener JS, Headley AA. Source: Respiratory Care. 2003 March; 48(3): 234-45; Discussion 246-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12667274&dopt=Abstract

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Cystic fibrosis: Indian experience. Author(s): Ahuja AS, Kabra SK. Source: Indian Pediatrics. 2002 September; 39(9): 813-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12368524&dopt=Abstract

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Cystic fibrosis: selecting the prenatal screening strategy of choice. Author(s): Wald NJ, Morris JK, Rodeck CH, Haddow JE, Palomaki GE. Source: Prenatal Diagnosis. 2003 June; 23(6): 474-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12813761&dopt=Abstract

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Cystic fibrosis: when to refer for lung transplantation-is the answer clear? Author(s): Noone PG, Egan TM. Source: American Journal of Respiratory and Critical Care Medicine. 2002 December 15; 166(12 Pt 1): 1531-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12471067&dopt=Abstract

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Cystic fibrosis--a probable cause of Frederic Chopin's suffering and death. Author(s): Majka L, Gozdzik J, Witt M. Source: Journal of Applied Genetics. 2003; 44(1): 77-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12590184&dopt=Abstract

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Cytokine pattern in cystic fibrosis patients during antibiotic therapy and gene therapy using adenoviral vector. Author(s): Reix P, Bellon G, Bienvenu J, Pavirani A, Levrey-Hadden H. Source: Eur Cytokine Netw. 2002 July-September; 13(3): 324-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12231476&dopt=Abstract

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Cytokine profile of chronic sinusitis in patients with cystic fibrosis. Author(s): Sobol SE, Christodoulopoulos P, Manoukian JJ, Hauber HP, Frenkiel S, Desrosiers M, Fukakusa M, Schloss MD, Hamid Q. Source: Archives of Otolaryngology--Head & Neck Surgery. 2002 November; 128(11): 1295-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12431174&dopt=Abstract

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Decisions facing the cystic fibrosis clinician at first isolation of Pseudomonas aeruginosa. Author(s): Bush A. Source: Paediatric Respiratory Reviews. 2002 March; 3(1): 82-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12065187&dopt=Abstract

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Decreased bone mineral density in normal-growing patients with cystic fibrosis. Author(s): Gronowitz E, Garemo M, Lindblad A, Mellstrom D, Strandvik B. Source: Acta Paediatrica (Oslo, Norway : 1992). 2003 June; 92(6): 688-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12856979&dopt=Abstract

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Defective activation of c-Src in cystic fibrosis airway epithelial cells results in loss of tumor necrosis factor-alpha-induced gap junction regulation. Author(s): Huang S, Dudez T, Scerri I, Thomas MA, Giepmans BN, Suter S, Chanson M. Source: The Journal of Biological Chemistry. 2003 March 7; 278(10): 8326-32. Epub 2002 December 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12506110&dopt=Abstract

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Defective regulatory volume decrease in human cystic fibrosis tracheal cells because of altered regulation of intermediate conductance Ca2+-dependent potassium channels. Author(s): Vazquez E, Nobles M, Valverde MA. Source: Proceedings of the National Academy of Sciences of the United States of America. 2001 April 24; 98(9): 5329-34. Epub 2001 Apr 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11309505&dopt=Abstract

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Defining a pulmonary exacerbation in cystic fibrosis. Author(s): Rosenfeld M, Emerson J, Williams-Warren J, Pepe M, Smith A, Montgomery AB, Ramsey B. Source: The Journal of Pediatrics. 2001 September; 139(3): 359-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11562614&dopt=Abstract

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Defining an exacerbation of pulmonary disease in cystic fibrosis. Author(s): Dakin C, Henry RL, Field P, Morton J. Source: Pediatric Pulmonology. 2001 June; 31(6): 436-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11389576&dopt=Abstract

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Delayed diagnosis of US females with cystic fibrosis. Author(s): Lai HC, Kosorok MR, Laxova A, Makholm LM, Farrell PM. Source: American Journal of Epidemiology. 2002 July 15; 156(2): 165-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12117708&dopt=Abstract

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DeltaF508-CFTR causes constitutive NF-kappaB activation through an ER-overload response in cystic fibrosis lungs. Author(s): Knorre A, Wagner M, Schaefer HE, Colledge WH, Pahl HL. Source: Biological Chemistry. 2002 February; 383(2): 271-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11934265&dopt=Abstract

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Demographic transition of the Swedish cystic fibrosis community--results of modern care. Author(s): Lannefors L, Lindgren A. Source: Respiratory Medicine. 2002 September; 96(9): 681-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12243313&dopt=Abstract

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Demographics of the UK cystic fibrosis population: implications for neonatal screening. Author(s): McCormick J, Green MW, Mehta G, Culross F, Mehta A. Source: European Journal of Human Genetics : Ejhg. 2002 October; 10(10): 583-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12357328&dopt=Abstract

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Deposition of nacystelyn from a dry powder inhaler in healthy volunteers and cystic fibrosis patients. Author(s): Vanderbist F, Wery B, Baran D, Van Gansbeke B, Schoutens A, Moes AJ. Source: Drug Development and Industrial Pharmacy. 2001; 27(3): 205-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11291200&dopt=Abstract

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Design of clinical trials in cystic fibrosis. Author(s): Southern KW, Smyth RL. Source: Lancet. 2003 January 25; 361(9354): 349-50; Aurhor Reply 350. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559892&dopt=Abstract

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Detecting early structural lung damage in cystic fibrosis. Author(s): Tiddens HA. Source: Pediatric Pulmonology. 2002 September; 34(3): 228-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12203854&dopt=Abstract

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Detecting Stenotrophomonas maltophilia does not reduce survival of patients with cystic fibrosis. Author(s): Goss CH, Otto K, Aitken ML, Rubenfeld GD. Source: American Journal of Respiratory and Critical Care Medicine. 2002 August 1; 166(3): 356-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12153970&dopt=Abstract

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Detection of a widespread clone of Pseudomonas aeruginosa in a pediatric cystic fibrosis clinic. Author(s): Armstrong DS, Nixon GM, Carzino R, Bigham A, Carlin JB, Robins-Browne RM, Grimwood K. Source: American Journal of Respiratory and Critical Care Medicine. 2002 October 1; 166(7): 983-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12359658&dopt=Abstract

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Detection of cystic fibrosis mutations by peptide mass signature genotyping. Author(s): Malehorn DE, Telmer CA, McEwen SB, An J, Kinsey AD, Retchless AC, Mason C, Vieta WM, Jarvik JW. Source: Clinical Chemistry. 2003 August; 49(8): 1318-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12881448&dopt=Abstract

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Detection of novel CFTR mutations in Taiwanese cystic fibrosis patients. Author(s): Alper OM, Shu SG, Lee MH, Wang BT, Lo SY, Lin KL, Chiu YL, Wong LJ. Source: J Formos Med Assoc. 2003 May; 102(5): 287-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12874665&dopt=Abstract

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Detection of Pseudomonas aeruginosa cell-to-cell signals in lung tissue of cystic fibrosis patients. Author(s): Favre-Bonte S, Pache JC, Robert J, Blanc D, Pechere JC, van Delden C. Source: Microbial Pathogenesis. 2002 March; 32(3): 143-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11855945&dopt=Abstract

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Determinants of adherence in adults with cystic fibrosis. Author(s): Kettler LJ, Sawyer SM, Winefield HR, Greville HW. Source: Thorax. 2002 May; 57(5): 459-64. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11978927&dopt=Abstract

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Determination of maximal voluntary ventilation in children with cystic fibrosis. Author(s): Stein R, Selvadurai H, Coates A, Wilkes DL, Schneiderman-Walker J, Corey M. Source: Pediatric Pulmonology. 2003 June; 35(6): 467-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746945&dopt=Abstract

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Determination of the relative contribution of three genes-the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene-to the etiology of idiopathic chronic pancreatitis. Author(s): Audrezet MP, Chen JM, Le Marechal C, Ruszniewski P, Robaszkiewicz M, Raguenes O, Quere I, Scotet V, Ferec C. Source: European Journal of Human Genetics : Ejhg. 2002 February; 10(2): 100-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11938439&dopt=Abstract

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Developing cystic fibrosis lung transplant referral criteria using predictors of 2-year mortality. Author(s): Mayer-Hamblett N, Rosenfeld M, Emerson J, Goss CH, Aitken ML. Source: American Journal of Respiratory and Critical Care Medicine. 2002 December 15; 166(12 Pt 1): 1550-5. Epub 2002 August 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12406843&dopt=Abstract

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Development and evaluation of a PCR-based, line probe assay for the detection of 58 alleles in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Author(s): Wang X, Myers A, Saiki RK, Cutting GR. Source: Clinical Chemistry. 2002 July; 48(7): 1121-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12089190&dopt=Abstract

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Development of a diagnostic PCR assay that targets a heat-shock protein gene (groES) for detection of Pseudomonas spp. in cystic fibrosis patients. Author(s): Clarke L, Moore JE, Millar BC, Garske L, Xu J, Heuzenroeder MW, Crowe M, Elborn JS. Source: Journal of Medical Microbiology. 2003 September; 52(Pt 9): 759-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12909651&dopt=Abstract

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Development of a Gram-negative selective agar (GNSA) for the detection of Gramnegative microflora in sputa in patients with cystic fibrosis. Author(s): Moore JE, Xu J, Millar BC, Courtney J, Elborn JS. Source: Journal of Applied Microbiology. 2003; 95(1): 160-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807467&dopt=Abstract

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Development of cystic fibrosis and noncystic fibrosis airway cell lines. Author(s): Zabner J, Karp P, Seiler M, Phillips SL, Mitchell CJ, Saavedra M, Welsh M, Klingelhutz AJ. Source: American Journal of Physiology. Lung Cellular and Molecular Physiology. 2003 May; 284(5): L844-54. Epub 2003 January 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12676769&dopt=Abstract

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Development of population pharmacokinetic models and optimal sampling times for ibuprofen tablet and suspension formulations in children with cystic fibrosis. Author(s): Beringer P, Aminimanizani A, Synold T, Scott C. Source: Therapeutic Drug Monitoring. 2002 April; 24(2): 315-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11897978&dopt=Abstract

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Development of resistance in Pseudomonas aeruginosa obtained from patients with cystic fibrosis at different times. Author(s): Spencker FB, Staber L, Lietz T, Schille R, Rodloff AC. Source: Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2003 May; 9(5): 370-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848749&dopt=Abstract

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Development of the Cystic Fibrosis Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Author(s): Henry B, Aussage P, Grosskopf C, Goehrs JM. Source: Quality of Life Research : an International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation. 2003 February; 12(1): 63-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12625519&dopt=Abstract

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DHPLC screening of cystic fibrosis gene mutations. Author(s): Ravnik-Glavac M, Atkinson A, Glavac D, Dean M. Source: Human Mutation. 2002 April; 19(4): 374-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11933191&dopt=Abstract

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Diabetes mellitus and cystic fibrosis: comparison of clinical parameters in patients treated with insulin versus oral glucose-lowering agents. Author(s): Rosenecker J, Eichler I, Barmeier H, von der Hardt H. Source: Pediatric Pulmonology. 2001 November; 32(5): 351-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11596159&dopt=Abstract

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Diabetes mellitus in patients with cystic fibrosis: the impact of diabetes mellitus on pulmonary function and clinical outcome. Author(s): Rosenecker J, Hofler R, Steinkamp G, Eichler I, Smaczny C, Ballmann M, Posselt HG, Bargon J, von der Hardt H. Source: European Journal of Medical Research. 2001 August 27; 6(8): 345-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11549516&dopt=Abstract

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Diagnosis, screening, and management of cystic fibrosis-related diabetes. Author(s): Moran A. Source: Curr Diab Rep. 2002 April; 2(2): 111-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12643130&dopt=Abstract

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Differences in resting energy expenditure between male and female children with cystic fibrosis. Author(s): Allen JR, McCauley JC, Selby AM, Waters DL, Gruca MA, Baur LA, Van Asperen P, Gaskin KJ. Source: The Journal of Pediatrics. 2003 January; 142(1): 15-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12520248&dopt=Abstract

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Differential interactions of nucleotides at the two nucleotide binding domains of the cystic fibrosis transmembrane conductance regulator. Author(s): Aleksandrov L, Mengos A, Chang X, Aleksandrov A, Riordan JR. Source: The Journal of Biological Chemistry. 2001 April 20; 276(16): 12918-23. Epub 2001 January 29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11279083&dopt=Abstract

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Digestive system involvement in cystic fibrosis. Author(s): Modolell I, Guarner L, Malagelada JR. Source: Pancreatology : Official Journal of the International Association of Pancreatology (Iap) . [et Al.]. 2002; 2(1): 12-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12119999&dopt=Abstract

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Diminished and erratic absorption of ergocalciferol in adult cystic fibrosis patients. Author(s): Lark RK, Lester GE, Ontjes DA, Blackwood AD, Hollis BW, Hensler MM, Aris RM. Source: The American Journal of Clinical Nutrition. 2001 March; 73(3): 602-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11237938&dopt=Abstract

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Direct detection of N-acylhomoserine lactones in cystic fibrosis sputum. Author(s): Middleton B, Rodgers HC, Camara M, Knox AJ, Williams P, Hardman A. Source: Fems Microbiology Letters. 2002 January 22; 207(1): 1-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11886742&dopt=Abstract

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Directed neutrophil migration to IL-8 is increased in cystic fibrosis: a study of the effect of erythromycin. Author(s): Brennan S, Cooper D, Sly PD. Source: Thorax. 2001 January; 56(1): 62-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11120907&dopt=Abstract

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Discrimination between cystic fibrosis and CFTR-corrected epithelial cells by a membrane potential-sensitive probe. Author(s): Coclet-Ninin J, Rochat T, Poitry S, Chanson M. Source: Experimental Lung Research. 2002 April-May; 28(3): 181-99. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11936773&dopt=Abstract

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Disease knowledge in a high-risk population for cystic fibrosis. Author(s): Braekeleer MD, Bellis G, Rault G, Allard C, Milot M, Simard F. Source: Patient Education and Counseling. 2001 June; 43(3): 263-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11384824&dopt=Abstract

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Disproportionate distribution of Burkholderia cepacia complex species and transmissibility markers in cystic fibrosis. Author(s): LiPuma JJ, Spilker T, Gill LH, Campbell PW 3rd, Liu L, Mahenthiralingam E. Source: American Journal of Respiratory and Critical Care Medicine. 2001 July 1; 164(1): 92-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11435245&dopt=Abstract

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Distinct cytokine production by lung and blood neutrophils from children with cystic fibrosis. Author(s): Corvol H, Fitting C, Chadelat K, Jacquot J, Tabary O, Boule M, Cavaillon JM, Clement A. Source: American Journal of Physiology. Lung Cellular and Molecular Physiology. 2003 June; 284(6): L997-1003. Epub 2003 January 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12547728&dopt=Abstract

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Distinct pattern of immune cell population in the lung of human fetuses with cystic fibrosis. Author(s): Hubeau C, Puchelle E, Gaillard D. Source: The Journal of Allergy and Clinical Immunology. 2001 October; 108(4): 524-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11590376&dopt=Abstract

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Distribution and elimination of tobramycin administered in single or multiple daily doses in adult patients with cystic fibrosis. Author(s): Aminimanizani A, Beringer PM, Kang J, Tsang L, Jelliffe RW, Shapiro BJ. Source: The Journal of Antimicrobial Chemotherapy. 2002 October; 50(4): 553-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12356801&dopt=Abstract

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Distribution and function of the peptide transporter PEPT2 in normal and cystic fibrosis human lung. Author(s): Groneberg DA, Eynott PR, Doring F, Thai Dinh Q, Oates T, Barnes PJ, Chung KF, Daniel H, Fischer A. Source: Thorax. 2002 January; 57(1): 55-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11809991&dopt=Abstract

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DNA and actin bind and inhibit interleukin-8 function in cystic fibrosis sputa: in vitro effects of mucolytics. Author(s): Perks B, Shute JK. Source: American Journal of Respiratory and Critical Care Medicine. 2000 November; 162(5): 1767-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11069810&dopt=Abstract

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Does deficiency of arylsulfatase B have a role in cystic fibrosis? Author(s): Tobacman JK. Source: Chest. 2003 June; 123(6): 2130-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12796199&dopt=Abstract

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Domain-domain associations in cystic fibrosis transmembrane conductance regulator. Author(s): Wang W, He Z, O'Shaughnessy TJ, Rux J, Reenstra WW. Source: American Journal of Physiology. Cell Physiology. 2002 May; 282(5): C1170-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11940532&dopt=Abstract

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Dornase alfa in early cystic fibrosis lung disease. Author(s): Robinson PJ. Source: Pediatric Pulmonology. 2002 September; 34(3): 237-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12203856&dopt=Abstract

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Dornase alfa in young patients with cystic fibrosis. Author(s): Carter ER. Source: The Journal of Pediatrics. 2002 December; 141(6): 838; Author Reply 838-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12461504&dopt=Abstract

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Dose-finding and 24-h monitoring for efficacy and safety of aerosolized Nacystelyn in cystic fibrosis. Author(s): App EM, Baran D, Dab I, Malfroot A, Coffiner M, Vanderbist F, King M. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 February; 19(2): 294-302. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11866009&dopt=Abstract

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Drug therapies for reducing gastric acidity in people with cystic fibrosis. Author(s): Ng SM, Jones AP. Source: Cochrane Database Syst Rev. 2003; (2): Cd003424. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804466&dopt=Abstract

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Drug-induced fever and bone marrow suppression in a 12-year-old girl with cystic fibrosis. Author(s): Gore C, David TJ. Source: Journal of the Royal Society of Medicine. 2001; 94 Suppl 40: 35-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11601163&dopt=Abstract

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Dry powder inhalation of antibiotics in cystic fibrosis therapy: part 2. Inhalation of a novel colistin dry powder formulation: a feasibility study in healthy volunteers and patients. Author(s): Le Brun PP, de Boer AH, Mannes GP, de Fraiture DM, Brimicombe RW, Touw DJ, Vinks AA, Frijlink HW, Heijerman HG. Source: European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V. 2002 July; 54(1): 2532. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12084499&dopt=Abstract

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Duration of effect of intravenous antibiotics on spirometry and sputum cytokines in children with cystic fibrosis. Author(s): Cunningham S, McColm JR, Mallinson A, Boyd I, Marshall TG. Source: Pediatric Pulmonology. 2003 July; 36(1): 43-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12772222&dopt=Abstract

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Dynamics of bacterial colonisation in the respiratory tract of patients with cystic fibrosis. Author(s): Renders N, Verbrugh H, Van Belkum A. Source: Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases. 2001 July; 1(1): 29-39. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12798048&dopt=Abstract

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Dysregulated cytokine production in human cystic fibrosis bronchial epithelial cells. Author(s): Stecenko AA, King G, Torii K, Breyer RM, Dworski R, Blackwell TS, Christman JW, Brigham KL. Source: Inflammation. 2001 June; 25(3): 145-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11403205&dopt=Abstract

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Early aggressive intervention in cystic fibrosis: is it time to redefine our "best practice" strategies? Author(s): Fiel SB. Source: Chest. 2003 January; 123(1): 1-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12527589&dopt=Abstract

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Early airway infection, inflammation, and lung function in cystic fibrosis. Author(s): Nixon GM, Armstrong DS, Carzino R, Carlin JB, Olinsky A, Robertson CF, Grimwood K, Wainwright C. Source: Archives of Disease in Childhood. 2002 October; 87(4): 306-11. Erratum In: Arch Dis Child. 2003 Oct; 88(10): 946. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12244003&dopt=Abstract

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Early infection and progression of cystic fibrosis lung disease. Author(s): Koch C. Source: Pediatric Pulmonology. 2002 September; 34(3): 232-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12203855&dopt=Abstract

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Early Pseudomonas aeruginosa colonisation in cystic fibrosis patients. Author(s): Marchetti F, Candusso M, Faraguna D, Assael BM. Source: Lancet. 2002 February 16; 359(9306): 626-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11867141&dopt=Abstract

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Early Pseudomonas aeruginosa colonisation in cystic fibrosis patients. Author(s): Taccetti G, Repetto T, Procopio E, Farina S, Campana S. Source: Lancet. 2002 February 16; 359(9306): 625-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11867138&dopt=Abstract

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Early versus late diagnosis: psychological impact on parents of children with cystic fibrosis. Author(s): Merelle ME, Huisman J, Alderden-van der Vecht A, Taat F, Bezemer D, Griffioen RW, Brinkhorst G, Dankert-Roelse JE. Source: Pediatrics. 2003 February; 111(2): 346-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12563062&dopt=Abstract

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Effect of a microaerosol filter on spirometry in children with cystic fibrosis. Author(s): Rogers D, Doull IJ. Source: Acta Paediatrica (Oslo, Norway : 1992). 2002; 91(11): 1257-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12463328&dopt=Abstract

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Effect of Burkholderia cepacia infection in the clinical course of patients with cystic fibrosis: a pilot study in a Sydney clinic. Author(s): Soni R, Marks G, Henry DA, Robinson M, Moriarty C, Parsons S, Taylor P, Mahenthiralingam E, Speert DP, Bye PT. Source: Respirology (Carlton, Vic.). 2002 September; 7(3): 241-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12153690&dopt=Abstract

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Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Author(s): McKone EF, Emerson SS, Edwards KL, Aitken ML. Source: Lancet. 2003 May 17; 361(9370): 1671-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767731&dopt=Abstract

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Effect of growth hormone on exercise tolerance in children with cystic fibrosis. Author(s): Hutler M, Schnabel D, Staab D, Tacke A, Wahn U, Boning D, Beneke R. Source: Medicine and Science in Sports and Exercise. 2002 April; 34(4): 567-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11932561&dopt=Abstract

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Effect of ibuprofen on neutrophil migration in vivo in cystic fibrosis and healthy subjects. Author(s): Konstan MW, Krenicky JE, Finney MR, Kirchner HL, Hilliard KA, Hilliard JB, Davis PB, Hoppel CL. Source: The Journal of Pharmacology and Experimental Therapeutics. 2003 September; 306(3): 1086-91. Epub 2003 June 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807998&dopt=Abstract

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Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Author(s): Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J. Source: Thorax. 2002 March; 57(3): 212-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11867823&dopt=Abstract

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Effectiveness and tolerability of high-dose salmeterol in cystic fibrosis. Author(s): Hordvik NL, Sammut PH, Judy CG, Colombo JL. Source: Pediatric Pulmonology. 2002 October; 34(4): 287-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12205570&dopt=Abstract

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Effects of an intensive 4-week summer camp on cystic fibrosis: pulmonary function, exercise tolerance, and nutrition. Author(s): Blau H, Mussaffi-Georgy H, Fink G, Kaye C, Szeinberg A, Spitzer SA, Yahav J. Source: Chest. 2002 April; 121(4): 1117-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11948041&dopt=Abstract

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Effects of C-terminal deletions on cystic fibrosis transmembrane conductance regulator function in cystic fibrosis airway epithelia. Author(s): Ostedgaard LS, Randak C, Rokhlina T, Karp P, Vermeer D, Ashbourne Excoffon KJ, Welsh MJ. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 February 18; 100(4): 1937-42. Epub 2003 Feb 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12578973&dopt=Abstract

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Effects of hypertonic saline, alternate day and daily rhDNase on healthcare use, costs and outcomes in children with cystic fibrosis. Author(s): Suri R, Grieve R, Normand C, Metcalfe C, Thompson S, Wallis C, Bush A. Source: Thorax. 2002 October; 57(10): 841-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12324668&dopt=Abstract

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Effects of megestrol acetate on weight gain, body composition, and pulmonary function in patients with cystic fibrosis. Author(s): Eubanks V, Koppersmith N, Wooldridge N, Clancy JP, Lyrene R, Arani RB, Lee J, Moldawer L, Atchison J, Sorscher EJ, Makris CM. Source: The Journal of Pediatrics. 2002 April; 140(4): 439-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12006958&dopt=Abstract

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Effects of nitric oxide on Pseudomonas aeruginosa infection of epithelial cells from a human respiratory cell line derived from a patient with cystic fibrosis. Author(s): Darling KE, Evans TJ. Source: Infection and Immunity. 2003 May; 71(5): 2341-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12704103&dopt=Abstract

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Effects of positive end-expiratory pressure on oscillated volume during high frequency chest compression in children with cystic fibrosis. Author(s): Dosman CF, Zuberbuhler PC, Tabak JI, Jones RL. Source: Can Respir J. 2003 March; 10(2): 94-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687028&dopt=Abstract

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Effects of recombinant human DNase and hypertonic saline on airway inflammation in children with cystic fibrosis. Author(s): Suri R, Marshall LJ, Wallis C, Metcalfe C, Bush A, Shute JK. Source: American Journal of Respiratory and Critical Care Medicine. 2002 August 1; 166(3): 352-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12153969&dopt=Abstract

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Effects of salmeterol on arterial oxyhemoglobin saturations in patients with cystic fibrosis. Author(s): Salvatore D, D'Andria M. Source: Pediatric Pulmonology. 2002 July; 34(1): 11-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12112791&dopt=Abstract

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Effects of tobramycin solution for inhalation on global ratings of quality of life in patients with cystic fibrosis and Pseudomonas aeruginosa infection. Author(s): Quittner AL, Buu A. Source: Pediatric Pulmonology. 2002 April; 33(4): 269-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11921456&dopt=Abstract

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Efficiency of calcium absorption is not compromised in clinically stable prepubertal and pubertal girls with cystic fibrosis. Author(s): Schulze KJ, O'Brien KO, Germain-Lee EL, Baer DJ, Leonard A, Rosenstein BJ. Source: The American Journal of Clinical Nutrition. 2003 July; 78(1): 110-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816779&dopt=Abstract

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Efficiency of pulmonary administration of tobramycin solution for inhalation in cystic fibrosis using an improved drug delivery system. Author(s): Geller DE, Rosenfeld M, Waltz DA, Wilmott RW; AeroDose TOBI Study Group. Source: Chest. 2003 January; 123(1): 28-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12527599&dopt=Abstract

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Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. Author(s): Vandivier RW, Fadok VA, Hoffmann PR, Bratton DL, Penvari C, Brown KK, Brain JD, Accurso FJ, Henson PM. Source: The Journal of Clinical Investigation. 2002 March; 109(5): 661-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11877474&dopt=Abstract

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Electrogastrography in children with cystic fibrosis. Author(s): Aktay AN, Splaingard ML, Miller T, Freeman ME, Hoeppner H, Werlin SL. Source: Digestive Diseases and Sciences. 2002 April; 47(4): 699-703. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11991595&dopt=Abstract

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Emergence of nontuberculous mycobacteria as pathogens in cystic fibrosis. Author(s): Griffith DE. Source: American Journal of Respiratory and Critical Care Medicine. 2003 March 15; 167(6): 810-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12623856&dopt=Abstract

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Emergency colonoscopy for distal intestinal obstruction syndrome in cystic fibrosis patients. Author(s): Shidrawi RG, Murugan N, Westaby D, Gyi K, Hodson ME. Source: Gut. 2002 August; 51(2): 285-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12117896&dopt=Abstract

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Employing the nasal potential difference as a diagnostic test for cystic fibrosis in neonates: potential pitfalls. Author(s): Gaillard EA, Shaw NJ, Subhedar NV, Wallace HL, Southern KW. Source: The Journal of Pediatrics. 2002 August; 141(2): 295-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12183735&dopt=Abstract

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End-organ dysfunction in cystic fibrosis: association with angiotensin I converting enzyme and cytokine gene polymorphisms. Author(s): Arkwright PD, Pravica V, Geraghty PJ, Super M, Webb AK, Schwarz M, Hutchinson IV. Source: American Journal of Respiratory and Critical Care Medicine. 2003 February 1; 167(3): 384-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554626&dopt=Abstract

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Endothelial nitric oxide synthase variants in cystic fibrosis lung disease. Author(s): Grasemann H, van's Gravesande KS, Buscher R, Knauer N, Silverman ES, Palmer LJ, Drazen JM, Ratjen F. Source: American Journal of Respiratory and Critical Care Medicine. 2003 February 1; 167(3): 390-4. Epub 2002 August 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12406848&dopt=Abstract

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Endotoxin activity and inflammatory markers in the airways of young patients with cystic fibrosis. Author(s): Muhlebach MS, Noah TL. Source: American Journal of Respiratory and Critical Care Medicine. 2002 April 1; 165(7): 911-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11934713&dopt=Abstract

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Energy metabolism in infants with cystic fibrosis. Author(s): Bines JE, Truby HD, Armstrong DS, Phelan PD, Grimwood K. Source: The Journal of Pediatrics. 2002 May; 140(5): 527-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12032517&dopt=Abstract

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Epidemiology and survival analysis of cystic fibrosis in an area of intense neonatal screening over 30 years. Author(s): Assael BM, Castellani C, Ocampo MB, Iansa P, Callegaro A, Valsecchi MG. Source: American Journal of Epidemiology. 2002 September 1; 156(5): 397-401. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12196308&dopt=Abstract

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Epidemiology of Burkholderia cepacia complex in patients with cystic fibrosis, Canada. Author(s): Speert DP, Henry D, Vandamme P, Corey M, Mahenthiralingam E. Source: Emerging Infectious Diseases. 2002 February; 8(2): 181-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11897071&dopt=Abstract

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Epidemiology of Pseudomonas aeruginosa in cystic fibrosis in British Columbia, Canada. Author(s): Speert DP, Campbell ME, Henry DA, Milner R, Taha F, Gravelle A, Davidson AG, Wong LT, Mahenthiralingam E. Source: American Journal of Respiratory and Critical Care Medicine. 2002 October 1; 166(7): 988-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12359659&dopt=Abstract

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Epithelial cell chloride channel activity correlates with improved airway function in cystic fibrosis patients with the major mutant: Delta F508. Author(s): Kidd JF, Bear CE. Source: Pediatric Research. 2002 November; 52(5): 625-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409505&dopt=Abstract

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Eradication of initial Pseudomonas aeruginosa colonization in patients with cystic fibrosis. Author(s): Griese M, Muller I, Reinhardt D. Source: European Journal of Medical Research. 2002 February 21; 7(2): 79-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11891148&dopt=Abstract

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Ethical issues in cystic fibrosis newborn screening: from data to public health policy. Author(s): Wilfond B, Rothenberg LS. Source: Current Opinion in Pulmonary Medicine. 2002 November; 8(6): 529-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12394162&dopt=Abstract

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Evaluation of bronchial constriction in children with cystic fibrosis after inhaling two different preparations of tobramycin. Author(s): Alothman GA, Alsaadi MM, Ho BL, Ho SL, Dupuis A, Corey M, Coates AL. Source: Chest. 2002 September; 122(3): 930-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12226034&dopt=Abstract

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Evaluation of cystic fibrosis carrier screening programs according to genetic screening criteria. Author(s): Henneman L, Poppelaars FA, ten Kate LP. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2002 July-August; 4(4): 241-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12172390&dopt=Abstract

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Evaluation of dietary fiber intake in Belgian children with cystic fibrosis: is there a link with gastrointestinal complaints? Author(s): Proesmans M, De Boeck K. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002 November; 35(5): 6104. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454573&dopt=Abstract

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Evaluation of MicroScan Autoscan for identification of Pseudomonas aeruginosa isolates from cystic fibrosis patients. Author(s): Saiman L, Burns JL, Larone D, Chen Y, Garber E, Whittier S. Source: Journal of Clinical Microbiology. 2003 January; 41(1): 492-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12517904&dopt=Abstract

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Evidence against transmission of Pseudomonas aeruginosa by hands and stethoscopes in a cystic fibrosis unit. Author(s): Kerr JR, Martin H, Chadwick MV, Edwards A, Hodson ME, Geddes DM. Source: The Journal of Hospital Infection. 2002 April; 50(4): 324-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12014913&dopt=Abstract

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Evidence for direct interaction between actin and the cystic fibrosis transmembrane conductance regulator. Author(s): Chasan B, Geisse NA, Pedatella K, Wooster DG, Teintze M, Carattino MD, Goldmann WH, Cantiello HF. Source: European Biophysics Journal : Ebj. 2002 February; 30(8): 617-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11908853&dopt=Abstract

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Evidence for spread of a clonal strain of Pseudomonas aeruginosa among cystic fibrosis clinics. Author(s): Armstrong D, Bell S, Robinson M, Bye P, Rose B, Harbour C, Lee C, Service H, Nissen M, Syrmis M, Wainwright C. Source: Journal of Clinical Microbiology. 2003 May; 41(5): 2266-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12734299&dopt=Abstract

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Evidence of CFTR function in cystic fibrosis after systemic administration of 4phenylbutyrate. Author(s): Zeitlin PL, Diener-West M, Rubenstein RC, Boyle MP, Lee CK, Brass-Ernst L. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2002 July; 6(1): 119-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12095312&dopt=Abstract

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Evidence-based medicine in cystic fibrosis: how should practice change? Author(s): Conway SP. Source: Pediatric Pulmonology. 2002 September; 34(3): 242-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12203857&dopt=Abstract

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Exercise testing in children with cystic fibrosis. Author(s): Rogers D, Prasad SA, Doull I. Source: Journal of the Royal Society of Medicine. 2003; 96 Suppl 43: 23-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906322&dopt=Abstract

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Exhaled carbon monoxide is not elevated in patients with asthma or cystic fibrosis. Author(s): Zetterquist W, Marteus H, Johannesson M, Nordval SL, Ihre E, Lundberg JO, Alving K. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 July; 20(1): 92-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12166588&dopt=Abstract

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Exhaled nitric oxide in cystic fibrosis patients with allergic bronchopulmonary aspergillosis. Author(s): Lim AY, Chambers DC, Ayres JG, Stableforth DE, Honeybourne D. Source: Respiratory Medicine. 2003 April; 97(4): 331-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12693794&dopt=Abstract

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Exploring family systems nursing and the community children's nurse's role in caring for children with cystic fibrosis. Author(s): Cummings JM. Source: Journal of Child Health Care : for Professionals Working with Children in the Hospital and Community. 2002 June; 6(2): 120-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12136816&dopt=Abstract

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Expression of cystic fibrosis transmembrane conductance regulator during early human embryo development. Author(s): Ben-Chetrit A, Antenos M, Jurisicova A, Pasyk EA, Chitayat D, Foskett JK, Casper RF. Source: Molecular Human Reproduction. 2002 August; 8(8): 758-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12149408&dopt=Abstract

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Expression of cystic fibrosis transmembrane conductance regulator in the skin of the toad, Bufo bufo and possible role for Cl- transport across the heterocellular epithelium. Author(s): Amstrup J, Froslev J, Willumsen NJ, Mobjerg N, Jespersen A, Larse EH. Source: Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology. 2001 October; 130(3): 539-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11913465&dopt=Abstract

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Expression of S100A12 (EN-RAGE) in cystic fibrosis. Author(s): Foell D, Seeliger S, Vogl T, Koch HG, Maschek H, Harms E, Sorg C, Roth J. Source: Thorax. 2003 July; 58(7): 613-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12832680&dopt=Abstract

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Extensive sequencing of the cystic fibrosis transmembrane regulator gene: assay validation and unexpected benefits of developing a comprehensive test. Author(s): Strom CM, Huang D, Chen C, Buller A, Peng M, Quan F, Redman J, Sun W. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2003 January-February; 5(1): 9-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544470&dopt=Abstract

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FAB-MS characterization of sialyl Lewis x determinants on polylactosamine chains of human airway mucins secreted by patients suffering from cystic fibrosis or chronic bronchitis. Author(s): Morelle W, Sutton-Smith M, Morris HR, Davril M, Roussel P, Dell A. Source: Glycoconjugate Journal. 2001 September; 18(9): 699-708. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12386455&dopt=Abstract

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Factors affecting the incidence of Stenotrophomonas maltophilia isolation in cystic fibrosis. Author(s): Graff GR, Burns JL. Source: Chest. 2002 June; 121(6): 1754-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12065335&dopt=Abstract

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Factors associated with poor pulmonary function: cross-sectional analysis of data from the ERCF. European Epidemiologic Registry of Cystic Fibrosis. Author(s): Navarro J, Rainisio M, Harms HK, Hodson ME, Koch C, Mastella G, Strandvik B, McKenzie SG. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 August; 18(2): 298-305. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11529288&dopt=Abstract

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Factors influencing outcomes in cystic fibrosis: a center-based analysis. Author(s): Johnson C, Butler SM, Konstan MW, Morgan W, Wohl ME. Source: Chest. 2003 January; 123(1): 20-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12527598&dopt=Abstract

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Factors that influence adherence to exercise and their effectiveness: application to cystic fibrosis. Author(s): Prasad SA, Cerny FJ. Source: Pediatric Pulmonology. 2002 July; 34(1): 66-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12112800&dopt=Abstract

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Failure of local defense mechanisms in cystic fibrosis. Author(s): Proesmans M, De Boeck K. Source: Acta Otorhinolaryngol Belg. 2000; 54(3): 367-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11082773&dopt=Abstract

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Failure to recognize the association of cystic fibrosis and metabolic alkalosis. Author(s): Kurlandsky LE. Source: Clinical Pediatrics. 2002 November-December; 41(9): 715-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12462323&dopt=Abstract

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Failure to refer for testing for cystic fibrosis. Doctors must ensure that those with a family history are advised appropriately. Author(s): Super M, Barnes R, Greig D. Source: Bmj (Clinical Research Ed.). 2001 February 10; 322(7282): 310-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11159639&dopt=Abstract

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Family life and the daily cystic fibrosis routine. Author(s): David TJ. Source: Journal of the Royal Society of Medicine. 2003 July; 96(7): 317. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12835440&dopt=Abstract

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Fat absorption in cystic fibrosis after correction of hypokalaemia. Author(s): Hunter I, Stewart L, Mukhopadhyay S. Source: Lancet. 2000 March 11; 355(9207): 900. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10752711&dopt=Abstract

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Fatal outcome of lung transplantation in cystic fibrosis patients due to small-colony variants of the Burkholderia cepacia complex. Author(s): Haussler S, Lehmann C, Breselge C, Rohde M, Classen M, Tummler B, Vandamme P, Steinmetz I. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2003 April; 22(4): 249-53. Epub 2003 March 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687415&dopt=Abstract

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Fatal pulmonary infection due to multidrug-resistant Mycobacterium abscessus in a patient with cystic fibrosis. Author(s): Sanguinetti M, Ardito F, Fiscarelli E, La Sorda M, D'Argenio P, Ricciotti G, Fadda G. Source: Journal of Clinical Microbiology. 2001 February; 39(2): 816-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11158161&dopt=Abstract

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Fecal elastase-1 is superior to fecal chymotrypsin in the assessment of pancreatic involvement in cystic fibrosis. Author(s): Walkowiak J, Herzig KH, Strzykala K, Przyslawski J, Krawczynski M. Source: Pediatrics. 2002 July; 110(1 Pt 1): E7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12093988&dopt=Abstract

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Feeding behavior problems in children with cystic fibrosis in the UK: prevalence and comparison with healthy controls. Author(s): Duff AJ, Wolfe SP, Dickson C, Conway SP, Brownlee KG. Source: Journal of Pediatric Gastroenterology and Nutrition. 2003 April; 36(4): 443-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12658032&dopt=Abstract

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Female sexual health care in cystic fibrosis. Author(s): Nixon GM, Glazner JA, Martin JM, Sawyer SM. Source: Archives of Disease in Childhood. 2003 March; 88(3): 265-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12598401&dopt=Abstract

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Fertility in men with cystic fibrosis: an update on current surgical practices and outcomes. Author(s): McCallum TJ, Milunsky JM, Cunningham DL, Harris DH, Maher TA, Oates RD. Source: Chest. 2000 October; 118(4): 1059-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11035677&dopt=Abstract

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Fertility in patients with cystic fibrosis. Author(s): Oermann CM. Source: Chest. 2000 October; 118(4): 893-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11035652&dopt=Abstract

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Fertility issues in cystic fibrosis. Author(s): Lyon A, Bilton D. Source: Paediatric Respiratory Reviews. 2002 September; 3(3): 236-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12376060&dopt=Abstract

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Fetal bowel hyperechogenicity may indicate mild atypical cystic fibrosis: a case associated with a complex CFTR allele. Author(s): Abramowicz MJ, Dessars B, Sevens C, Goossens M, Girodon-Boulandet E. Source: Journal of Medical Genetics. 2000 August; 37(8): E15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10922395&dopt=Abstract

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FEV(1) as a guide to lung transplant referral in young patients with cystic fibrosis. Author(s): Robinson W, Waltz DA. Source: Pediatric Pulmonology. 2000 September; 30(3): 198-202. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10973037&dopt=Abstract

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Fibrosis: a general feature in cystic fibrosis? Author(s): Hausler M, Heimann G, Biesterfeld S. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002 February; 34(2): 236-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11840048&dopt=Abstract

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Fifteen-year follow-up of pulmonary function in individuals heterozygous for the cystic fibrosis phenylalanine-508 deletion. Author(s): Dahl M, Nordestgaard BG, Lange P, Tybjaerg-Hansen A. Source: The Journal of Allergy and Clinical Immunology. 2001 May; 107(5): 818-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11344348&dopt=Abstract

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Fitness, acute exercise, and anabolic and catabolic mediators in cystic fibrosis. Author(s): Tirakitsoontorn P, Nussbaum E, Moser C, Hill M, Cooper DM. Source: American Journal of Respiratory and Critical Care Medicine. 2001 October 15; 164(8 Pt 1): 1432-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11704591&dopt=Abstract

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Five percent of normal cystic fibrosis transmembrane conductance regulator mRNA ameliorates the severity of pulmonary disease in cystic fibrosis. Author(s): Ramalho AS, Beck S, Meyer M, Penque D, Cutting GR, Amaral MD. Source: American Journal of Respiratory Cell and Molecular Biology. 2002 November; 27(5): 619-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12397022&dopt=Abstract

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Flow-independent nitric oxide exchange parameters in cystic fibrosis. Author(s): Shin HW, Rose-Gottron CM, Sufi RS, Perez F, Cooper DM, Wilson AF, George SC. Source: American Journal of Respiratory and Critical Care Medicine. 2002 February 1; 165(3): 349-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11818320&dopt=Abstract

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Fluorescent, multiplexed, automated, primer-extension assay for 3120+1G-->A and I148T mutations in cystic fibrosis. Author(s): Brown NM, Bernacki S, Pratt VM, Stenzel TT. Source: Clinical Chemistry. 2001 November; 47(11): 2053-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11673382&dopt=Abstract

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Fluticasone propionate inhibits lipopolysaccharide-induced proinflammatory response in human cystic fibrosis airway grafts. Author(s): Escotte S, Danel C, Gaillard D, Benoit S, Jacquot J, Dusser D, Triglia JM, Majer-Teboul C, Puchelle E. Source: The Journal of Pharmacology and Experimental Therapeutics. 2002 September; 302(3): 1151-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12183675&dopt=Abstract

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Fluticasone reduces IL-6 and IL-8 production of cystic fibrosis bronchial epithelial cells via IKK-beta kinase pathway. Author(s): Escotte S, Tabary O, Dusser D, Majer-Teboul C, Puchelle E, Jacquot J. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 April; 21(4): 574-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12762338&dopt=Abstract

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Flying and cystic fibrosis: getting there and back safely. Author(s): Webb AK. Source: Thorax. 2001 November; 56(11): 821-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11641503&dopt=Abstract

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Formulation of synthetic vectors for cystic fibrosis gene therapy. Author(s): Marshall J, Cheng SH. Source: Methods in Molecular Medicine. 2002; 70: 585-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11917553&dopt=Abstract

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Frequency and clinical significance of the S1235R mutation in the cystic fibrosis transmembrane conductance regulator gene: results from a collaborative study. Author(s): Monaghan KG, Feldman GL, Barbarotto GM, Manji S, Desai TK, Snow K. Source: American Journal of Medical Genetics. 2000 December 11; 95(4): 361-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11186891&dopt=Abstract

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Frequency of cystic fibrosis transmembrane conductance regulator gene mutations and 5T allele in patients with allergic bronchopulmonary aspergillosis. Author(s): Marchand E, Verellen-Dumoulin C, Mairesse M, Delaunois L, Brancaleone P, Rahier JF, Vandenplas O. Source: Chest. 2001 March; 119(3): 762-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11243954&dopt=Abstract

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Frequency, consequences and pharmacological treatment of gastroesophageal reflux in children with cystic fibrosis. Author(s): Brodzicki J, Trawinska-Bartnicka M, Korzon M. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2002 July; 8(7): Cr529-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12118204&dopt=Abstract

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Functional cystic fibrosis transmembrane conductance regulator tagged with an epitope of the vesicular stomatis virus glycoprotein can be addressed to the apical domain of polarized cells. Author(s): Costa de Beauregard MA, Edelman A, Chesnoy-Marchais D, Tondelier D, Lapillonne A, El Marjou F, Robine S, Louvard D. Source: European Journal of Cell Biology. 2000 November; 79(11): 795-802. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11139142&dopt=Abstract

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Functional evidence of CFTR gene transfer in nasal epithelium of cystic fibrosis mice in vivo following luminal application of DNA complexes targeted to the serpinenzyme complex receptor. Author(s): Ziady AG, Kelley TJ, Milliken E, Ferkol T, Davis PB. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2002 April; 5(4): 413-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11945068&dopt=Abstract

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Functional IL-10 deficiency in the lung of cystic fibrosis (cftr(-/-)) and IL-10 knockout mice causes increased expression and function of B7 costimulatory molecules on alveolar macrophages. Author(s): Soltys J, Bonfield T, Chmiel J, Berger M. Source: Journal of Immunology (Baltimore, Md. : 1950). 2002 February 15; 168(4): 190310. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11823525&dopt=Abstract

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Functional interactions of HCO3- with cystic fibrosis transmembrane conductance regulator. Author(s): Gray MA, O'Reilly C, Winpenny J, Argent B. Source: Jop [electronic Resource] : Journal of the Pancreas. 2001 July; 2(4 Suppl): 207-11. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11875261&dopt=Abstract

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Fungal atopy in adult cystic fibrosis. Author(s): Henry M, Bennett DM, Kiely J, Kelleher N, Bredin CP. Source: Respiratory Medicine. 2000 November; 94(11): 1092-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11127497&dopt=Abstract

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Gadolinium as an opener of the outwardly rectifying Cl(-) channel (ORCC). Is there relevance for cystic fibrosis therapy? Author(s): Thinnes FP, Walter G, Hellmann KP, Hellmann T, Merker R, Kiafard Z, EbenBrunnen J, Schwarzer C, Gotz H, Hilschmann N. Source: Pflugers Archiv : European Journal of Physiology. 2001; 443 Suppl 1: S111-6. Epub 2001 July 07. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11845315&dopt=Abstract

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Gas exchange and heart rate kinetics during binary sequence exercise in cystic fibrosis. Author(s): Massin MM, Leclercq-Foucart J, Sacre JP. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2000 January-February; 6(1): 55-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11208284&dopt=Abstract

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Gastric IgA in cystic fibrosis in relation to the migrating motor complex. Author(s): Hallberg K, Mattsson-Rydberg A, Fandriks L, Strandvik B. Source: Scandinavian Journal of Gastroenterology. 2001 August; 36(8): 843-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11495080&dopt=Abstract

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Gastric secretion in cystic fibrosis in relation to the migrating motor complex. Author(s): Hallberg K, Abrahamsson H, Dalenback J, Fandriks L, Strandvik B. Source: Scandinavian Journal of Gastroenterology. 2001 February; 36(2): 121-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11252402&dopt=Abstract

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Gastrointestinal, liver, and pancreatic involvement in adult patients with cystic fibrosis. Author(s): Modolell I, Alvarez A, Guarner L, De Gracia J, Malagelada JR. Source: Pancreas. 2001 May; 22(4): 395-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11345141&dopt=Abstract

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Gender differences in psychosocial reactions to cystic fibrosis carrier testing. Author(s): Newman JE, Sorenson JR, DeVellis BM, Cheuvront B. Source: American Journal of Medical Genetics. 2002 November 22; 113(2): 151-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12407705&dopt=Abstract

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Gender, death and cystic fibrosis: is energy expenditure a component? Author(s): Stallings VA. Source: The Journal of Pediatrics. 2003 January; 142(1): 4-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12520245&dopt=Abstract

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Gendered embodiment and survival for young people with cystic fibrosis. Author(s): Willis E, Miller R, Wyn J. Source: Social Science & Medicine (1982). 2001 November; 53(9): 1163-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11556607&dopt=Abstract

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Gene complementation of airway epithelium in the cystic fibrosis mouse is necessary and sufficient to correct the pathogen clearance and inflammatory abnormalities. Author(s): Oceandy D, McMorran BJ, Smith SN, Schreiber R, Kunzelmann K, Alton EW, Hume DA, Wainwright BJ. Source: Human Molecular Genetics. 2002 May 1; 11(9): 1059-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11978765&dopt=Abstract

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Gene therapy for cystic fibrosis by means of aerosol. Author(s): Rochat T, Morris MA. Source: Journal of Aerosol Medicine : the Official Journal of the International Society for Aerosols in Medicine. 2002 Summer; 15(2): 229-35. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12184873&dopt=Abstract

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Gene therapy for cystic fibrosis. Author(s): Flotte TR. Source: Curr Opin Mol Ther. 1999 August; 1(4): 510-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11713767&dopt=Abstract

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Gene therapy for cystic fibrosis. Author(s): Davies JC, Geddes DM, Alton EW. Source: The Journal of Gene Medicine. 2001 September-October; 3(5): 409-17. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11601754&dopt=Abstract

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Gene therapy for cystic fibrosis. Author(s): Alton E, Kitson C. Source: Expert Opinion on Investigational Drugs. 2000 July; 9(7): 1523-35. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11060757&dopt=Abstract

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Gene therapy in cystic fibrosis. Author(s): Flotte TR, Laube BL. Source: Chest. 2001 September; 120(3 Suppl): 124S-131S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11555567&dopt=Abstract

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Gene therapy of cystic fibrosis (CF) airways: a review emphasizing targeting with lactose. Author(s): Klink DT, Glick MC, Scanlin TF. Source: Glycoconjugate Journal. 2001 September; 18(9): 731-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12386459&dopt=Abstract

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Gene therapy of cystic fibrosis: the glycofection approach. Author(s): Fajac I, Briand P, Monsigny M. Source: Glycoconjugate Journal. 2001 September; 18(9): 723-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12386458&dopt=Abstract

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Gene therapy progress and prospects: cystic fibrosis. Author(s): Griesenbach U, Ferrari S, Geddes DM, Alton EW. Source: Gene Therapy. 2002 October; 9(20): 1344-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12364999&dopt=Abstract

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Gene therapy trials for cystic fibrosis. Author(s): Brown M. Source: Drug Discovery Today. 2002 August 1; 7(15): 788-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546958&dopt=Abstract

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Genes in the vicinity of CFTR modulate the cystic fibrosis phenotype in highly concordant or discordant F508del homozygous sib pairs. Author(s): Mekus F, Laabs U, Veeze H, Tummler B. Source: Human Genetics. 2003 January; 112(1): 1-11. Epub 2002 October 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12483292&dopt=Abstract

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Genetic analysis of cystic fibrosis in Pakistan: a preliminary report. Author(s): Bhutta ZA, Moattar T, Shah U. Source: J Pak Med Assoc. 2000 July; 50(7): 217-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10992696&dopt=Abstract

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Genetic analysis of Pseudomonas aeruginosa isolates from the sputa of Australian adult cystic fibrosis patients. Author(s): Anthony M, Rose B, Pegler MB, Elkins M, Service H, Thamotharampillai K, Watson J, Robinson M, Bye P, Merlino J, Harbour C. Source: Journal of Clinical Microbiology. 2002 August; 40(8): 2772-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12149328&dopt=Abstract

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Genetic and clinical features of false-negative infants in a neonatal screening programme for cystic fibrosis. Author(s): Padoan R, Genoni S, Moretti E, Seia M, Giunta A, Corbetta C. Source: Acta Paediatrica (Oslo, Norway : 1992). 2002; 91(1): 82-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11883825&dopt=Abstract

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Genetic counseling after implementation of statewide cystic fibrosis newborn screening: Two years' experience in one medical center. Author(s): Wheeler PG, Smith R, Dorkin H, Parad RB, Comeau AM, Bianchi DW. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2001 November-December; 3(6): 411-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11715005&dopt=Abstract

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Genetic counseling and neonatal screening for cystic fibrosis: an assessment of the communication process. Author(s): Ciske DJ, Haavisto A, Laxova A, Rock LZ, Farrell PM. Source: Pediatrics. 2001 April; 107(4): 699-705. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11335747&dopt=Abstract

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Genetic markers of male infertility: Y chromosome microdeletions and cystic fibrosis transmembrane conductance gene mutations. Author(s): Sertic J, Cvitkovic P, Myers A, Saiki RK, Stavljenic Rukavina A. Source: Croatian Medical Journal. 2001 August; 42(4): 416-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11471192&dopt=Abstract

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Genetic screening for cystic fibrosis. Author(s): Gregg AR, Simpson JL. Source: Obstetrics and Gynecology Clinics of North America. 2002 June; 29(2): 329-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12108832&dopt=Abstract

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Genetic testing for cystic fibrosis: a personal perspective. Author(s): Tomlinson SP. Source: Harv J Law Technol. 1998 Summer; 11(3): 551-64. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12731545&dopt=Abstract

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Genomovar distribution of the Burkholderia cepacia complex differs significantly between Czech and Slovak patients with cystic fibrosis. Author(s): Drevinek P, Cinek O, Melter J, Langsadl L, Navesnakova Y, Vavrova V. Source: Journal of Medical Microbiology. 2003 July; 52(Pt 7): 603-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12808084&dopt=Abstract

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Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis. Author(s): Durno C, Corey M, Zielenski J, Tullis E, Tsui LC, Durie P. Source: Gastroenterology. 2002 December; 123(6): 1857-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454843&dopt=Abstract

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Genotype-phenotype correlation in cystic fibrosis: the role of modifier genes. Author(s): Salvatore F, Scudiero O, Castaldo G. Source: American Journal of Medical Genetics. 2002 July 22; 111(1): 88-95. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12124743&dopt=Abstract

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Genotypic characterization of Pseudomonas aeruginosa strains recovered from patients with cystic fibrosis after initial and subsequent colonization. Author(s): Munck A, Bonacorsi S, Mariani-Kurkdjian P, Lebourgeois M, Gerardin M, Brahimi N, Navarro J, Bingen E. Source: Pediatric Pulmonology. 2001 October; 32(4): 288-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11568989&dopt=Abstract

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Genotyping study of Scedosporium apiospermum isolates from patients with cystic fibrosis. Author(s): Defontaine A, Zouhair R, Cimon B, Carrere J, Bailly E, Symoens F, Diouri M, Hallet JN, Bouchara JP. Source: Journal of Clinical Microbiology. 2002 June; 40(6): 2108-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12037073&dopt=Abstract

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Gentamicin in pharmacogenetic approach to treatment of cystic fibrosis. Author(s): Hamilton JW. Source: Lancet. 2001 December 15; 358(9298): 2014-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11755605&dopt=Abstract

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Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. Author(s): Wilschanski M, Yahav Y, Yaacov Y, Blau H, Bentur L, Rivlin J, Aviram M, Bdolah-Abram T, Bebok Z, Shushi L, Kerem B, Kerem E. Source: The New England Journal of Medicine. 2003 October 9; 349(15): 1433-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14534336&dopt=Abstract

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Geographic distribution of cystic fibrosis transmembrane regulator gene mutations in Saudi Arabia. Author(s): Banjar H. Source: East Mediterr Health J. 1999 November; 5(6): 1230-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11924117&dopt=Abstract

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GI complications after lung transplantation in patients with cystic fibrosis. Author(s): Gilljam M, Chaparro C, Tullis E, Chan C, Keshavjee S, Hutcheon M. Source: Chest. 2003 January; 123(1): 37-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12527600&dopt=Abstract

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Global genomic analysis of AlgU (sigma(E))-dependent promoters (sigmulon) in Pseudomonas aeruginosa and implications for inflammatory processes in cystic fibrosis. Author(s): Firoved AM, Boucher JC, Deretic V. Source: Journal of Bacteriology. 2002 February; 184(4): 1057-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11807066&dopt=Abstract

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Glucocorticoid treatment reduces exhaled nitric oxide in cystic fibrosis patients. Author(s): Linnane SJ, Thin AG, Keatings VM, Moynihan JB, McLoughlin P, FitzGerald MX. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 June; 17(6): 1267-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11491175&dopt=Abstract

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Glucose intolerance in children with cystic fibrosis. Author(s): Solomon MP, Wilson DC, Corey M, Kalnins D, Zielenski J, Tsui LC, Pencharz P, Durie P, Sweezey NB. Source: The Journal of Pediatrics. 2003 February; 142(2): 128-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12584532&dopt=Abstract

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Glucose intolerance in cystic fibrosis patients. Author(s): Lanng S. Source: Paediatric Respiratory Reviews. 2001 September; 2(3): 253-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052327&dopt=Abstract

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Glutathione levels and BAX activation during apoptosis due to oxidative stress in cells expressing wild-type and mutant cystic fibrosis transmembrane conductance regulator. Author(s): Jungas T, Motta I, Duffieux F, Fanen P, Stoven V, Ojcius DM. Source: The Journal of Biological Chemistry. 2002 August 2; 277(31): 27912-8. Epub 2002 May 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12023951&dopt=Abstract

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Glycosylation and the cystic fibrosis transmembrane conductance regulator. Author(s): Scanlin TF, Glick MC. Source: Respiratory Research. 2001; 2(5): 276-9. Epub 2001 August 07. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11686896&dopt=Abstract

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Growing up and living with cystic fibrosis: everyday life and encounters with the health care and social services--a qualitative study. Author(s): Gjengedal E, Rustoen T, Wahl AK, Hanesta BR. Source: Ans. Advances in Nursing Science. 2003 April-June; 26(2): 149-59. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12795543&dopt=Abstract

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Growing up with chronic illness: psychosocial adjustment of children and adolescents with cystic fibrosis. Author(s): Christian B. Source: Annu Rev Nurs Res. 2003; 21: 151-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858696&dopt=Abstract

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Growth and growth charts in cystic fibrosis. Author(s): Patel L, Dixon M, David TJ. Source: Journal of the Royal Society of Medicine. 2003; 96 Suppl 43: 35-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906324&dopt=Abstract

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Growth and nutritional indexes in early life predict pulmonary function in cystic fibrosis. Author(s): Konstan MW, Butler SM, Wohl ME, Stoddard M, Matousek R, Wagener JS, Johnson CA, Morgan WJ; Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Source: The Journal of Pediatrics. 2003 June; 142(6): 624-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12838189&dopt=Abstract

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Growth factors in cystic fibrosis - when more is not enough. Author(s): Shute J, Marshall L, Bodey K, Bush A. Source: Paediatric Respiratory Reviews. 2003 June; 4(2): 120-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12758049&dopt=Abstract

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Growth hormone and cystic fibrosis: good for more than growth? Author(s): Bucuvalas JC, Chernausek SD. Source: The Journal of Pediatrics. 2001 November; 139(5): 616-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11713433&dopt=Abstract

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Growth hormone decreases protein catabolism in children with cystic fibrosis. Author(s): Hardin DS, Ellis KJ, Dyson M, Rice J, McConnell R, Seilheimer DK. Source: The Journal of Clinical Endocrinology and Metabolism. 2001 September; 86(9): 4424-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11549686&dopt=Abstract

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Growth hormone improves clinical status in prepubertal children with cystic fibrosis: results of a randomized controlled trial. Author(s): Hardin DS, Ellis KJ, Dyson M, Rice J, McConnell R, Seilheimer DK. Source: The Journal of Pediatrics. 2001 November; 139(5): 636-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11713439&dopt=Abstract

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Growth hormone treatment in children with cystic fibrosis. Author(s): Hardin DS. Source: Minerva Pediatr. 2002 October; 54(5): 365-71. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12244275&dopt=Abstract

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Growth problems and growth hormone treatment in children with cystic fibrosis. Author(s): Hardin DS. Source: J Pediatr Endocrinol Metab. 2002 May; 15 Suppl 2: 731-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12092687&dopt=Abstract

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Habitual physical activity in children and adolescents with cystic fibrosis. Author(s): Nixon PA, Orenstein DM, Kelsey SF. Source: Medicine and Science in Sports and Exercise. 2001 January; 33(1): 30-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11194108&dopt=Abstract

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Head and neck manifestations of cystic fibrosis and ciliary dyskinesia. Author(s): Hulka GF. Source: Otolaryngologic Clinics of North America. 2000 December; 33(6): 1333-41, ViiViii. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11449790&dopt=Abstract

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Health service careers for people with cystic fibrosis. Author(s): Walters S. Source: Journal of the Royal Society of Medicine. 2002; 95 Suppl 41: 41-51. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12216274&dopt=Abstract

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Health status and sociodemographic characteristics of adults receiving a cystic fibrosis diagnosis after age 18 years. Author(s): Widerman E, Millner L, Sexauer W, Fiel S. Source: Chest. 2000 August; 118(2): 427-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10936136&dopt=Abstract

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Health values of adolescents with cystic fibrosis. Author(s): Yi MS, Britto MT, Wilmott RW, Kotagal UR, Eckman MH, Nielson DW, Kociela VL, Tsevat J. Source: The Journal of Pediatrics. 2003 February; 142(2): 133-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12584533&dopt=Abstract

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Health-related quality of life for adults with cystic fibrosis: a regression approach to assessing the impact of recombinant human DNase. Author(s): Johnson JA, Connolly M, Zuberbuhler P, Brown NE. Source: Pharmacotherapy. 2000 October; 20(10): 1167-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11034039&dopt=Abstract

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Heart-lung-liver transplant for cystic fibrosis. Author(s): Wise PE, Wright JK, Chapman WC, Drinkwater DC, Slovis BS, Pierson RN, Pinson CW. Source: Transplantation Proceedings. 2001 November-December; 33(7-8): 3568-71. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11750518&dopt=Abstract

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Height and weight fail to detect early signs of malnutrition in children with cystic fibrosis. Author(s): Stapleton D, Kerr D, Gurrin L, Sherriff J, Sly P. Source: Journal of Pediatric Gastroenterology and Nutrition. 2001 September; 33(3): 31925. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11593129&dopt=Abstract

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Hepatitis C in a ward for cystic fibrosis and diabetic patients: possible transmission by spring-loaded finger-stick devices for self-monitoring of capillary blood glucose. Author(s): Desenclos JC, Bourdiol-Razes M, Rolin B, Garandeau P, Ducos J, Brechot C, Thiers V. Source: Infection Control and Hospital Epidemiology : the Official Journal of the Society of Hospital Epidemiologists of America. 2001 November; 22(11): 701-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11842991&dopt=Abstract

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Hepatobiliary manifestations of cystic fibrosis in children: correlation of CT and US findings. Author(s): Akata D, Akhan O, Ozcelik U, Ozmen MN, Oguzkurt L, Haliloglu M, Gocmen A. Source: European Journal of Radiology. 2002 January; 41(1): 26-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11750149&dopt=Abstract

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Heterogeneity of Pseudomonas aeruginosa in Brazilian cystic fibrosis patients. Author(s): Silbert S, Barth AL, Sader HS. Source: Journal of Clinical Microbiology. 2001 November; 39(11): 3976-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11682517&dopt=Abstract

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Heterogeneity of the cystic fibrosis phenotype in a large kindred family in Qatar with cystic fibrosis mutation (I1234V). Author(s): Abdul Wahab A, Al Thani G, Dawod ST, Kambouris M, Al Hamed M. Source: Journal of Tropical Pediatrics. 2001 April; 47(2): 110-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11336127&dopt=Abstract

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High incidence of cystic fibrosis in children born in Italy to Albanian immigrants. Author(s): Festini F, Taccetti G, Cioni ML, Repetto T, De Martino M. Source: Thorax. 2003 January; 58(1): 93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12511734&dopt=Abstract

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High morbidity and mortality in cystic fibrosis patients compound heterozygous for 3905insT and deltaF508. Author(s): Schibler A, Bolt I, Gallati S, Schoni MH, Kraemer R. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 June; 17(6): 1181-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11491162&dopt=Abstract

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High rate of macrolide resistance in Staphylococcus aureus strains from patients with cystic fibrosis reveals high proportions of hypermutable strains. Author(s): Prunier AL, Malbruny B, Laurans M, Brouard J, Duhamel JF, Leclercq R. Source: The Journal of Infectious Diseases. 2003 June 1; 187(11): 1709-16. Epub 2003 May 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12751028&dopt=Abstract

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High resolution CT in children with cystic fibrosis: correlation with pulmonary functions and radiographic scores. Author(s): Demirkazik FB, Ariyurek OM, Ozcelik U, Gocmen A, Hassanabad HK, Kiper N. Source: European Journal of Radiology. 2001 January; 37(1): 54-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11274840&dopt=Abstract

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High-affinity activators of cystic fibrosis transmembrane conductance regulator (CFTR) chloride conductance identified by high-throughput screening. Author(s): Ma T, Vetrivel L, Yang H, Pedemonte N, Zegarra-Moran O, Galietta LJ, Verkman AS. Source: The Journal of Biological Chemistry. 2002 October 4; 277(40): 37235-41. Epub 2002 August 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12161441&dopt=Abstract

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Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients. Author(s): Kilinc MO, Ninis VN, Dagli E, Demirkol M, Ozkinay F, Arikan Z, Cogulu O, Huner G, Karakoc F, Tolun A. Source: American Journal of Medical Genetics. 2002 December 1; 113(3): 250-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12439892&dopt=Abstract

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Highly adherent small-colony variants of Pseudomonas aeruginosa in cystic fibrosis lung infection. Author(s): Haussler S, Ziegler I, Lottel A, von Gotz F, Rohde M, Wehmhohner D, Saravanamuthu S, Tummler B, Steinmetz I. Source: Journal of Medical Microbiology. 2003 April; 52(Pt 4): 295-301. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12676867&dopt=Abstract

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Histidylated polylysine as a synthetic vector for gene transfer into immortalized cystic fibrosis airway surface and airway gland serous cells. Author(s): Fajac I, Allo JC, Souil E, Merten M, Pichon C, Figarella C, Monsigny M, Briand P, Midoux P. Source: The Journal of Gene Medicine. 2000 September-October; 2(5): 368-78. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11045431&dopt=Abstract

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Histomorphometric analysis of bone biopsies from the iliac crest of adults with cystic fibrosis. Author(s): Elkin SL, Vedi S, Bord S, Garrahan NJ, Hodson ME, Compston JE. Source: American Journal of Respiratory and Critical Care Medicine. 2002 December 1; 166(11): 1470-4. Epub 2002 September 11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12406824&dopt=Abstract

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Holidays and cystic fibrosis. Author(s): Verma A, Dodd ME, Haworth CS, Webb AK. Source: Journal of the Royal Society of Medicine. 2000; 93 Suppl 38: 20-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10911815&dopt=Abstract

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Home and hospital antibiotic treatment prove similarly effective in cystic fibrosis. Author(s): Riethmueller J, Busch A, Damm V, Ziebach R, Stern M. Source: Infection. 2002 December; 30(6): 387-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12478330&dopt=Abstract

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Home intravenous antibiotics for cystic fibrosis. Author(s): Marco T, Asensio O, Bosque M, de Gracia J, Serra C. Source: Cochrane Database Syst Rev. 2000; (4): Cd001917. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11034733&dopt=Abstract

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How do we choose a therapeutic regimen in cystic fibrosis? Author(s): Robertson CF. Source: Thorax. 2002 October; 57(10): 839-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12324667&dopt=Abstract

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Human airway mucin glycosylation: a combinatory of carbohydrate determinants which vary in cystic fibrosis. Author(s): Lamblin G, Degroote S, Perini JM, Delmotte P, Scharfman A, Davril M, LoGuidice JM, Houdret N, Dumur V, Klein A, Rousse P. Source: Glycoconjugate Journal. 2001 September; 18(9): 661-84. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12386453&dopt=Abstract

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Hyperacidification in cystic fibrosis: links with lung disease and new prospects for treatment. Author(s): Poschet J, Perkett E, Deretic V. Source: Trends in Molecular Medicine. 2002 November; 8(11): 512-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12421684&dopt=Abstract

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Hyperacidification of cellubrevin endocytic compartments and defective endosomal recycling in cystic fibrosis respiratory epithelial cells. Author(s): Poschet JF, Skidmore J, Boucher JC, Firoved AM, Van Dyke RW, Deretic V. Source: The Journal of Biological Chemistry. 2002 April 19; 277(16): 13959-65. Epub 2002 January 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11809765&dopt=Abstract

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Hyperechogenic bowel loops and meconium ileus in a fetus carrying the D1152H and G542X cystic fibrosis CFTR mutations. Author(s): Orgad S, Berkenstadt M, Achiron R, Yahav Y, Gazit E, Barkai G, Loewenthal R. Source: Prenatal Diagnosis. 2002 July; 22(7): 636-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12124706&dopt=Abstract

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Identification and antimicrobial susceptibility of Alcaligenes xylosoxidans isolated from patients with cystic fibrosis. Author(s): Saiman L, Chen Y, Tabibi S, San Gabriel P, Zhou J, Liu Z, Lai L, Whittier S. Source: Journal of Clinical Microbiology. 2001 November; 39(11): 3942-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11682511&dopt=Abstract

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Identification of a new cystic fibrosis transmembrane regulator mutation in a severely affected patient. Author(s): Spitzer E, Staab D, Hanke R, Wahn U, Grosse R. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 February; 19(2): 374-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11866018&dopt=Abstract

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IL-10 controls Aspergillus fumigatus- and Pseudomonas aeruginosa-specific T-cell response in cystic fibrosis. Author(s): Casaulta C, Schoni MH, Weichel M, Crameri R, Jutel M, Daigle I, Akdis M, Blaser K, Akdis CA. Source: Pediatric Research. 2003 February; 53(2): 313-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12538792&dopt=Abstract

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Immunohistochemical investigation with carbohydrate monoclonal antibodies in cystic fibrosis. Author(s): Makovitzky J, Gotze S. Source: Anticancer Res. 2000 November-December; 20(6D): 5121-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11326681&dopt=Abstract

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Impact of inhaled corticosteroids on the risk of early Pseudomonas aeruginosa acquisition in cystic fibrosis. Author(s): Minicucci L, Severi G, Cresta L, Giannattasio A, Lorini R, Haupt R. Source: Acta Paediatrica (Oslo, Norway : 1992). 2003 June; 92(6): 684-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12856978&dopt=Abstract

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Impact of large chromosomal inversions on the adaptation and evolution of Pseudomonas aeruginosa chronically colonizing cystic fibrosis lungs. Author(s): Kresse AU, Dinesh SD, Larbig K, Romling U. Source: Molecular Microbiology. 2003 January; 47(1): 145-58. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12492860&dopt=Abstract

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Impact of lung inflammation on bone metabolism in adolescents with cystic fibrosis. Author(s): Conway SP. Source: Paediatric Respiratory Reviews. 2001 December; 2(4): 324-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052304&dopt=Abstract

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Impact of public health strategies on the birth prevalence of cystic fibrosis in Brittany, France. Author(s): Scotet V, Audrezet MP, Roussey M, Rault G, Blayau M, De Braekeleer M, Ferec C. Source: Human Genetics. 2003 August; 113(3): 280-5. Epub 2003 May 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12768409&dopt=Abstract

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Impact of recent pulmonary exacerbations on quality of life in patients with cystic fibrosis. Author(s): Britto MT, Kotagal UR, Hornung RW, Atherton HD, Tsevat J, Wilmott RW. Source: Chest. 2002 January; 121(1): 64-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11796433&dopt=Abstract

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Impact of respiratory viral infections on cystic fibrosis. Author(s): Wat D. Source: Postgraduate Medical Journal. 2003 April; 79(930): 201-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12743335&dopt=Abstract

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Impaired clearance of apoptotic cells from cystic fibrosis airways. Author(s): Vandivier RW, Fadok VA, Ogden CA, Hoffmann PR, Brain JD, Accurso FJ, Fisher JH, Greene KE, Henson PM. Source: Chest. 2002 March; 121(3 Suppl): 89S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11893715&dopt=Abstract

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Impaired innate host defense causes susceptibility to respiratory virus infections in cystic fibrosis. Author(s): Zheng S, De BP, Choudhary S, Comhair SA, Goggans T, Slee R, Williams BR, Pilewski J, Haque SJ, Erzurum SC. Source: Immunity. 2003 May; 18(5): 619-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12753739&dopt=Abstract

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Impaired pancreatic ductal bicarbonate secretion in cystic fibrosis. Author(s): Soleimani M. Source: Jop [electronic Resource] : Journal of the Pancreas. 2001 July; 2(4 Suppl): 237-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11875265&dopt=Abstract

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Improved activity of an actin-resistant DNase I variant on the cystic fibrosis airway secretions. Author(s): Zahm JM, Debordeaux C, Maurer C, Hubert D, Dusser D, Bonnet N, Lazarus RA, Puchelle E. Source: American Journal of Respiratory and Critical Care Medicine. 2001 April; 163(5): 1153-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11316652&dopt=Abstract

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Improved decontamination method for recovering mycobacteria from patients with cystic fibrosis. Author(s): Bange FC, Bottger EC. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2002 July; 21(7): 546-8. Epub 2002 July 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12172748&dopt=Abstract

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Improved molecular detection of Burkholderia cepacia genomovar III and Burkholderia multivorans directly from sputum of patients with cystic fibrosis. Author(s): Moore JE, Xu J, Millar BC, Crowe M, Elborn JS. Source: Journal of Microbiological Methods. 2002 April; 49(2): 183-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11830304&dopt=Abstract

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Improved survival among young patients with cystic fibrosis. Author(s): Kulich M, Rosenfeld M, Goss CH, Wilmott R. Source: The Journal of Pediatrics. 2003 June; 142(6): 631-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12838190&dopt=Abstract

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Improvements of lung function in cystic fibrosis. Author(s): Tauber E, Eichler I, Gartner C, Halmerbauer G, Gotz M, Rath R, Wojnarowski C, Frischer T. Source: Pediatric Pulmonology. 2002 April; 33(4): 263-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11921455&dopt=Abstract

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In vitro activity of the aerosolized agents colistin and tobramycin and five intravenous agents against Pseudomonas aeruginosa isolated from cystic fibrosis patients in southwestern Germany. Author(s): Schulin T. Source: The Journal of Antimicrobial Chemotherapy. 2002 February; 49(2): 403-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11815589&dopt=Abstract

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In vitro expression of fas and CD40 and induction of apoptosis in human cystic fibrosis airway epithelial cells. Author(s): Amsellem C, Durieu, Chambe MT, Peyrol S, Pacheco Y. Source: Respiratory Medicine. 2002 April; 96(4): 244-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12000003&dopt=Abstract

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In vivo physiologic comparison of two ventilators used for domiciliary ventilation in children with cystic fibrosis. Author(s): Fauroux B, Pigeot J, Polkey MI, Isabey D, Clement A, Lofaso F. Source: Critical Care Medicine. 2001 November; 29(11): 2097-105. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11700403&dopt=Abstract

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Inclusion of heterozygotes for cystic fibrosis in the egg donor pool. Author(s): Zenke U, Chetkowski RJ. Source: Fertility and Sterility. 2002 September; 78(3): 557-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12215333&dopt=Abstract

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Incontinence in adult females with cystic fibrosis: a Northern Ireland survey. Author(s): Moran F, Bradley JM, Boyle L, Elborn JS. Source: Int J Clin Pract. 2003 April; 57(3): 182-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12723720&dopt=Abstract

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Increased expression of G protein-coupled receptor kinases in cystic fibrosis lung. Author(s): Mak JC, Chuang TT, Harris CA, Barnes PJ. Source: European Journal of Pharmacology. 2002 February 2; 436(3): 165-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11858796&dopt=Abstract

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Increased expression of interleukin-9, interleukin-9 receptor, and the calciumactivated chloride channel hCLCA1 in the upper airways of patients with cystic fibrosis. Author(s): Hauber HP, Manoukian JJ, Nguyen LH, Sobol SE, Levitt RC, Holroyd KJ, McElvaney NG, Griffin S, Hamid Q. Source: The Laryngoscope. 2003 June; 113(6): 1037-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12782818&dopt=Abstract

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Increased leukotriene B4 and interleukin-6 in exhaled breath condensate in cystic fibrosis. Author(s): Carpagnano GE, Barnes PJ, Geddes DM, Hodson ME, Kharitonov SA. Source: American Journal of Respiratory and Critical Care Medicine. 2003 April 15; 167(8): 1109-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12684249&dopt=Abstract

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Increased plasma fatty acid concentrations after respiratory exacerbations are associated with elevated oxidative stress in cystic fibrosis patients. Author(s): Wood LG, Fitzgerald DA, Gibson PG, Cooper DM, Garg ML. Source: The American Journal of Clinical Nutrition. 2002 April; 75(4): 668-75. Erratum In: Am J Clin Nutr 2002 October; 76(4): 907. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11916752&dopt=Abstract

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Increased prevalence of mutations in the cystic fibrosis transmembrane conductance regulator in children with chronic rhinosinusitis. Author(s): Raman V, Clary R, Siegrist KL, Zehnbauer B, Chatila TA. Source: Pediatrics. 2002 January; 109(1): E13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11773581&dopt=Abstract

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Increased treatment requirements of patients with cystic fibrosis who harbour a highly transmissible strain of Pseudomonas aeruginosa. Author(s): Jones AM, Dodd ME, Doherty CJ, Govan JR, Webb AK. Source: Thorax. 2002 November; 57(11): 924-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12403871&dopt=Abstract

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Increasing nursing research in cystic fibrosis. Author(s): Sigmon HD, Grady PA. Source: Heart & Lung : the Journal of Critical Care. 2002 March-April; 31(2): 81-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11910382&dopt=Abstract

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Individuals with cystic fibrosis do not display impaired endothelial function or evidence of oxidative damage in endothelial cells exposed to serum. Author(s): McGrath LT, McCall D, Hanratty CG, Brennan S, Devine A, McCauley DF, Silke B, Elborn S. Source: Clinical Science (London, England : 1979). 2001 November; 101(5): 507-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11672456&dopt=Abstract

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Induced sputum inflammatory measures correlate with lung function in children with cystic fibrosis. Author(s): Sagel SD, Sontag MK, Wagener JS, Kapsner RK, Osberg I, Accurso FJ. Source: The Journal of Pediatrics. 2002 December; 141(6): 811-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12461498&dopt=Abstract

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Infection by Ralstonia species in cystic fibrosis patients: identification of R. pickettii and R. mannitolilytica by polymerase chain reaction. Author(s): Coenye T, Vandamme P, LiPuma JJ. Source: Emerging Infectious Diseases. 2002 July; 8(7): 692-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12095436&dopt=Abstract

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Infection control recommendations for patients with cystic fibrosis: microbiology, important pathogens, and infection control practices to prevent patient-to-patient transmission. Author(s): Saiman L, Siegel J; Cystic Fibrosis Foundation. Source: Infection Control and Hospital Epidemiology : the Official Journal of the Society of Hospital Epidemiologists of America. 2003 May; 24(5 Suppl): S6-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12789902&dopt=Abstract

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Infection control recommendations for patients with cystic fibrosis: Microbiology, important pathogens, and infection control practices to prevent patient-to-patient transmission. Author(s): Saiman L, Siegel J; Cystic Fibrosis Foundation Consensus Conference on Infection Control Participants. Source: American Journal of Infection Control. 2003 May; 31(3 Suppl): S1-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12762292&dopt=Abstract

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Infertility in men with cystic fibrosis. Author(s): Sokol RZ. Source: Current Opinion in Pulmonary Medicine. 2001 November; 7(6): 421-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11706320&dopt=Abstract

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Inflammation and infection in cystic fibrosis--hen or egg? Author(s): Hoiby N. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 January; 17(1): 4-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11307753&dopt=Abstract

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Inflammation in cystic fibrosis airways: relationship to increased bacterial adherence. Author(s): Scheid P, Kempster L, Griesenbach U, Davies JC, Dewar A, Weber PP, Colledge WH, Evans MJ, Geddes DM, Alton EW. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 January; 17(1): 27-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11307750&dopt=Abstract

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Inflammation, infection, and pulmonary function in infants and young children with cystic fibrosis. Author(s): Dakin CJ, Numa AH, Wang H, Morton JR, Vertzyas CC, Henry RL. Source: American Journal of Respiratory and Critical Care Medicine. 2002 April 1; 165(7): 904-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11934712&dopt=Abstract

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Inflammatory endobronchial polyposis with bronchiectasis in cystic fibrosis. Author(s): Roberts C, Devenny AM, Brooker R, Cockburn JS, Kerr KM. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 September; 18(3): 612-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11589360&dopt=Abstract

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Inflammatory mediators in cystic fibrosis lung disease. Author(s): Berger M. Source: Allergy and Asthma Proceedings : the Official Journal of Regional and State Allergy Societies. 2002 January-February; 23(1): 19-25. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11894730&dopt=Abstract

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Inflammatory response in airway epithelial cells isolated from patients with cystic fibrosis. Author(s): Aldallal N, McNaughton EE, Manzel LJ, Richards AM, Zabner J, Ferkol TW, Look DC. Source: American Journal of Respiratory and Critical Care Medicine. 2002 November 1; 166(9): 1248-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12403695&dopt=Abstract

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Influenza vaccination coverage level at a cystic fibrosis center. Author(s): Marshall BC, Henshaw C, Evans DA, Bleyl K, Alder S, Liou TG. Source: Pediatrics. 2002 May; 109(5): E80-0. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11986486&dopt=Abstract

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Information needs of young people with cystic fibrosis. Author(s): Hinton S, Watson S, Chesson R, Mathers S. Source: Paediatric Nursing. 2002 July; 14(6): 18-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12219390&dopt=Abstract

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Inhalation of alpha(1)-protease inhibitor in cystic fibrosis does not affect surfactant convertase and surface activity. Author(s): Griese M, von Bredow C, Birrer P, Schams A. Source: Pulmonary Pharmacology & Therapeutics. 2001; 14(6): 461-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11782126&dopt=Abstract

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Inhaled P2Y2 receptor agonists as a treatment for patients with Cystic Fibrosis lung disease. Author(s): Kellerman D, Evans R, Mathews D, Shaffer C. Source: Advanced Drug Delivery Reviews. 2002 December 5; 54(11): 1463-74. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458155&dopt=Abstract

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Inpatient care of the adult with an exacerbation of cystic fibrosis. Author(s): Elpern EH, Cheatham J. Source: Aacn Clinical Issues. 2001 May; 12(2): 293-304. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11759556&dopt=Abstract

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Interhelical packing in detergent micelles. Folding of a cystic fibrosis transmembrane conductance regulator construct. Author(s): Therien AG, Deber CM. Source: The Journal of Biological Chemistry. 2002 February 22; 277(8): 6067-72. Epub 2001 December 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11748233&dopt=Abstract

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Interleukin-10 inhibits elevated chemokine interleukin-8 and regulated on activation normal T cell expressed and secreted production in cystic fibrosis bronchial epithelial cells by targeting the I(k)B kinase alpha/beta complex. Author(s): Tabary O, Muselet C, Escotte S, Antonicelli F, Hubert D, Dusser D, Jacquot J. Source: American Journal of Pathology. 2003 January; 162(1): 293-302. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12507912&dopt=Abstract

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Interleukin-18 expression in cystic fibrosis lungs. Author(s): Chan ED, Choi HS, Cool C, Accurso FJ, Fantuzzi G. Source: Chest. 2002 March; 121(3 Suppl): 84S-85S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11893709&dopt=Abstract

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Intracellular cysteines of the cystic fibrosis transmembrane conductance regulator (CFTR) modulate channel gating. Author(s): Ketchum CJ, Yue H, Alessi KA, Devidas S, Guggino WB, Maloney PC. Source: Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology. 2002; 12(1): 1-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11914543&dopt=Abstract

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Intracellular rate-limiting steps of gene transfer using glycosylated polylysines in cystic fibrosis airway epithelial cells. Author(s): Grosse S, Tremeau-Bravard A, Aron Y, Briand P, Fajac I. Source: Gene Therapy. 2002 August; 9(15): 1000-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12101430&dopt=Abstract

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Intracutaneous tests with recombinant allergens in cystic fibrosis patients with allergic bronchopulmonary aspergillosis and Aspergillus allergy. Author(s): Nikolaizik WH, Weichel M, Blaser K, Crameri R. Source: American Journal of Respiratory and Critical Care Medicine. 2002 April 1; 165(7): 916-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11934714&dopt=Abstract

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Intravenous long-lines in children with cystic fibrosis: a multidisciplinary approach. Author(s): Turner MA, Unsworth V, David TJ. Source: Journal of the Royal Society of Medicine. 2002; 95 Suppl 41: 11-21. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12216269&dopt=Abstract

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Introduction of the most common cystic fibrosis mutation (Delta F508) into human Pglycoprotein disrupts packing of the transmembrane segments. Author(s): Loo TW, Bartlett MC, Clarke DM. Source: The Journal of Biological Chemistry. 2002 August 2; 277(31): 27585-8. Epub 2002 June 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12070134&dopt=Abstract

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Invasive mechanical ventilation for acute respiratory failure in children with cystic fibrosis: outcome analysis and case-control study. Author(s): Berlinski A, Fan LL, Kozinetz CA, Oermann CM. Source: Pediatric Pulmonology. 2002 October; 34(4): 297-303. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12205571&dopt=Abstract

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Investigation into the selection frequency of resistant mutants and the bacterial kill rate by levofloxacin and ciprofloxacin in non-mucoid Pseudomonas aeruginosa isolates from cystic fibrosis patients. Author(s): Gillespie T, Masterton RG. Source: International Journal of Antimicrobial Agents. 2002 May; 19(5): 377-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12007845&dopt=Abstract

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Iron deficiency in cystic fibrosis: relationship to lung disease severity and chronic Pseudomonas aeruginosa infection. Author(s): Reid DW, Withers NJ, Francis L, Wilson JW, Kotsimbos TC. Source: Chest. 2002 January; 121(1): 48-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11796431&dopt=Abstract

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Itraconazole treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. Author(s): Skov M, Hoiby N, Koch C. Source: Allergy. 2002 August; 57(8): 723-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12121192&dopt=Abstract

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Jointly modelling the relationship between survival and pulmonary function in cystic fibrosis patients. Author(s): Schluchter MD, Konstan MW, Davis PB. Source: Statistics in Medicine. 2002 May 15; 21(9): 1271-87. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12111878&dopt=Abstract

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Kidney stones and cystic fibrosis. Author(s): Gutknecht DR. Source: The American Journal of Medicine. 2001 July; 111(1): 83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11460857&dopt=Abstract

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Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Author(s): Press RD. Source: Molecular Diagnosis : a Journal Devoted to the Understanding of Human Disease Through the Clinical Application of Molecular Biology. 2001 September; 6(3): 212-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11686124&dopt=Abstract

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Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Author(s): Grody WW, Cutting GR, Klinger KW, Richards CS, Watson MS, Desnick RJ; Subcommittee on Cystic Fibrosis Screening, Accreditation of Genetic Services Committee, ACMG. American College of Medical Genetics. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2001 March-April; 3(2): 149-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11280952&dopt=Abstract

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Lack of concordance in the use and monitoring of intravenous aminoglycosides in UK cystic fibrosis centers. Author(s): Tan KH, Hyman-Tylor P, Mulheran M, Knox A, Smyth A. Source: Pediatric Pulmonology. 2002 February; 33(2): 165. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11802256&dopt=Abstract

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Lack of transmission of mycobacterium abscessus among patients with cystic fibrosis attending a single clinic. Author(s): Bange FC, Brown BA, Smaczny C, Wallace Jr RJ, Bottger EC. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2001 June 1; 32(11): 1648-50. Epub 2001 April 30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11340540&dopt=Abstract

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Lactosylated poly-L-lysine targets a potential lactose receptor in cystic fibrosis and non-cystic fibrosis airway epithelial cells. Author(s): Klink D, Yu QC, Glick MC, Scanlin T. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2003 January; 7(1): 73-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12573620&dopt=Abstract

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Lateral thoracic artery embolization in cystic fibrosis. Author(s): Salerno S, Mercadante GG, Rabiolo A, Furnari ML, Pardo F. Source: Acta Radiologica (Stockholm, Sweden : 1987). 2002 March; 43(2): 167-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12010297&dopt=Abstract

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Lean body mass in children with cystic fibrosis. Author(s): Sood M, Adams JE, Mughal MZ. Source: Archives of Disease in Childhood. 2003 September; 88(9): 836. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12937118&dopt=Abstract

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Left ventricular diastolic function in patients with advanced cystic fibrosis. Author(s): Koelling TM, Dec GW, Ginns LC, Semigran MJ. Source: Chest. 2003 May; 123(5): 1488-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12740265&dopt=Abstract

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Lessons (re)learned from cystic fibrosis carrier screening. Author(s): Clayton EW. Source: J Gend Specif Med. 1999 November-December; 2(6): 21-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11279867&dopt=Abstract

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Letter to the editor--multifocal myocardial apoptoses: distinctive cardiac lesions in cystic fibrosis and other diseases. Author(s): Beranek JT. Source: Pediatric Pathology & Molecular Medicine. 2003 March-April; 22(2): 187-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12556300&dopt=Abstract

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Liver and intestinal transplantation in a child with cystic fibrosis: a case report. Author(s): Fridell JA, Mazariegos GV, Orenstein D, Sindhi R, Reyes J. Source: Pediatric Transplantation. 2003 June; 7(3): 240-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12756051&dopt=Abstract

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Liver disease in children with cystic fibrosis. Author(s): Diwakar V, Pearson L, Beath S. Source: Paediatric Respiratory Reviews. 2001 December; 2(4): 340-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052306&dopt=Abstract

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Liver disease in cystic fibrosis. Author(s): Tombazzi CR, Riely CA. Source: Rev Med Chil. 2001 September; 129(9): 1071-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11725473&dopt=Abstract

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Liver disease in cystic fibrosis: A prospective study on incidence, risk factors, and outcome. Author(s): Colombo C, Battezzati PM, Crosignani A, Morabito A, Costantini D, Padoan R, Giunta A. Source: Hepatology (Baltimore, Md.). 2002 December; 36(6): 1374-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12447862&dopt=Abstract

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Liver disease in pediatric patients with cystic fibrosis is associated with glutathione S-transferase P1 polymorphism. Author(s): Henrion-Caude A, Flamant C, Roussey M, Housset C, Flahault A, Fryer AA, Chadelat K, Strange RC, Clement A. Source: Hepatology (Baltimore, Md.). 2002 October; 36(4 Pt 1): 913-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12297838&dopt=Abstract

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Liver expression in cystic fibrosis could be modulated by genetic factors different from the cystic fibrosis transmembrane regulator genotype. Author(s): Castaldo G, Fuccio A, Salvatore D, Raia V, Santostasi T, Leonardi S, Lizzi N, La Rosa M, Rigillo N, Salvatore F. Source: American Journal of Medical Genetics. 2001 February 1; 98(4): 294-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11170070&dopt=Abstract

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Liver transplantation for cholestasis associated with cystic fibrosis in the pediatric population. Author(s): Molmenti EP, Squires RH, Nagata D, Roden JS, Molmenti H, Fasola CG, Prestidge C, D'Amico L, Casey D, Sanchez EQ, Goldstein RM, Levy MF, Benser M, McPhail W, Andrews W, Andersen JA, Klintmalm GB. Source: Pediatric Transplantation. 2003 April; 7(2): 93-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12654048&dopt=Abstract

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Liver transplantation for liver cirrhosis in cystic fibrosis. Author(s): Pfister E, Strassburg A, Nashan B, Becker T, Ballmann M, Arning A, Ehrich J, Melter M. Source: Transplantation Proceedings. 2002 September; 34(6): 2281-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12270399&dopt=Abstract

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Liver transplantation in cystic fibrosis. Author(s): Genyk YS, Quiros JA, Jabbour N, Selby RR, Thomas DW. Source: Current Opinion in Pulmonary Medicine. 2001 November; 7(6): 441-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11706323&dopt=Abstract

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Localization of cystic fibrosis transmembrane conductance regulator in epithelial cells of nasal polyps and postoperative polypoid mucosae. Author(s): Jang YJ, Lee CH. Source: Acta Oto-Laryngologica. 2001 January; 121(1): 93-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11270501&dopt=Abstract

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Localization of sequences within the C-terminal domain of the cystic fibrosis transmembrane conductance regulator which impact maturation and stability. Author(s): Gentzsch M, Riordan JR. Source: The Journal of Biological Chemistry. 2001 January 12; 276(2): 1291-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11022033&dopt=Abstract

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Long term azithromycin in children with cystic fibrosis: a randomised, placebocontrolled crossover trial. Author(s): Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Source: Lancet. 2002 September 28; 360(9338): 978-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12383667&dopt=Abstract

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Long term results of lung resection in cystic fibrosis patients with localised lung disease. Author(s): Lucas JS, Connett GJ, Fairhurst J. Source: Archives of Disease in Childhood. 2002 January; 86(1): 66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11806895&dopt=Abstract

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Long term results of lung transplantation for cystic fibrosis. Author(s): Egan TM, Detterbeck FC, Mill MR, Bleiweis MS, Aris R, Paradowski L, Retsch-Bogart G, Mueller BS. Source: European Journal of Cardio-Thoracic Surgery : Official Journal of the European Association for Cardio-Thoracic Surgery. 2002 October; 22(4): 602-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12297180&dopt=Abstract

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Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis. Author(s): Burns JL, Gibson RL, McNamara S, Yim D, Emerson J, Rosenfeld M, Hiatt P, McCoy K, Castile R, Smith AL, Ramsey BW. Source: The Journal of Infectious Diseases. 2001 February 1; 183(3): 444-52. Epub 2000 December 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11133376&dopt=Abstract

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Longitudinal follow-up of exocrine pancreatic function in pancreatic sufficient cystic fibrosis patients using the fecal elastase-1 test. Author(s): Walkowiak J, Nousia-Arvanitakis S, Agguridaki C, Fotoulaki M, Strzykala K, Balassopoulou A, Witt M, Herzig KH. Source: Journal of Pediatric Gastroenterology and Nutrition. 2003 April; 36(4): 474-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12658038&dopt=Abstract

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Longitudinal investigation of energy expenditure in infants with cystic fibrosis. Author(s): Davies PS, Erskine JM, Hambidge KM, Accurso FJ. Source: European Journal of Clinical Nutrition. 2002 October; 56(10): 940-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12373612&dopt=Abstract

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Longitudinal relationship among growth, nutritional status, and pulmonary function in children with cystic fibrosis: analysis of the Cystic Fibrosis Foundation National CF Patient Registry. Author(s): Zemel BS, Jawad AF, FitzSimmons S, Stallings VA. Source: The Journal of Pediatrics. 2000 September; 137(3): 374-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10969263&dopt=Abstract

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Long-term benefits of inhaled tobramycin in adolescent patients with cystic fibrosis. Author(s): Moss RB. Source: Chest. 2002 January; 121(1): 55-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11796432&dopt=Abstract

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Long-term comparative trial of positive expiratory pressure versus oscillating positive expiratory pressure (flutter) physiotherapy in the treatment of cystic fibrosis. Author(s): McIlwaine PM, Wong LT, Peacock D, Davidson AG. Source: The Journal of Pediatrics. 2001 June; 138(6): 845-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11391327&dopt=Abstract

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Long-term preservation of strains of Burkholderia cepacia, Pseudomonas spp. and Stenotrophomonas maltophilia isolated from patients with cystic fibrosis. Author(s): Moore JE, Shaw AB, Stanley T, Crowe MJ, Elborn JS. Source: Letters in Applied Microbiology. 2001 July; 33(1): 82-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11442821&dopt=Abstract

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Long-term prospective study of the effect of ursodeoxycholic acid on cystic fibrosisrelated liver disease. Author(s): Nousia-Arvanitakis S, Fotoulaki M, Economou H, Xefteri M, GalliTsinopoulou A. Source: Journal of Clinical Gastroenterology. 2001 April; 32(4): 324-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11276276&dopt=Abstract

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Long-term results of lung transplantation for cystic fibrosis. Author(s): Lama R, Alvarez A, Santos F, Algar J, Aranda JL, Baamonde C, Salvatierra A. Source: Transplantation Proceedings. 2001 February-March; 33(1-2): 1624-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11267446&dopt=Abstract

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Loss of FEV1 in cystic fibrosis: correlation with HRCT features. Author(s): Oikonomou A, Manavis J, Karagianni P, Tsanakas J, Wells AU, Hansell DM, Papadopoulou F, Efremidis SC. Source: European Radiology. 2002 September; 12(9): 2229-35. Epub 2002 March 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12195474&dopt=Abstract

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Low bone mineral density in cystic fibrosis patients. Author(s): Fok J, Brown NE, Zuberbuhler P, Tabak J, Tom M. Source: Can J Diet Pract Res. 2002 Winter; 63(4): 192-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12506947&dopt=Abstract

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Low-dose methotrexate for advanced pulmonary disease in patients with cystic fibrosis. Author(s): Ballmann M, Junge S, von der Hardt H. Source: Respiratory Medicine. 2003 May; 97(5): 498-500. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12735666&dopt=Abstract

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Low-flow oxygen and bilevel ventilatory support: effects on ventilation during sleep in cystic fibrosis. Author(s): Milross MA, Piper AJ, Norman M, Becker HF, Willson GN, Grunstein RR, Sullivan CE, Bye PT. Source: American Journal of Respiratory and Critical Care Medicine. 2001 January; 163(1): 129-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11208637&dopt=Abstract

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Lung and heart-lung transplantation in patients with end-stage cystic fibrosis: the Stanford experience. Author(s): Vricella LA, Karamichalis JM, Ahmad S, Robbins RC, Whyte RI, Reitz BA. Source: The Annals of Thoracic Surgery. 2002 July; 74(1): 13-7; Discussion 17-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12118744&dopt=Abstract

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Lung deposition in cystic fibrosis patients using an ultrasonic or a jet nebulizer. Author(s): Kohler E, Sollich V, Schuster-Wonka R, Huhnerbein J. Source: Journal of Aerosol Medicine : the Official Journal of the International Society for Aerosols in Medicine. 2003 Spring; 16(1): 37-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12737683&dopt=Abstract

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Lung disease in cystic fibrosis: is airway surface liquid composition abnormal? Author(s): Verkman AS. Source: American Journal of Physiology. Lung Cellular and Molecular Physiology. 2001 August; 281(2): L306-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11435202&dopt=Abstract

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Lung function changes in relation to menstrual cycle in females with cystic fibrosis. Author(s): Johannesson M, Ludviksdottir D, Janson C. Source: Respiratory Medicine. 2000 November; 94(11): 1043-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11127489&dopt=Abstract

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Lung function testing in infants with cystic fibrosis: lessons from the past and future directions. Author(s): Gappa M, Ranganathan SC, Stocks J. Source: Pediatric Pulmonology. 2001 September; 32(3): 228-45. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11536453&dopt=Abstract

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Lung infections associated with cystic fibrosis. Author(s): Lyczak JB, Cannon CL, Pier GB. Source: Clinical Microbiology Reviews. 2002 April; 15(2): 194-222. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11932230&dopt=Abstract

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Lung inflammation early in cystic fibrosis: bugs are indicted, but the defense is guilty. Author(s): Berger M. Source: American Journal of Respiratory and Critical Care Medicine. 2002 April 1; 165(7): 857-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11934707&dopt=Abstract

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Lung transplantation and cystic fibrosis: the psychosocial toll. Author(s): Kurland G, Orenstein DM. Source: Pediatrics. 2001 June; 107(6): 1419-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11389266&dopt=Abstract

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Lung transplantation for cystic fibrosis patients with Burkholderia cepacia complex. Survival linked to genomovar type. Author(s): Aris RM, Routh JC, LiPuma JJ, Heath DG, Gilligan PH. Source: American Journal of Respiratory and Critical Care Medicine. 2001 December 1; 164(11): 2102-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11739142&dopt=Abstract

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Lung transplantation for cystic fibrosis: additional considerations. Author(s): Vittone S. Source: Pediatric Nursing. 2001 January-February; 27(1): 90-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12025157&dopt=Abstract

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Lung transplantation for cystic fibrosis: immune system and autoimmunity. Author(s): Sediva A, Lischke R, Simonek J, Tkaczyk J, Vavrova V, Bartosova J, Pohunek P, Bartunkova J, Pafko P. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2001 November-December; 7(6): 1219-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11687733&dopt=Abstract

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Macrolide antibiotics and cystic fibrosis. Author(s): Peckham DG. Source: Thorax. 2002 March; 57(3): 189-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11867820&dopt=Abstract

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Macrolide antibiotics for cystic fibrosis. Author(s): Southern KW, Barker PM, Solis A. Source: Cochrane Database Syst Rev. 2003; (3): Cd002203. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917924&dopt=Abstract

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Macrolides in the respiratory tract in cystic fibrosis. Author(s): Jaffe A, Rosenthal M. Source: Journal of the Royal Society of Medicine. 2002; 95 Suppl 41: 27-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12216272&dopt=Abstract

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Management of an older patient with Stenotrophomonas maltophilia: is it an emerging pathogen in cystic fibrosis? Author(s): Dobbin CJ, Bye PT. Source: Internal Medicine Journal. 2001 November; 31(8): 499-500. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11720067&dopt=Abstract

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Management of assisted reproductive technologies in women with cystic fibrosis. Author(s): Epelboin S, Hubert D, Patrat C, Abirached F, Bienvenu T, Lepercq J. Source: Fertility and Sterility. 2001 December; 76(6): 1280-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11730769&dopt=Abstract

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Management of cystic fibrosis-related diabetes in adolescence. Author(s): Azzopardi K, Lowes L. Source: British Journal of Nursing (Mark Allen Publishing). 2003 March 27- April 9; 12(6): 359-63. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682587&dopt=Abstract

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Mannose-binding lectin (MBL) therapy in an MBL-deficient patient with severe cystic fibrosis lung disease. Author(s): Garred P, Pressler T, Lanng S, Madsen HO, Moser C, Laursen I, Balstrup F, Koch C, Koch C. Source: Pediatric Pulmonology. 2002 March; 33(3): 201-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11836800&dopt=Abstract

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Massive nasal polyposis in pediatric cystic fibrosis: report of an unusually severe case. Author(s): Senocak D, Organ Y. Source: Ear, Nose, & Throat Journal. 2003 April; 82(4): 313-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12735163&dopt=Abstract

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Maternal and fetal morbidity in pregnancies of Norwegian and Swedish women with cystic fibrosis. Author(s): Odegaard I, Stray-Pedersen B, Hallberg K, Haanaes OC, Storrosten OT, Johannesson M. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2002 August; 81(8): 698-705. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12174152&dopt=Abstract

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Matrix metalloproteases in BAL fluid of patients with cystic fibrosis and their modulation by treatment with dornase alpha. Author(s): Ratjen F, Hartog CM, Paul K, Wermelt J, Braun J. Source: Thorax. 2002 November; 57(11): 930-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12403873&dopt=Abstract

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Measuring ease of breathing in young patients with cystic fibrosis. Author(s): Orenstein DM, Holt LS, Rebovich P, Campbell T, Nixon P. Source: Pediatric Pulmonology. 2002 December; 34(6): 473-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12422345&dopt=Abstract

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Mechanism of restriction of normal and cystic fibrosis transmembrane conductance regulator-deficient human tracheal gland cells to adenovirus infection and admediated gene transfer. Author(s): Gaden F, Franqueville L, Hong SS, Legrand V, Figarella C, Boulanger P. Source: American Journal of Respiratory Cell and Molecular Biology. 2002 November; 27(5): 628-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12397023&dopt=Abstract

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Mechanisms and markers of airway inflammation in cystic fibrosis. Author(s): De Rose V. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 February; 19(2): 333-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11866015&dopt=Abstract

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Mechanisms involved in cystic fibrosis airway inflammation. Author(s): Puchelle E, De Bentzmann S, Hubeau C, Jacquot J, Gaillard D. Source: Pediatric Pulmonology. 2001; Suppl 23: 143-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11886121&dopt=Abstract

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Median household income and mortality rate in cystic fibrosis. Author(s): O'Connor GT, Quinton HB, Kneeland T, Kahn R, Lever T, Maddock J, Robichaud P, Detzer M, Swartz DR. Source: Pediatrics. 2003 April; 111(4 Pt 1): E333-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12671148&dopt=Abstract

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Medical genetic test reporting for cystic fibrosis (deltaF508) and factor V Leiden in North American laboratories. Author(s): Andersson HC, Krousel-Wood MA, Jackson KE, Rice J, Lubin IM. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2002 September-October; 4(5): 324-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12394344&dopt=Abstract

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Medication interaction causing seizures in a patient with bipolar disorder and cystic fibrosis. Author(s): Munera PA, Perel JM, Asato M. Source: Journal of Child and Adolescent Psychopharmacology. 2002 Fall; 12(3): 275-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12427303&dopt=Abstract

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Metabolic alkalosis and cystic fibrosis. Author(s): Baird JS, Walker P, Urban A, Berdella M. Source: Chest. 2002 August; 122(2): 755-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12171867&dopt=Abstract

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Metabolic alkalosis contributes to acute hypercapnic respiratory failure in adult cystic fibrosis. Author(s): Holland AE, Wilson JW, Kotsimbos TC, Naughton MT. Source: Chest. 2003 August; 124(2): 490-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12907533&dopt=Abstract

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Metabolic alkalosis with hypoelectrolytemia in infants with cystic fibrosis. Author(s): Fustik S, Pop-Jordanova N, Slaveska N, Koceva S, Efremov G. Source: Pediatrics International : Official Journal of the Japan Pediatric Society. 2002 June; 44(3): 289-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11982899&dopt=Abstract

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Metabolic risk factors for stone formation in patients with cystic fibrosis. Author(s): Perez-Brayfield MR, Caplan D, Gatti JM, Smith EA, Kirsch AJ. Source: The Journal of Urology. 2002 February; 167(2 Pt 1): 480-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11792901&dopt=Abstract

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Microbiologic investigation on patients with cystic fibrosis subjected to bilateral lung transplantation. Author(s): Trancassini M, Mosca G, Margiotta MC, Pecoraro C, Quattrucci S, Venuta F, Cipriani P. Source: Transplantation. 2001 November 15; 72(9): 1575-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11707748&dopt=Abstract

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Microbiological characterisation of Burkholderia cepacia isolates from cystic fibrosis patients: investigation of the exopolysaccharides produced. Author(s): Lagatolla C, Skerlavaj S, Dolzani L, Tonin EA, Monti Bragadin C, Bosco M, Rizzo R, Giglio L, Cescutti P. Source: Fems Microbiology Letters. 2002 March 19; 209(1): 99-106. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12007661&dopt=Abstract

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Microvascular complications in cystic fibrosis-related diabetes mellitus: a case report. Author(s): Scott AI, Clarke BE, Healy H, D Emden M, Bell SC. Source: Jop [electronic Resource] : Journal of the Pancreas. 2000 November; 1(4): 208-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11856863&dopt=Abstract

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Mineral content of calcified tissues in cystic fibrosis mice. Author(s): Gawenis LR, Spencer P, Hillman LS, Harline MC, Morris JS, Clarke LL. Source: Biological Trace Element Research. 2001 October; 83(1): 69-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11694004&dopt=Abstract

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Missense, nonsense, and neutral mutations define juxtaposed regulatory elements of splicing in cystic fibrosis transmembrane regulator exon 9. Author(s): Pagani F, Buratti E, Stuani C, Baralle FE. Source: The Journal of Biological Chemistry. 2003 July 18; 278(29): 26580-8. Epub 2003 May 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12732620&dopt=Abstract

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Modifier genes and cystic fibrosis liver disease. Author(s): Pirzada O, Taylor C. Source: Hepatology (Baltimore, Md.). 2003 March; 37(3): 714; Author Reply 714. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12601371&dopt=Abstract

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Modifier genes and variation in cystic fibrosis. Author(s): Drumm ML. Source: Respiratory Research. 2001; 2(3): 125-8. Epub 2001 March 23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11686874&dopt=Abstract

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Modifier genes in cystic fibrosis lung disease. Author(s): Merlo CA, Boyle MP. Source: The Journal of Laboratory and Clinical Medicine. 2003 April; 141(4): 237-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12677168&dopt=Abstract

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Molecular basis for defective glycosylation and Pseudomonas pathogenesis in cystic fibrosis lung. Author(s): Poschet JF, Boucher JC, Tatterson L, Skidmore J, Van Dyke RW, Deretic V. Source: Proceedings of the National Academy of Sciences of the United States of America. 2001 November 20; 98(24): 13972-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11717455&dopt=Abstract

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Molecular consequences of cystic fibrosis transmembrane regulator (CFTR) gene mutations in the exocrine pancreas. Author(s): Ahmed N, Corey M, Forstner G, Zielenski J, Tsui LC, Ellis L, Tullis E, Durie P. Source: Gut. 2003 August; 52(8): 1159-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865275&dopt=Abstract

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Molecular determinants of Au(CN)(2)(-) binding and permeability within the cystic fibrosis transmembrane conductance regulator Cl(-) channel pore. Author(s): Gong X, Burbridge SM, Cowley EA, Linsdell P. Source: The Journal of Physiology. 2002 April 1; 540(Pt 1): 39-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11927667&dopt=Abstract

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Molecular diagnosis of cystic fibrosis in South African populations. Author(s): Goldman A, Graf C, Ramsay M, Leisegang F, Westwood AT. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 2003 July; 93(7): 518-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939925&dopt=Abstract

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Molecular diagnosis of cystic fibrosis. Author(s): Shrimpton AE. Source: Expert Rev Mol Diagn. 2002 May; 2(3): 240-56. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12050863&dopt=Abstract

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Molecular diagnosis of cystic fibrosis: comparison of four analytical procedures. Author(s): Tomaiuolo R, Spina M, Castaldo G. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2003 January; 41(1): 26-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12636046&dopt=Abstract

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Molecular epidemiology of cystic fibrosis-linked Burkholderia cepacia complex isolates from three national referral centres in Ireland. Author(s): Crowley D, Daly M, Lucey B, Shine P, Collins JJ, Cryan B, Moore JE, Murphy P, Buckley G, Fanning S. Source: Journal of Applied Microbiology. 2002; 92(5): 992-1004. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11972706&dopt=Abstract

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Molecular epidemiology of Stenotrophomonas maltophilia isolated from cystic fibrosis patients. Author(s): Denton M, Kerr KG. Source: Journal of Clinical Microbiology. 2002 May; 40(5): 1884. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11980986&dopt=Abstract

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Montelukast pharmacokinetics in cystic fibrosis. Author(s): Graff GR, Weber A, Wessler-Starman D, Smith AL. Source: The Journal of Pediatrics. 2003 January; 142(1): 53-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12520255&dopt=Abstract

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Mortality of cystic fibrosis patients treated with tobramycin solution for inhalation. Author(s): Rothman KJ, Wentworth CE 3rd. Source: Epidemiology (Cambridge, Mass.). 2003 January; 14(1): 55-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12500046&dopt=Abstract

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Mucociliary clearance in cystic fibrosis. Author(s): Robinson M, Bye PT. Source: Pediatric Pulmonology. 2002 April; 33(4): 293-306. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11921459&dopt=Abstract

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Mucolytic therapy in cystic fibrosis. Author(s): Wallis C. Source: Journal of the Royal Society of Medicine. 2001; 94 Suppl 40: 17-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11601159&dopt=Abstract

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Mucosal immunity--basic principles, ontogeny, cystic fibrosis and mucosal vaccination. Author(s): Vancikova Z. Source: Current Drug Targets. Immune, Endocrine and Metabolic Disorders. 2002 April; 2(1): 83-95. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12477298&dopt=Abstract

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Multifocal myocardial necrosis: a distinctive cardiac lesion in cystic fibrosis, lipomatous pancreatic atrophy, and Keshan disease. Author(s): Nezelof C, Bouvier R, Dijoud F. Source: Pediatric Pathology & Molecular Medicine. 2002 May-June; 21(3): 343-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12056507&dopt=Abstract

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Multilocus restriction typing: a novel tool for studying global epidemiology of Burkholderia cepacia complex infection in cystic fibrosis. Author(s): Coenye T, LiPuma JJ. Source: The Journal of Infectious Diseases. 2002 May 15; 185(10): 1454-62. Epub 2002 April 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11992281&dopt=Abstract

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Multiple inhibitory effects of Au(CN)(2-) ions on cystic fibrosis transmembrane conductance regulator Cl(-) channel currents. Author(s): Linsdell P, Gong X. Source: The Journal of Physiology. 2002 April 1; 540(Pt 1): 29-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11927666&dopt=Abstract

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Multiple vertebral compression fractures in a patient treated with corticosteroids for cystic fibrosis. Author(s): Yen D, Hedden D. Source: Canadian Journal of Surgery. Journal Canadien De Chirurgie. 2002 October; 45(5): 383-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12387548&dopt=Abstract

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Multiplex PCR combining deltaF508 mutation and intragenic microsatellites of the CFTR gene for pre-implantation genetic diagnosis (PGD) of cystic fibrosis. Author(s): Moutou C, Gardes N, Viville S. Source: European Journal of Human Genetics : Ejhg. 2002 April; 10(4): 231-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12032730&dopt=Abstract

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Multiplex sequence variation detection throughout the CFTR gene appropriate for preimplantation genetic diagnosis in populations with heterogeneity of cystic fibrosis mutations. Author(s): Vrettou C, Tzetis M, Traeger-Synodinos J, Palmer G, Kanavakis E. Source: Molecular Human Reproduction. 2002 September; 8(9): 880-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12200467&dopt=Abstract

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Multiresistant Pseudomonas aeruginosa in a pediatric cystic fibrosis center: natural history and implications for segregation. Author(s): Davies G, McShane D, Davies JC, Bush A. Source: Pediatric Pulmonology. 2003 April; 35(4): 253-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12629620&dopt=Abstract

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Mutans streptococci, lactobacilli and caries experience in cystic fibrosis homozygotes, heterozygotes and healthy controls. Author(s): Aps JK, Van Maele GO, Claeys G, Martens LC. Source: Caries Research. 2001 November-December; 35(6): 407-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11799280&dopt=Abstract

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Mutations of the cystic fibrosis gene and intermediate sweat chloride levels in children. Author(s): Lebecque P, Leal T, De Boeck C, Jaspers M, Cuppens H, Cassiman JJ. Source: American Journal of Respiratory and Critical Care Medicine. 2002 March 15; 165(6): 757-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11897640&dopt=Abstract

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Na+/HCO3- cotransport in normal and cystic fibrosis intestine. Author(s): Seidler U, Bachmann O, Jacob P, Christiani S, Blumenstein I, Rossmann H. Source: Jop [electronic Resource] : Journal of the Pancreas. 2001 July; 2(4 Suppl): 247-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11875267&dopt=Abstract

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Nasal nitric oxide levels in cystic fibrosis patients are associated with a neuronal NO synthase (NOS1) gene polymorphism. Author(s): Grasemann H, Storm van's Gravesande K, Gartig S, Kirsch M, Buscher R, Drazen JM, Ratjen F. Source: Nitric Oxide : Biology and Chemistry / Official Journal of the Nitric Oxide Society. 2002 March; 6(2): 236-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11890749&dopt=Abstract

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Nasal polyposis in children with cystic fibrosis: a long-term follow-up study. Author(s): Yung MW, Gould J, Upton GJ. Source: The Annals of Otology, Rhinology, and Laryngology. 2002 December; 111(12 Pt 1): 1081-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12498368&dopt=Abstract

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Nasal polyps in cystic fibrosis: clinical endoscopic study with nasal lavage fluid analysis. Author(s): Henriksson G, Westrin KM, Karpati F, Wikstrom AC, Stierna P, Hjelte L. Source: Chest. 2002 January; 121(1): 40-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11796430&dopt=Abstract

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Nasal potential difference measurements in patients with atypical cystic fibrosis. Author(s): Wilschanski M, Famini H, Strauss-Liviatan N, Rivlin J, Blau H, Bibi H, Bentur L, Yahav Y, Springer H, Kramer MR, Klar A, Ilani A, Kerem B, Kerem E. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 June; 17(6): 1208-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11491166&dopt=Abstract

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National Health Services for patients with cystic fibrosis: the good, the bad and the ugly. Author(s): Walters S. Source: Journal of the Royal Society of Medicine. 2002; 95 Suppl 41: 32-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12216273&dopt=Abstract

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Natural history of glucose tolerance, beta-cell function and peripheral insulin sensitivity in cystic fibrosis patients with fasting euglycemia. Author(s): Lombardo F, De Luca F, Rosano M, Sferlazzas C, Lucanto C, Arrigo T, Messina MF, Crisafulli G, Wasniewska M, Valenzise M, Cucinotta D. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 July; 149(1): 53-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824866&dopt=Abstract

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Natural history of pancreatitis associated with cystic fibrosis gene mutations. Author(s): Frulloni L, Castellani C, Bovo P, Vaona B, Calore B, Liani C, Mastella G, Cavallini G. Source: Dig Liver Dis. 2003 March; 35(3): 179-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12779072&dopt=Abstract

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Nebulised anti-pseudomonal antibiotics for cystic fibrosis. Author(s): Ryan G, Mukhopadhyay S, Singh M. Source: Cochrane Database Syst Rev. 2003; (3): Cd001021. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917897&dopt=Abstract

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Nebulised hypertonic saline for cystic fibrosis. Author(s): Wark PA, McDonald V. Source: Cochrane Database Syst Rev. 2003; (1): Cd001506. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12535409&dopt=Abstract

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Nebulized antibiotics in cystic fibrosis. Author(s): Sermet-Gaudelus I, Le Cocguic Y, Ferroni A, Clairicia M, Barthe J, Delaunay JP, Brousse V, Lenoir G. Source: Paediatric Drugs. 2002; 4(7): 455-67. Review. Erratum In: Paediatr Drugs. 2003; 5(1): 40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12083973&dopt=Abstract

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Nebulized heparin in Burkholderia cepacia colonized adult cystic fibrosis patients. Author(s): Ledson M, Gallagher M, Hart CA, Walshaw M. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 January; 17(1): 36-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11307751&dopt=Abstract

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Nebulized morphine as a treatment for dyspnea in a child with cystic fibrosis. Author(s): Cohen SP, Dawson TC. Source: Pediatrics. 2002 September; 110(3): E38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12205288&dopt=Abstract

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Nebulizer choice for inhaled colistin treatment in cystic fibrosis. Author(s): Katz SL, Ho SL, Coates AL. Source: Chest. 2001 January; 119(1): 250-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11157612&dopt=Abstract

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Negative sweat test in hypertrypsinaemic infants with cystic fibrosis carrying rare CFTR mutations. Author(s): Padoan R, Bassotti A, Seia M, Corbetta C. Source: European Journal of Pediatrics. 2002 April; 161(4): 212-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12014388&dopt=Abstract

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Neonatal screening for cystic fibrosis. Author(s): Dudding T, Wilcken B, Burgess B, Turner G. Source: Lancet. 2000 December 2; 356(9245): 1930. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11130407&dopt=Abstract

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Neonatal screening for cystic fibrosis: long-term clinical balance. Author(s): Mastella G, Zanolla L, Castellani C, Altieri S, Furnari M, Giglio L, Lombardo M, Miano A, Sciuto C, Pardo F, Magazzu G. Source: Pancreatology : Official Journal of the International Association of Pancreatology (Iap) . [et Al.]. 2001; 1(5): 531-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12120233&dopt=Abstract

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New antimicrobials in the management of cystic fibrosis. Author(s): Hoiby N. Source: The Journal of Antimicrobial Chemotherapy. 2002 February; 49(2): 235-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11815562&dopt=Abstract

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New approaches to cystic fibrosis. Author(s): Moss RB. Source: Hosp Pract (Off Ed). 2001 January 15; 36(1): 25-7, 31-2, 35-7. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11197941&dopt=Abstract

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New therapeutic approaches for cystic fibrosis lung disease. Author(s): Davies JC. Source: Journal of the Royal Society of Medicine. 2002; 95 Suppl 41: 58-67. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12216276&dopt=Abstract

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Newborn screening for cystic fibrosis. Author(s): Wagener JS, Sontag MK, Accurso FJ. Source: Current Opinion in Pediatrics. 2003 June; 15(3): 309-15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12806263&dopt=Abstract

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Newborn screening for cystic fibrosis. Author(s): Cochrane Database Syst Rev. 2003;(3):CD001912 Source: Cochrane Database Syst Rev. 2001; (3): Cd001402. Review. /entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12917916

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NF-kappaB activation is involved in regulation of cystic fibrosis transmembrane conductance regulator (CFTR) by interleukin-1beta. Author(s): Cafferata EG, Guerrico AM, Pivetta OH, Santa-Coloma TA. Source: The Journal of Biological Chemistry. 2001 May 4; 276(18): 15441-4. Epub 2001 February 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11278608&dopt=Abstract

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Nitric oxide and protein nitration in the cystic fibrosis airway. Author(s): Morrissey BM, Schilling K, Weil JV, Silkoff PE, Rodman DM. Source: Archives of Biochemistry and Biophysics. 2002 October 1; 406(1): 33-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12234487&dopt=Abstract

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Nitric oxide has no beneficial effects on ion transport defects in cystic fibrosis human nasal epithelium. Author(s): Ruckes-Nilges C, Lindemann H, Klimek T, Glanz H, Weber WM. Source: Pflugers Archiv : European Journal of Physiology. 2000 November; 441(1): 133-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11205052&dopt=Abstract

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Nitrogen redox balance in the cystic fibrosis airway: effects of antipseudomonal therapy. Author(s): Gaston B, Ratjen F, Vaughan JW, Malhotra NR, Canady RG, Snyder AH, Hunt JF, Gaertig S, Goldberg JB. Source: American Journal of Respiratory and Critical Care Medicine. 2002 February 1; 165(3): 387-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11818326&dopt=Abstract

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Nocardia asteroides isolated from three patients with cystic fibrosis. Author(s): Lumb R, Greville H, Martin J, Sangster N, Holmes M. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2002 March; 21(3): 230-3. Epub 2002 March 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11957029&dopt=Abstract

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Non invasive mechanical ventilation in cystic fibrosis: physiological effects and monitoring. Author(s): Fauroux B, Hart N, Lofaso F. Source: Monaldi Arch Chest Dis. 2002 October-December; 57(5-6): 268-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814039&dopt=Abstract

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Nonclassic cystic fibrosis: a clinical conundrum. Author(s): Rosenstein BJ. Source: Pediatric Pulmonology. 2003 July; 36(1): 10-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12772217&dopt=Abstract

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Non-conventional trafficking of the cystic fibrosis transmembrane conductance regulator through the early secretory pathway. Author(s): Yoo JS, Moyer BD, Bannykh S, Yoo HM, Riordan JR, Balch WE. Source: The Journal of Biological Chemistry. 2002 March 29; 277(13): 11401-9. Epub 2002 January 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11799116&dopt=Abstract

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Noninvasive nocturnal ventilatory support in advanced lung disease from cystic fibrosis. Author(s): Granton JT, Shapiro C, Kesten S. Source: Respiratory Care. 2002 June; 47(6): 675-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12036437&dopt=Abstract

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Non-invasive proportional assist and pressure support ventilation in patients with cystic fibrosis and chronic respiratory failure. Author(s): Serra A, Polese G, Braggion C, Rossi A. Source: Thorax. 2002 January; 57(1): 50-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11809990&dopt=Abstract

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Non-invasive ventilation for cystic fibrosis. Author(s): Moran F, Bradley J. Source: Cochrane Database Syst Rev. 2003; (2): Cd002769. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804435&dopt=Abstract

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Noninvasive ventilation in chronic obstructive pulmonary disease, bronchiectasis and cystic fibrosis. Author(s): Wedzicha JA, Muir JF. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 September; 20(3): 777-84. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12358358&dopt=Abstract

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Noninvasive ventilation in cystic fibrosis patients with acute or chronic respiratory failure. Author(s): Madden BP, Kariyawasam H, Siddiqi AJ, Machin A, Pryor JA, Hodson ME. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 February; 19(2): 310-3. Erratum In: Eur Respir J. 2002 September; 20(3): 790. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11866011&dopt=Abstract

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Noninvasive ventilation in respiratory failure due to cystic fibrosis. Author(s): Sprague K, Graff G, Tobias DJ. Source: Southern Medical Journal. 2000 October; 93(10): 954-61. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11147476&dopt=Abstract

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Nontuberculous mycobacteria in cystic fibrosis. Author(s): Ebert DL, Olivier KN. Source: Infectious Disease Clinics of North America. 2002 March; 16(1): 221-33. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11917814&dopt=Abstract

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Nontuberculous mycobacteria in patients with cystic fibrosis. Author(s): Oliver A, Maiz L, Canton R, Escobar H, Baquero F, Gomez-Mampaso E. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2001 May 1; 32(9): 1298-303. Epub 2001 April 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11303264&dopt=Abstract

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Nontuberculous mycobacteria in the setting of cystic fibrosis. Author(s): Ebert DL, Olivier KN. Source: Clinics in Chest Medicine. 2002 September; 23(3): 655-63. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12371001&dopt=Abstract

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Nontuberculous mycobacteria. I: multicenter prevalence study in cystic fibrosis. Author(s): Olivier KN, Weber DJ, Wallace RJ Jr, Faiz AR, Lee JH, Zhang Y, Brown-Elliot BA, Handler A, Wilson RW, Schechter MS, Edwards LJ, Chakraborti S, Knowles MR; Nontuberculous Mycobacteria in Cystic Fibrosis Study Group. Source: American Journal of Respiratory and Critical Care Medicine. 2003 March 15; 167(6): 828-34. Epub 2002 November 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12433668&dopt=Abstract

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Nontuberculous mycobacteria. II: nested-cohort study of impact on cystic fibrosis lung disease. Author(s): Olivier KN, Weber DJ, Lee JH, Handler A, Tudor G, Molina PL, Tomashefski J, Knowles MR; Nontuberculous Mycobacteria in Cystic Fibrosis Study Group. Source: American Journal of Respiratory and Critical Care Medicine. 2003 March 15; 167(6): 835-40. Epub 2002 November 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12433669&dopt=Abstract

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Non-viral approach toward gene therapy of cystic fibrosis lung disease. Author(s): Bragonzi A, Conese M. Source: Current Gene Therapy. 2002 September; 2(3): 295-305. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12189717&dopt=Abstract

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Normal bone mineral density in cystic fibrosis. Author(s): Hardin DS, Arumugam R, Seilheimer DK, LeBlanc A, Ellis KJ. Source: Archives of Disease in Childhood. 2001 April; 84(4): 363-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11259244&dopt=Abstract

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Normal function of the cystic fibrosis conductance regulator protein can be associated with homozygous (Delta)F508 mutation. Author(s): Sermet-Gaudelus I, Vallee B, Urbin I, Torossi T, Marianovski R, Fajac A, Feuillet MN, Bresson JL, Lenoir G, Bernaudin JF, Edelman A. Source: Pediatric Research. 2002 November; 52(5): 628-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409506&dopt=Abstract

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Novel application of biological glue in the management of a complicated pneumothorax in cystic fibrosis. Author(s): Garske LA, Tam RK, Windsor MF, Bell SC. Source: Pediatric Pulmonology. 2002 August; 34(2): 138-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12112781&dopt=Abstract

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Novel approaches to inflammation and infection in the cystic fibrosis lung. Author(s): Cantin AM. Source: Pediatric Pulmonology. 2001; Suppl 23: 94-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11886164&dopt=Abstract

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Nuclear translocation of lactosylated poly-L-lysine/cDNA complex in cystic fibrosis airway epithelial cells. Author(s): Klink DT, Chao S, Glick MC, Scanlin TF. Source: Molecular Therapy : the Journal of the American Society of Gene Therapy. 2001 June; 3(6): 831-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11407896&dopt=Abstract

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Nutritional challenges of infants with cystic fibrosis. Author(s): Koletzko S, Reinhardt D. Source: Early Human Development. 2001 November; 65 Suppl: S53-61. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11755035&dopt=Abstract

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Objective monitoring of cough in children with cystic fibrosis. Author(s): Hamutcu R, Francis J, Karakoc F, Bush A. Source: Pediatric Pulmonology. 2002 November; 34(5): 331-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12357476&dopt=Abstract

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Observational assessment of family functioning at mealtime in preschool children with cystic fibrosis. Author(s): Spieth LE, Stark LJ, Mitchell MJ, Schiller M, Cohen LL, Mulvihill M, Hovell MF. Source: Journal of Pediatric Psychology. 2001 June; 26(4): 215-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11329481&dopt=Abstract

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Occurrence and risk of cochleotoxicity in cystic fibrosis patients receiving repeated high-dose aminoglycoside therapy. Author(s): Mulheran M, Degg C, Burr S, Morgan DW, Stableforth DE. Source: Antimicrobial Agents and Chemotherapy. 2001 September; 45(9): 2502-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11502521&dopt=Abstract

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Occurrence of Burkholderia cepacia in foods and waters: clinical implications for patients with cystic fibrosis. Author(s): Moore JE, McIlhatton B, Shaw A, Murphy PG, Elborn JS. Source: J Food Prot. 2001 July; 64(7): 1076-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11456196&dopt=Abstract

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Of isolates and isolation: Pseudomonas aeruginosa in adults with cystic fibrosis. Author(s): Geddes DM. Source: Lancet. 2001 August 18; 358(9281): 522-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11520516&dopt=Abstract

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Offering preconceptional cystic fibrosis carrier couple screening in the absence of established preconceptional care services. Author(s): Henneman L, Bramsen I, van Kempen L, van Acker MB, Pals G, van der Horst HE, Ader HJ, van der Ploeg HM, ten Kate LP. Source: Community Genetics. 2003; 6(1): 5-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12748433&dopt=Abstract

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On the transport of lipoplexes through cystic fibrosis sputum. Author(s): Sanders NN, Van Rompaey E, De Smedt SC, Demeester J. Source: Pharmaceutical Research. 2002 April; 19(4): 451-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12033379&dopt=Abstract

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Once daily versus multiple daily dosing with intravenous aminoglycosides for cystic fibrosis. Author(s): Tan K, Bunn H. Source: Cochrane Database Syst Rev. 2000; (4): Cd002009. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11034740&dopt=Abstract

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Once-daily tobramycin in the treatment of adult patients with cystic fibrosis. Author(s): Whitehead A, Conway SP, Etherington C, Caldwell NA, Setchfield N, Bogle S. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 February; 19(2): 303-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11866010&dopt=Abstract

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Once-daily tobramycin monotherapy in cystic fibrosis. Author(s): Tan KH, Hyman-Taylor P, Mulheran M, Knox A, Smyth A. Source: Pediatric Pulmonology. 2002 May; 33(5): 406; Author Reply 407. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11948989&dopt=Abstract

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Optimization of aerosol deposition by pressure support in children with cystic fibrosis: an experimental and clinical study. Author(s): Fauroux B, Itti E, Pigeot J, Isabey D, Meignan M, Ferry G, Lofaso F, Willemot JM, Clement A, Harf A. Source: American Journal of Respiratory and Critical Care Medicine. 2000 December; 162(6): 2265-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11112150&dopt=Abstract

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Oral administration of specific yolk antibodies (IgY) may prevent Pseudomonas aeruginosa infections in patients with cystic fibrosis: a phase I feasibility study. Author(s): Kollberg H, Carlander D, Olesen H, Wejaker PE, Johannesson M, Larsson A. Source: Pediatric Pulmonology. 2003 June; 35(6): 433-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746939&dopt=Abstract

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Oral health and related factors in cystic fibrosis and other chronic respiratory disorders. Author(s): Narang A, Maguire A, Nunn JH, Bush A. Source: Archives of Disease in Childhood. 2003 August; 88(8): 702-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12876168&dopt=Abstract

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Osteoporosis and osteopenia in adults and adolescents with cystic fibrosis: prevalence and associated factors. Author(s): Conway SP, Morton AM, Oldroyd B, Truscott JG, White H, Smith AH, Haigh I. Source: Thorax. 2000 September; 55(9): 798-804. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10950902&dopt=Abstract

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Otoacoustic emissions for monitoring aminoglycoside-induced ototoxicity in children with cystic fibrosis. Author(s): Stavroulaki P, Vossinakis IC, Dinopoulou D, Doudounakis S, Adamopoulos G, Apostolopoulos N. Source: Archives of Otolaryngology--Head & Neck Surgery. 2002 February; 128(2): 1505. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11843723&dopt=Abstract

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Outcome of Burkholderia cepacia colonisation in an adult cystic fibrosis centre. Author(s): Ledson MJ, Gallagher MJ, Jackson M, Hart CA, Walshaw MJ. Source: Thorax. 2002 February; 57(2): 142-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11828044&dopt=Abstract

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Outcome of patients with cystic fibrosis awaiting lung transplantation. Author(s): Vizza CD, Yusen RD, Lynch JP, Fedele F, Alexander Patterson G, Trulock EP. Source: American Journal of Respiratory and Critical Care Medicine. 2000 September; 162(3 Pt 1): 819-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10988089&dopt=Abstract

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Outcomes of intensive care unit care in adults with cystic fibrosis. Author(s): Sood N, Paradowski LJ, Yankaskas JR. Source: American Journal of Respiratory and Critical Care Medicine. 2001 February; 163(2): 335-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11179102&dopt=Abstract

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Outpatient care of the cystic fibrosis patient after lung transplantation. Author(s): Yankaskas JR, Aris R. Source: Current Opinion in Pulmonary Medicine. 2000 November; 6(6): 551-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11100968&dopt=Abstract

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Oxalate and calcium excretion in cystic fibrosis. Author(s): Turner MA, Goldwater D, David TJ. Source: Archives of Disease in Childhood. 2000 September; 83(3): 244-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10952645&dopt=Abstract

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Oxidant stress stimulates anion secretion from the human airway epithelial cell line Calu-3: implications for cystic fibrosis lung disease. Author(s): Cowley EA, Linsdell P. Source: The Journal of Physiology. 2002 August 15; 543(Pt 1): 201-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12181292&dopt=Abstract

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Oxidative stress in cystic fibrosis: dietary and metabolic factors. Author(s): Wood LG, Fitzgerald DA, Gibson PG, Cooper DM, Collins CE, Garg ML. Source: Journal of the American College of Nutrition. 2001 April; 20(2 Suppl): 157-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11349939&dopt=Abstract

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Oxygen saturation in adult cystic fibrosis patients during exercise at high altitude. Author(s): Ryujin DT, Mannebach SC, Samuelson WM, Marshall BC. Source: Pediatric Pulmonology. 2001 December; 32(6): 437-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11747246&dopt=Abstract

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Pancreatic disorders and cystic fibrosis: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. Author(s): Couper R, Belli D, Durie P, Gaskin K, Sarles J, Werlin S. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002; 35 Suppl 2: S213-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12192191&dopt=Abstract

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Pandoraea apista isolated from a patient with cystic fibrosis: problems associated with laboratory identification. Author(s): Moore JE, Reid A, Millar BC, Jiru X, Mccaughan J, Goldsmith CE, Collins J, Murphy PG, Elborn JS. Source: British Journal of Biomedical Science. 2002; 59(3): 164-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12371061&dopt=Abstract

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Parental attitudes: antenatal diagnosis of cystic fibrosis. Author(s): Polnay JC, Davidge A, Lyn U C, Smyth AR. Source: Archives of Disease in Childhood. 2002 October; 87(4): 284-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12243994&dopt=Abstract

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Parents and partners: lay carers' perceptions of their role in the treatment and care of adults with cystic fibrosis. Author(s): Lowton K. Source: Journal of Advanced Nursing. 2002 July; 39(2): 174-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12100661&dopt=Abstract

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Partial splenectomy in cystic fibrosis patients with hypersplenism. Author(s): Thalhammer GH, Eber E, Uranus S, Pfeifer J, Zach MS. Source: Archives of Disease in Childhood. 2003 February; 88(2): 143-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12538318&dopt=Abstract

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Patient advocacy and cystic fibrosis: political correctness or a real force for good? Author(s): Barnes R. Source: Journal of the Royal Society of Medicine. 2002; 95 Suppl 41: 52-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12216275&dopt=Abstract

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Peak inspiratory flows in children with cystic fibrosis. Author(s): Gauld LM, Briggs K, Robinson P. Source: Journal of Paediatrics and Child Health. 2003 April; 39(3): 210-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12654145&dopt=Abstract

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Pediatrics, surfactant, and cystic fibrosis in AJRCCM 2002. Author(s): Tobin MJ. Source: American Journal of Respiratory and Critical Care Medicine. 2003 February 1; 167(3): 333-44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554622&dopt=Abstract

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Personal experiences of cystic fibrosis (CF) carrier couples prospectively identified in CF families. Author(s): Henneman L, Kooij L, Bouman K, ten Kate LP. Source: American Journal of Medical Genetics. 2002 July 15; 110(4): 324-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12116205&dopt=Abstract

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Pharmaceutical and biotechnological aerosols for cystic fibrosis therapy. Author(s): Garcia-Contreras L, Hickey AJ. Source: Advanced Drug Delivery Reviews. 2002 December 5; 54(11): 1491-504. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458157&dopt=Abstract

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Pharmacokinetics and bioavailability of aerosolized tobramycin in cystic fibrosis. Author(s): Geller DE, Pitlick WH, Nardella PA, Tracewell WG, Ramsey BW. Source: Chest. 2002 July; 122(1): 219-26. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12114362&dopt=Abstract

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Pharmacokinetics of mycophenolic acid associated with calcineurin inhibitors: longterm monitoring in stable lung recipients with and without cystic fibrosis. Author(s): Gerbase MW, Fathi M, Spiliopoulos A, Rochat T, Nicod LP. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 May; 22(5): 587-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12742423&dopt=Abstract

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Pharmacologic approaches to correcting the basic defect in cystic fibrosis. Author(s): Lukacs GL, Durie PR. Source: The New England Journal of Medicine. 2003 October 9; 349(15): 1401-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14534332&dopt=Abstract

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Pharmacological approaches for the discovery and development of new antiinflammatory agents for the treatment of cystic fibrosis. Author(s): Konstan MW, Davis PB. Source: Advanced Drug Delivery Reviews. 2002 December 5; 54(11): 1409-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458152&dopt=Abstract

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Phase I trial of intranasal and endobronchial administration of a recombinant adenoassociated virus serotype 2 (rAAV2)-CFTR vector in adult cystic fibrosis patients: a two-part clinical study. Author(s): Flotte TR, Zeitlin PL, Reynolds TC, Heald AE, Pedersen P, Beck S, Conrad CK, Brass-Ernst L, Humphries M, Sullivan K, Wetzel R, Taylor G, Carter BJ, Guggino WB. Source: Human Gene Therapy. 2003 July 20; 14(11): 1079-88. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12885347&dopt=Abstract

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Phenotypic & genotypic variants of Pseudomonas aeruginosa isolated from children with cystic fibrosis in India. Author(s): Agarwal G, Kapil A, Kabra SK, Chandra R, Das B, Diwedi SN. Source: The Indian Journal of Medical Research. 2002 August; 116: 73-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12592994&dopt=Abstract

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Physical training for cystic fibrosis. Author(s): Bradley J, Moran F. Source: Cochrane Database Syst Rev. 2002; (2): Cd002768. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12076449&dopt=Abstract

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Physicians' perceived usefulness of and satisfaction with test reports for cystic fibrosis (DeltaF508) and factor V Leiden. Author(s): Krousel-Wood M, Andersson HC, Rice J, Jackson KE, Rosner ER, Lubin IM. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2003 May-June; 5(3): 166-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12792424&dopt=Abstract

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Plasma and red blood cell zinc in cystic fibrosis. Author(s): Akanli L, Lowenthal DB, Gjonaj S, Dozor AJ. Source: Pediatric Pulmonology. 2003 January; 35(1): 2-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12461732&dopt=Abstract

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Pneumonia due to Bordetella bronchiseptica in a cystic fibrosis patient: 16S rRNA sequencing for diagnosis confirmation. Author(s): Wallet F, Perez T, Armand S, Wallaert B, Courcol RJ. Source: Journal of Clinical Microbiology. 2002 June; 40(6): 2300-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12037116&dopt=Abstract

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Pneumothorax in cystic fibrosis. Author(s): Flume PA. Source: Chest. 2003 January; 123(1): 217-21. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12527625&dopt=Abstract

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Polarized expression of cystic fibrosis transmembrane conductance regulator and associated epithelial proteins during the regeneration of human airway surface epithelium in three-dimensional culture. Author(s): Castillon N, Hinnrasky J, Zahm JM, Kaplan H, Bonnet N, Corlieu P, Klossek JM, Taouil K, Avril-Delplanque A, Peault B, Puchelle E. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 2002 August; 82(8): 989-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12177237&dopt=Abstract

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Population pharmacokinetic analysis of nonlinear behavior of piperacillin during intermittent or continuous infusion in patients with cystic fibrosis. Author(s): Vinks AA, Den Hollander JG, Overbeek SE, Jelliffe RW, Mouton JW. Source: Antimicrobial Agents and Chemotherapy. 2003 February; 47(2): 541-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12543656&dopt=Abstract

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Potential role of macrolide antibiotics in the management of cystic fibrosis lung disease. Author(s): Nguyen T, Louie SG, Beringer PM, Gill MA. Source: Current Opinion in Pulmonary Medicine. 2002 November; 8(6): 521-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12394161&dopt=Abstract

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Preconception and prenatal screening for cystic fibrosis. Author(s): Baskin LB, Wians FH Jr, Elder F. Source: Mlo: Medical Laboratory Observer. 2002 October; 34(10): 8-12; Quiz 14, 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12385171&dopt=Abstract

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Preconception cystic fibrosis carrier couple screening: impact, understanding, and satisfaction. Author(s): Henneman L, Bramsen I, van der Ploeg HM, ten Kate LP. Source: Genetic Testing. 2002 Fall; 6(3): 195-202. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490059&dopt=Abstract

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Predicting the risk of cystic fibrosis with abnormal ultrasound signs of fetal bowel: results of a French molecular collaborative study based on 641 prospective cases. Author(s): Muller F, Simon-Bouy B, Girodon E, Monnier N, Malinge MC, Serre JL; French Collaborative Group. Source: American Journal of Medical Genetics. 2002 June 15; 110(2): 109-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12116247&dopt=Abstract

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Pregnancy in women with cystic fibrosis. Author(s): Edenborough FP. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2002 August; 81(8): 689-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12174150&dopt=Abstract

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Pregnant with cystic fibrosis. Author(s): Bussey CG, Mittelstaedt EA. Source: Awhonn Lifelines / Association of Women's Health, Obstetric and Neonatal Nurses. 2003 February-March; 7(1): 40-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12674060&dopt=Abstract

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Prenatal detection of a cystic fibrosis mutation in fetal DNA from maternal plasma. Author(s): Gonzalez-Gonzalez MC, Garcia-Hoyos M, Trujillo MJ, Rodriguez de Alba M, Lorda-Sanchez I, Diaz-Recasens J, Gallardo E, Ayuso C, Ramos C. Source: Prenatal Diagnosis. 2002 October; 22(10): 946-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12378583&dopt=Abstract

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Prenatal detection of cystic fibrosis by ultrasonography: a retrospective study of more than 346 000 pregnancies. Author(s): Scotet V, De Braekeleer M, Audrezet MP, Quere I, Mercier B, Dugueperoux I, Andrieux J, Blayau M, Ferec C. Source: Journal of Medical Genetics. 2002 June; 39(6): 443-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12070257&dopt=Abstract

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Prenatal screening for cystic fibrosis. Author(s): Tantravahi U. Source: Medicine and Health, Rhode Island. 2002 December; 85(12): 366-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12593354&dopt=Abstract

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Prenatal screening for cystic fibrosis: where are we now? Author(s): Farrell PM, Fost N. Source: The Journal of Pediatrics. 2002 December; 141(6): 758-63. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12461490&dopt=Abstract

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Pre-transplant mechanical ventilation and outcome in patients with cystic fibrosis. Author(s): Bartz RR, Love RB, Leverson GE, Will LR, Welter DL, Meyer KC. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 April; 22(4): 433-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12681421&dopt=Abstract

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Prevalence and outcome of pregnancies in Norwegian and Swedish women with cystic fibrosis. Author(s): Odegaard I, Stray-Pedersen B, Hallberg K, Haanaes OC, Storrosten OT, Johannesson M. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2002 August; 81(8): 693-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12174151&dopt=Abstract

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Prevalence of Aspergillus fumigatus and other fungal species in the sputum of adult patients with cystic fibrosis. Author(s): Bakare N, Rickerts V, Bargon J, Just-Nubling G. Source: Mycoses. 2003 February; 46(1-2): 19-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588478&dopt=Abstract

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Preventing Burkholderia cepacia complex infection in cystic fibrosis: is there a middle ground? Author(s): Lipuma JJ. Source: The Journal of Pediatrics. 2002 October; 141(4): 467-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12378182&dopt=Abstract

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Primary inflammation in human cystic fibrosis small airways. Author(s): Tirouvanziam R, Khazaal I, Peault B. Source: American Journal of Physiology. Lung Cellular and Molecular Physiology. 2002 August; 283(2): L445-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12114207&dopt=Abstract

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Profound adrenal suppression secondary to treatment with low dose inhaled steroids and itraconazole in allergic bronchopulmonary aspergillosis in cystic fibrosis. Author(s): Parmar JS, Howell T, Kelly J, Bilton D. Source: Thorax. 2002 August; 57(8): 749-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12149540&dopt=Abstract

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Prognostic factors in cystic fibrosis in a single center in Brazil: A survival analysis. Author(s): Oliveira MC, Reis FJ, Oliveira EA, Colosimo EA, Monteiro AP, Penna FJ. Source: Pediatric Pulmonology. 2002 July; 34(1): 3-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12112790&dopt=Abstract

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Prophylactic antibiotics for cystic fibrosis. Author(s): Smyth A, Walters S. Source: Cochrane Database Syst Rev. 2003; (3): Cd001912. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917916&dopt=Abstract

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Proposal of a CT scoring system of the paranasal sinuses in diagnosing cystic fibrosis. Author(s): Eggesbo HB, Sovik S, Dolvik S, Eiklid K, Kolmannskog F. Source: European Radiology. 2003 June; 13(6): 1451-60. Epub 2003 April 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12682781&dopt=Abstract

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Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Author(s): Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Source: Pediatric Pulmonology. 2002 August; 34(2): 91-100. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12112774&dopt=Abstract

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Pseudomonas aeruginosa in cystic fibrosis: pathogenesis and persistence. Author(s): Davies JC. Source: Paediatric Respiratory Reviews. 2002 June; 3(2): 128-34. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12297059&dopt=Abstract

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Pseudomonas aeruginosa-induced apoptosis is defective in respiratory epithelial cells expressing mutant cystic fibrosis transmembrane conductance regulator. Author(s): Cannon CL, Kowalski MP, Stopak KS, Pier GB. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 August; 29(2): 188-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12878584&dopt=Abstract

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Psychological interventions in cystic fibrosis and asthma. Author(s): Duff AJ. Source: Paediatric Respiratory Reviews. 2001 December; 2(4): 350-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052307&dopt=Abstract

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Pubertal development in cystic fibrosis: an overview. Author(s): Arrigo T, Rulli I, Sferlazzas C, De Luca F. Source: J Pediatr Endocrinol Metab. 2003 March; 16 Suppl 2: 267-70. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729402&dopt=Abstract

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Pulmonary function tests in preschool children with cystic fibrosis. Author(s): Beydon N, Amsallem F, Bellet M, Boule M, Chaussain M, Denjean A, Matran R, Pin I, Alberti C, Gaultier C. Source: American Journal of Respiratory and Critical Care Medicine. 2002 October 15; 166(8): 1099-104. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12379554&dopt=Abstract

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Quality of life in patients awaiting lung transplant: cystic fibrosis versus other endstage lung diseases. Author(s): Burker EJ, Carels RA, Thompson LF, Rodgers L, Egan T. Source: Pediatric Pulmonology. 2000 December; 30(6): 453-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11109056&dopt=Abstract

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Quantitative analysis of inflammatory cells infiltrating the cystic fibrosis airway mucosa. Author(s): Hubeau C, Lorenzato M, Couetil JP, Hubert D, Dusser D, Puchelle E, Gaillard D. Source: Clinical and Experimental Immunology. 2001 April; 124(1): 69-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11359444&dopt=Abstract

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Quantitative proteomic analysis indicates increased synthesis of a quinolone by Pseudomonas aeruginosa isolates from cystic fibrosis airways. Author(s): Guina T, Purvine SO, Yi EC, Eng J, Goodlett DR, Aebersold R, Miller SI. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 March 4; 100(5): 2771-6. Epub 2003 February 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12601166&dopt=Abstract

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Questionnaire survey of male infertility in cystic fibrosis. Author(s): Rodgers HC, Baldwin DR, Knox AJ. Source: Respiratory Medicine. 2000 October; 94(10): 1002-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11059956&dopt=Abstract

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Questionnaire survey of urinary incontinence in women with cystic fibrosis. Author(s): Orr A, McVean RJ, Webb AK, Dodd ME. Source: Bmj (Clinical Research Ed.). 2001 June 23; 322(7301): 1521. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11420273&dopt=Abstract

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Questions on life satisfaction for adolescents and adults with cystic fibrosis: development of a disease-specific questionnaire. Author(s): Goldbeck L, Schmitz TG, Henrich G, Herschbach P. Source: Chest. 2003 January; 123(1): 42-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12527601&dopt=Abstract

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RAD in stable lung and heart/lung transplant recipients: safety, tolerability, pharmacokinetics, and impact of cystic fibrosis. Author(s): Doyle RL, Hertz MI, Dunitz JM, Loyd JE, Stecenko AA, Wong RL, Chappell KA, Brazelton T, Kovarik JM, Appeldingemanse S, Dou L, Smith HT, Tudor D, Morris RE. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2001 March; 20(3): 330-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11257560&dopt=Abstract

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Ralstonia taiwanensis sp. nov., isolated from root nodules of Mimosa species and sputum of a cystic fibrosis patient. Author(s): Chen WM, Laevens S, Lee TM, Coenye T, De Vos P, Mergeay M, Vandamme P. Source: International Journal of Systematic and Evolutionary Microbiology. 2001 September; 51(Pt 5): 1729-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11594603&dopt=Abstract

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Randomized controlled study of in-hospital exercise training programs in children with cystic fibrosis. Author(s): Selvadurai HC, Blimkie CJ, Meyers N, Mellis CM, Cooper PJ, Van Asperen PP. Source: Pediatric Pulmonology. 2002 March; 33(3): 194-200. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11836799&dopt=Abstract

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Ranitidine and omeprazole as adjuvant therapy to pancrelipase to improve fat absorption in patients with cystic fibrosis. Author(s): Francisco MP, Wagner MH, Sherman JM, Theriaque D, Bowser E, Novak DA. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002 July; 35(1): 79-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12142815&dopt=Abstract

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Reactive oxygen nitrogen species decrease cystic fibrosis transmembrane conductance regulator expression and cAMP-mediated Cl- secretion in airway epithelia. Author(s): Bebok Z, Varga K, Hicks JK, Venglarik CJ, Kovacs T, Chen L, Hardiman KM, Collawn JF, Sorscher EJ, Matalon S. Source: The Journal of Biological Chemistry. 2002 November 8; 277(45): 43041-9. Epub 2002 August 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12194970&dopt=Abstract

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Recent advances in cross-infection in cystic fibrosis: Burkholderia cepacia complex, Pseudomonas aeruginosa, MRSA and Pandoraea spp. Author(s): Jones AM, Webb AK. Source: Journal of the Royal Society of Medicine. 2003; 96 Suppl 43: 66-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906328&dopt=Abstract

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Recent advances in cystic fibrosis. Author(s): Doull IJ. Source: Archives of Disease in Childhood. 2001 July; 85(1): 62-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11420207&dopt=Abstract

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Recent progress in gene therapy for cystic fibrosis. Author(s): Griesenbach U, Alton EW. Source: Curr Opin Mol Ther. 2001 August; 3(4): 385-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11525562&dopt=Abstract

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Recombinant adeno-associated virus gene therapy for cystic fibrosis and alpha(1)antitrypsin deficiency. Author(s): Flotte TR. Source: Chest. 2002 March; 121(3 Suppl): 98S-102S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11893723&dopt=Abstract

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Recombinant adeno-associated virus vectors for cystic fibrosis gene therapy. Author(s): Flotte TR. Source: Curr Opin Mol Ther. 2001 October; 3(5): 497-502. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11699895&dopt=Abstract

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Recombinant human deoxyribonuclease for cystic fibrosis. Author(s): Jones AP, Wallis CE. Source: Cochrane Database Syst Rev. 2003; (3): Cd001127. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917899&dopt=Abstract

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Recovery of airway cystic fibrosis transmembrane conductance regulator function in mice with cystic fibrosis after single-dose lentivirus-mediated gene transfer. Author(s): Limberis M, Anson DS, Fuller M, Parsons DW. Source: Human Gene Therapy. 2002 November 1; 13(16): 1961-70. Erratum In: Hum Gene Ther. 2002 Nov 20; 13(17)2112. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12427306&dopt=Abstract

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Recovery of Candida dubliniensis from sputum of cystic fibrosis patients. Author(s): Peltroche-Llacsahuanga H, Dohmen H, Haase G. Source: Mycoses. 2002 February; 45(1-2): 15-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11856431&dopt=Abstract

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Recurrent fevers in a five-year-old boy with cystic fibrosis. Author(s): Kohn AS, Conrad DA. Source: The Pediatric Infectious Disease Journal. 2003 May; 22(5): 474, 478-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797319&dopt=Abstract

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Reduced Smad3 protein expression and altered transforming growth factor-beta1mediated signaling in cystic fibrosis epithelial cells. Author(s): Kelley TJ, Elmer HL, Corey DA. Source: American Journal of Respiratory Cell and Molecular Biology. 2001 December; 25(6): 732-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11726399&dopt=Abstract

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Reduction of neuronal and inducible nitric oxide synthase gene expression in patients with cystic fibrosis. Author(s): Dotsch J, Puls J, Klimek T, Rascher W. Source: European Archives of Oto-Rhino-Laryngology : Official Journal of the European Federation of Oto-Rhino-Laryngological Societies (Eufos) : Affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 2002 April; 259(4): 222-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12064512&dopt=Abstract

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Regional deposition of coarse particles and ventilation distribution in healthy subjects and patients with cystic fibrosis. Author(s): Brown JS, Zeman KL, Bennett WD. Source: Journal of Aerosol Medicine : the Official Journal of the International Society for Aerosols in Medicine. 2001 Winter; 14(4): 443-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11791685&dopt=Abstract

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Regulation and properties of KCNQ1 (K(V)LQT1) and impact of the cystic fibrosis transmembrane conductance regulator. Author(s): Boucherot A, Schreiber R, Kunzelmann K. Source: The Journal of Membrane Biology. 2001 July 1; 182(1): 39-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11426298&dopt=Abstract

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Regulation of channel gating by AMP-activated protein kinase modulates cystic fibrosis transmembrane conductance regulator activity in lung submucosal cells. Author(s): Hallows KR, McCane JE, Kemp BE, Witters LA, Foskett JK. Source: The Journal of Biological Chemistry. 2003 January 10; 278(2): 998-1004. Epub 2002 November 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12427743&dopt=Abstract

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Regulation of gap junctional communication by a pro-inflammatory cytokine in cystic fibrosis transmembrane conductance regulator-expressing but not cystic fibrosis airway cells. Author(s): Chanson M, Berclaz PY, Scerri I, Dudez T, Wernke-Dollries K, Pizurki L, Pavirani A, Fiedler MA, Suter S. Source: American Journal of Pathology. 2001 May; 158(5): 1775-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11337375&dopt=Abstract

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Regulation of the cystic fibrosis transmembrane conductance regulator Cl- channel by its R domain. Author(s): Ostedgaard LS, Baldursson O, Welsh MJ. Source: The Journal of Biological Chemistry. 2001 March 16; 276(11): 7689-92. Epub 2001 January 23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11244086&dopt=Abstract

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Relationship between nutritional status and lung function in cystic fibrosis: cross sectional and longitudinal analyses from the German CF quality assurance (CFQA) project. Author(s): Steinkamp G, Wiedemann B. Source: Thorax. 2002 July; 57(7): 596-601. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12096202&dopt=Abstract

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Relationship between sputum inflammatory markers, lung function, and lung pathology on high-resolution computed tomography in children with cystic fibrosis. Author(s): Dakin CJ, Pereira JK, Henry RL, Wang H, Morton JR. Source: Pediatric Pulmonology. 2002 June; 33(6): 475-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12001282&dopt=Abstract

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Relative ability of full and partial forced expiratory maneuvers to identify diminished airway function in infants with cystic fibrosis. Author(s): Ranganathan SC, Bush A, Dezateux C, Carr SB, Hoo AF, Lum S, Madge S, Price J, Stroobant J, Wade A, Wallis C, Wyatt H, Stocks J. Source: American Journal of Respiratory and Critical Care Medicine. 2002 November 15; 166(10): 1350-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12421744&dopt=Abstract

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Renal failure and vestibular toxicity in an adolescent with cystic fibrosis receiving gentamicin and standard-dose ibuprofen. Author(s): Scott CS, Retsch-Bogart GZ, Henry MM. Source: Pediatric Pulmonology. 2001 April; 31(4): 314-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11288217&dopt=Abstract

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Renal problems after lung transplantation of cystic fibrosis patients. Author(s): Schindler R, Radke C, Paul K, Frei U. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2001 July; 16(7): 1324-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11427619&dopt=Abstract

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Rescuing protein conformation: prospects for pharmacological therapy in cystic fibrosis. Author(s): Gelman MS, Kopito RR. Source: The Journal of Clinical Investigation. 2002 December; 110(11): 1591-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12464661&dopt=Abstract

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Research agenda for pediatric gastroenterology, hepatology and nutrition: cystic fibrosis and pancreatic diseases. Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation. Author(s): Lowe ME, Ameen N, Freedman S, Mulberg AE, Werlin SL. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002; 35 Suppl 3: S258-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12394362&dopt=Abstract

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Respiratory infections with Pseudomonas aeruginosa in children with cystic fibrosis: early detection by serology and assessment of risk factors. Author(s): West SE, Zeng L, Lee BL, Kosorok MR, Laxova A, Rock MJ, Splaingard MJ, Farrell PM. Source: Jama : the Journal of the American Medical Association. 2002 June 12; 287(22): 2958-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052125&dopt=Abstract

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Respiratory tract infections in cystic fibrosis. Author(s): Weiner DJ. Source: Pediatric Annals. 2002 February; 31(2): 116-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11862722&dopt=Abstract

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Respiratory virus infections in cystic fibrosis. Author(s): Wat D, Doull I. Source: Paediatric Respiratory Reviews. 2003 September; 4(3): 172-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12880751&dopt=Abstract

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Response to "Use of nasal potential differences and sweat chloride as outcome measures in multicenter clinical trials in subjects with cystic fibrosis". Author(s): LeGrys VA. Source: Pediatric Pulmonology. 2002 August; 34(2): 155; Author Reply 156. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12112786&dopt=Abstract

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Resting energy expenditure in young patients with cystic fibrosis receiving antibiotic therapy for acute respiratory exacerbations. Author(s): Castro M, Diamanti A, Gambarara M, Bella S, Lucidi V, Papadatou B, Ferretti F, Rosati P, Rupi E. Source: Clinical Nutrition (Edinburgh, Lothian). 2002 April; 21(2): 141-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12056786&dopt=Abstract

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Rethinking cystic fibrosis pathology: the critical role of abnormal reduced glutathione (GSH) transport caused by CFTR mutation. Author(s): Hudson VM. Source: Free Radical Biology & Medicine. 2001 June 15; 30(12): 1440-61. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11390189&dopt=Abstract

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Retrospective clinical comparison of Celsior solution to modified blood Wallwork solution in lung transplantation for cystic fibrosis. Author(s): Baron O, Fabre S, Haloun A, Treilhaud M, al Habasch O, Duveau D, Michaud JL, Despins P. Source: Prog Transplant. 2002 September; 12(3): 176-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12371042&dopt=Abstract

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Retroviral approaches to gene therapy of cystic fibrosis. Author(s): Johnson LG. Source: Annals of the New York Academy of Sciences. 2001 December; 953: 43-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11795422&dopt=Abstract

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Reversal of digital clubbing after lung transplantation in cystic fibrosis patients: a clue to the pathogenesis of clubbing. Author(s): Augarten A, Goldman R, Laufer J, Szeinberg A, Efrati O, Barak A, Miller MS, Yahav Y. Source: Pediatric Pulmonology. 2002 November; 34(5): 378-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12357483&dopt=Abstract

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Rhinological aspects of cystic fibrosis. Author(s): Watelet JB, Van Cauwenberge P, Bachert C. Source: Monaldi Arch Chest Dis. 2000 December; 55(6): 475-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11272634&dopt=Abstract

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Ribosomal DNA-directed PCR for identification of Achromobacter (Alcaligenes) xylosoxidans recovered from sputum samples from cystic fibrosis patients. Author(s): Liu L, Coenye T, Burns JL, Whitby PW, Stull TL, LiPuma JJ. Source: Journal of Clinical Microbiology. 2002 April; 40(4): 1210-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11923333&dopt=Abstract

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Risk factors for Burkholderia cepacia complex colonization and infection among patients with cystic fibrosis. Author(s): Walsh NM, Casano AA, Manangan LP, Sinkowitz-Cochran RL, Jarvis WR. Source: The Journal of Pediatrics. 2002 October; 141(4): 512-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12378190&dopt=Abstract

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Risk factors for initial acquisition of Pseudomonas aeruginosa in children with cystic fibrosis identified by newborn screening. Author(s): Maselli JH, Sontag MK, Norris JM, MacKenzie T, Wagener JS, Accurso FJ. Source: Pediatric Pulmonology. 2003 April; 35(4): 257-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12629621&dopt=Abstract

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Risk factors for the development of cystic fibrosis related liver disease. Author(s): Slieker MG, Deckers-Kocken JM, Uiterwaal CS, van der Ent CK, Houwen RH. Source: Hepatology (Baltimore, Md.). 2003 September; 38(3): 775-6; Author Reply 776-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939606&dopt=Abstract

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Role of airway surface liquid and submucosal glands in cystic fibrosis lung disease. Author(s): Verkman AS, Song Y, Thiagarajah JR. Source: American Journal of Physiology. Cell Physiology. 2003 January; 284(1): C2-15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12475759&dopt=Abstract

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Role of enteral nutrition in the pathophysiology and treatment of pancreatitis and cystic fibrosis. Author(s): Freedman SD. Source: Nestle Nutr Workshop Ser Clin Perform Programme. 2000; 3: 239-43; Discussion 243-6. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11490609&dopt=Abstract

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Role of exercise and lung function in predicting work status in cystic fibrosis. Author(s): Frangolias DD, Holloway CL, Vedal S, Wilcox PG. Source: American Journal of Respiratory and Critical Care Medicine. 2003 January 15; 167(2): 150-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12524253&dopt=Abstract

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Routine ventilation scans in children with cystic fibrosis. Author(s): Piepsz A, Ham H. Source: European Journal of Nuclear Medicine and Molecular Imaging. 2002 February; 29(2): 276. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11926390&dopt=Abstract

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Routine ventilation scans in children with cystic fibrosis: diagnostic usefulness and prognostic value. Author(s): Jaffe A, Hamutcu R, Dhawan RT, Adler B, Rosenthal M, Bush A. Source: European Journal of Nuclear Medicine. 2001 September; 28(9): 1313-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11585289&dopt=Abstract

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Rules of conduct for the cystic fibrosis anion channel. Author(s): Wine JJ. Source: Nature Medicine. 2003 July; 9(7): 827-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12835696&dopt=Abstract

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Safety and use of sputum induction in children with cystic fibrosis. Author(s): Suri R, Marshall LJ, Wallis C, Metcalfe C, Shute JK, Bush A. Source: Pediatric Pulmonology. 2003 April; 35(4): 309-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12629630&dopt=Abstract

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Salivary electrolyte concentrations are associated with cystic fibrosis transmembrane regulator genotypes. Author(s): Aps JK, Delanghe J, Martens LC. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 April; 40(4): 345-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12059073&dopt=Abstract

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Salmonella enterica serovar typhi modulates cell surface expression of its receptor, the cystic fibrosis transmembrane conductance regulator, on the intestinal epithelium. Author(s): Lyczak JB, Pier GB. Source: Infection and Immunity. 2002 November; 70(11): 6416-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12379722&dopt=Abstract

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Screening for cystic fibrosis in newborn infants: results of a pilot programme based on a two tier protocol (IRT/DNA/IRT) in the Italian population. Author(s): Corbetta C, Seia M, Bassotti A, Ambrosioni A, Giunta A, Padoan R. Source: Journal of Medical Screening. 2002; 9(2): 60-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12133923&dopt=Abstract

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SCVIR 2002 Film Panel case 2: TIPS for bleeding varices in cystic fibrosis and liver cirrhosis. Author(s): Bloom AI, Verstandig A. Source: Journal of Vascular and Interventional Radiology : Jvir. 2002 May; 13(5): 533-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11997364&dopt=Abstract

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Secondary amyloidosis detected in a patient with cystic fibrosis after undergoing lung transplantation. Author(s): Munoz-Bonet JI, Ibarra I, Perez-Navero JL, Espino M, Ulloa E, Jose Velasco M, Frias M, Lamas R. Source: Transplantation. 2002 April 15; 73(7): 1173-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11965055&dopt=Abstract

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Seeking modifier genes in cystic fibrosis. Author(s): Accurso FJ, Sontag MK. Source: American Journal of Respiratory and Critical Care Medicine. 2003 February 1; 167(3): 289-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554616&dopt=Abstract

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Selection of patients with cystic fibrosis for lung transplantation. Author(s): Liou TG, Cahill BC, Adler FR, Marshall BC. Source: Current Opinion in Pulmonary Medicine. 2002 November; 8(6): 535-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12394163&dopt=Abstract

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Selective activation of cystic fibrosis transmembrane conductance regulator Cl- and HCO3- conductances. Author(s): Reddy MM, Quinton PM. Source: Jop [electronic Resource] : Journal of the Pancreas. 2001 July; 2(4 Suppl): 212-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11875262&dopt=Abstract

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Sequencing of the Pseudomonas aeruginosa and Burkholderia cepacia genomes and their applications in relation to cystic fibrosis. Author(s): Miller DA, Mahenthiralingam E. Source: Journal of the Royal Society of Medicine. 2003; 96 Suppl 43: 57-65. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906327&dopt=Abstract

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Sequential genotyping of Pseudomonas aeruginosa from upper and lower airways of cystic fibrosis patients. Author(s): Jung A, Kleinau I, Schonian G, Bauernfeind A, Chen C, Griese M, Doring G, Gobel U, Wahn U, Paul K. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 December; 20(6): 1457-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12503704&dopt=Abstract

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Serologic IgE immune responses against Aspergillus fumigatus and Candida albicans in patients with cystic fibrosis. Author(s): Maiz L, Cuevas M, Quirce S, Canon JF, Pacheco A, Sousa A, Escobar H. Source: Chest. 2002 March; 121(3): 782-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11888960&dopt=Abstract

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Serum and lower respiratory tract drug concentrations after tobramycin inhalation in young children with cystic fibrosis. Author(s): Rosenfeld M, Gibson R, McNamara S, Emerson J, McCoyd KS, Shell R, Borowitz D, Konstan MW, Retsch-Bogart G, Wilmott RW, Burns JL, Vicini P, Montgomery AB, Ramsey B. Source: The Journal of Pediatrics. 2001 October; 139(4): 572-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11598606&dopt=Abstract

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Serum hyaluronic acid concentrations are increased in cystic fibrosis patients with liver disease. Author(s): Wyatt HA, Dhawan A, Cheeseman P, Mieli-Vergani G, Price JF. Source: Archives of Disease in Childhood. 2002 March; 86(3): 190-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11861239&dopt=Abstract

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Severe antibiotic-associated colitis in a patient with cystic fibrosis and colonic wall thickening. Author(s): Schmitt-Grohe S, Wiggert E, Steffan J, Handke R, Zielen S. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002 February; 34(2): 224-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11840045&dopt=Abstract

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Sex steroids and body composition in men with cystic fibrosis. Author(s): Leifke E, Friemert M, Heilmann M, Puvogel N, Smaczny C, von zur Muhlen A, Brabant G. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 May; 148(5): 551-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12720539&dopt=Abstract

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Short-term calcitriol administration improves calcium homeostasis in adults with cystic fibrosis. Author(s): Brown SA, Ontjes DA, Lester GE, Lark RK, Hensler MB, Blackwood AD, Caminiti MJ, Backlund DC, Aris RM. Source: Osteoporosis International : a Journal Established As Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the Usa. 2003 June; 14(5): 442-9. Epub 2003 May 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12774194&dopt=Abstract

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Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis. Author(s): Gibson RL, Emerson J, McNamara S, Burns JL, Rosenfeld M, Yunker A, Hamblett N, Accurso F, Dovey M, Hiatt P, Konstan MW, Moss R, Retsch-Bogart G, Wagener J, Waltz D, Wilmott R, Zeitlin PL, Ramsey B; Cystic Fibrosis Therapeutics Development Network Study Group. Source: American Journal of Respiratory and Critical Care Medicine. 2003 March 15; 167(6): 841-9. Epub 2002 December 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12480612&dopt=Abstract

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Single and combination antibiotic susceptibilities of planktonic, adherent, and biofilm-grown Pseudomonas aeruginosa isolates cultured from sputa of adults with cystic fibrosis. Author(s): Aaron SD, Ferris W, Ramotar K, Vandemheen K, Chan F, Saginur R. Source: Journal of Clinical Microbiology. 2002 November; 40(11): 4172-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12409393&dopt=Abstract

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Six of the best: cystic fibrosis. Author(s): Bush A. Source: Paediatric Respiratory Reviews. 2001 December; 2(4): 287-93. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052299&dopt=Abstract

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Six-minute walking test in cystic fibrosis adults with mild to moderate lung disease: comparison to healthy subjects. Author(s): Chetta A, Pisi G, Zanini A, Foresi A, Grzincich GL, Aiello M, Battistini A, Olivieri D. Source: Respiratory Medicine. 2001 December; 95(12): 986-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11778797&dopt=Abstract

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Six-year molecular analysis of Burkholderia cepacia complex isolates among cystic fibrosis patients at a referral center for lung transplantation. Author(s): Heath DG, Hohneker K, Carriker C, Smith K, Routh J, LiPuma JJ, Aris RM, Weber D, Gilligan PH. Source: Journal of Clinical Microbiology. 2002 April; 40(4): 1188-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11923329&dopt=Abstract

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Sleep quality and daytime function in adults with cystic fibrosis and severe lung disease. Author(s): Dancey DR, Tullis ED, Heslegrave R, Thornley K, Hanly PJ. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 March; 19(3): 504-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11936530&dopt=Abstract

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Smoking and cystic fibrosis. Author(s): Verma A, Clough D, McKenna D, Dodd M, Webb AK. Source: Journal of the Royal Society of Medicine. 2001; 94 Suppl 40: 29-34. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11601162&dopt=Abstract

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So many drugs, so little time: the future challenge of cystic fibrosis care. Author(s): Boyle MP. Source: Chest. 2003 January; 123(1): 3-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12527590&dopt=Abstract

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Sonographic evaluation of bowel wall thickness in patients with cystic fibrosis. Author(s): Dialer I, Hundt C, Bertele-Harms RM, Harms HK. Source: Journal of Clinical Gastroenterology. 2003 July; 37(1): 55-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12811210&dopt=Abstract

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Sonographic findings of the hepatobiliary-pancreatic system in adult patients with cystic fibrosis. Author(s): Dietrich CF, Chichakli M, Hirche TO, Bargon J, Leitzmann P, Wagner TO, Lembcke B. Source: Journal of Ultrasound in Medicine : Official Journal of the American Institute of Ultrasound in Medicine. 2002 April; 21(4): 409-16; Quiz 417. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11934098&dopt=Abstract

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Spatial and temporal distribution of cystic fibrosis and of its mutations in Brittany, France: a retrospective study from 1960. Author(s): Scotet V, Gillet D, Dugueperoux I, Audrezet MP, Bellis G, Garnier B, Roussey M, Rault G, Parent P, De Braekeleer M, Ferec C; Reseau Mucoviscidose Bretagne et Pays de Loire. Source: Human Genetics. 2002 September; 111(3): 247-54. Epub 2002 August 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12215837&dopt=Abstract

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Spectrum of mutations in the CFTR gene of patients with classical and atypical forms of cystic fibrosis from southwestern Sweden: identification of 12 novel mutations. Author(s): Strandvik B, Bjorck E, Fallstrom M, Gronowitz E, Thountzouris J, Lindblad A, Markiewicz D, Wahlstrom J, Tsui LC, Zielenski J. Source: Genetic Testing. 2001 Fall; 5(3): 235-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11788090&dopt=Abstract

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Spirometry in 3- to 6-year-old children with cystic fibrosis. Author(s): Marostica PJ, Weist AD, Eigen H, Angelicchio C, Christoph K, Savage J, Grant D, Tepper RS. Source: American Journal of Respiratory and Critical Care Medicine. 2002 July 1; 166(1): 67-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12091173&dopt=Abstract

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Splice mutation 1811+1.6kbA>G causes severe cystic fibrosis with pancreatic insufficiency: report of 11 compound heterozygous and two homozygous patients. Author(s): Reboul MP, Bieth E, Fayon M, Biteau N, Barbier R, Dromer C, Desgeorges M, Claustres M, Bremont F, Lacombe D, Iron A. Source: Journal of Medical Genetics. 2002 November; 39(11): E73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12414835&dopt=Abstract

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Spread of an epidemic Pseudomonas aeruginosa strain from a patient with cystic fibrosis (CF) to non-CF relatives. Author(s): McCallum SJ, Gallagher MJ, Corkill JE, Hart CA, Ledson MJ, Walshaw MJ. Source: Thorax. 2002 June; 57(6): 559-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12037234&dopt=Abstract

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Sputum isolation of Wangiella dermatitidis in patients with cystic fibrosis. Author(s): Diemert D, Kunimoto D, Sand C, Rennie R. Source: Scandinavian Journal of Infectious Diseases. 2001; 33(10): 777-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11728050&dopt=Abstract

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Stature as a prognostic factor in cystic fibrosis survival. Author(s): Beker LT, Russek-Cohen E, Fink RJ. Source: Journal of the American Dietetic Association. 2001 April; 101(4): 438-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11320950&dopt=Abstract

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Stenotrophomonas maltophilia bacteraemia in two patients with cystic fibrosis associated with totally implantable venous access devices. Author(s): Ratnalingham RA, Peckham D, Denton M, Kerr K, Conway S. Source: The Journal of Infection. 2002 January; 44(1): 53-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11972423&dopt=Abstract

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Stimulation of beta 2-adrenergic receptor increases cystic fibrosis transmembrane conductance regulator expression in human airway epithelial cells through a cAMP/protein kinase A-independent pathway. Author(s): Taouil K, Hinnrasky J, Hologne C, Corlieu P, Klossek JM, Puchelle E. Source: The Journal of Biological Chemistry. 2003 May 9; 278(19): 17320-7. Epub 2003 March 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12621035&dopt=Abstract

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Strategies for improving transition to adult cystic fibrosis care, based on patient and parent views. Author(s): Boyle MP, Farukhi Z, Nosky ML. Source: Pediatric Pulmonology. 2001 December; 32(6): 428-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11747245&dopt=Abstract

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Stresses and coping strategies of mothers living with a child with cystic fibrosis: implications for nursing professionals. Author(s): Hodgkinson R, Lester H. Source: Journal of Advanced Nursing. 2002 August; 39(4): 377-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12139650&dopt=Abstract

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Structural analysis of the lipopolysaccharide core of a rough, cystic fibrosis isolate of Pseudomonas aeruginosa. Author(s): Knirel YA, Bystrova OV, Shashkov AS, Lindner B, Kocharova NA, Senchenkova SN, Moll H, Zahringer U, Hatano K, Pier GB. Source: European Journal of Biochemistry / Febs. 2001 September; 268(17): 4708-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11532007&dopt=Abstract

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Structural basis for oligosaccharide-mediated adhesion of Pseudomonas aeruginosa in the lungs of cystic fibrosis patients. Author(s): Mitchell E, Houles C, Sudakevitz D, Wimmerova M, Gautier C, Perez S, Wu AM, Gilboa-Garber N, Imberty A. Source: Nature Structural Biology. 2002 December; 9(12): 918-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12415289&dopt=Abstract

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Subclinical right ventricular dysfunction in cystic fibrosis. A study using tissue Doppler echocardiography. Author(s): Ionescu AA, Ionescu AA, Payne N, Obieta-Fresnedo I, Fraser AG, Shale DJ. Source: American Journal of Respiratory and Critical Care Medicine. 2001 April; 163(5): 1212-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11316661&dopt=Abstract

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Successful treatment of methicillin-resistant Staphylococcus aureus pulmonary infection with linezolid in a patient with cystic fibrosis. Author(s): Ferrin M, Zuckerman JB, Meagher A, Blumberg EA. Source: Pediatric Pulmonology. 2002 March; 33(3): 221-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11836802&dopt=Abstract

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Sulphation of the salivary mucin MG1 (MUC-5B) is not correlated to the degree of its sialylation and is unaffected by cystic fibrosis. Author(s): Shori DK, Kariyawasam HH, Knight RA, Hodson ME, Genter T, Hansen J, Koch C, Kalogeridis A. Source: Pflugers Archiv : European Journal of Physiology. 2001; 443 Suppl 1: S50-4. Epub 2001 September 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11845303&dopt=Abstract

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Surgical experience in patients with cystic fibrosis: a 25-year perspective. Author(s): Saltzman DA, Johnson EM, Feltis BA, Wilienski C, Warwick WJ, Leonard AS. Source: Pediatric Pulmonology. 2002 February; 33(2): 106-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11802246&dopt=Abstract

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Survey of resistance of Pseudomonas aeruginosa from UK patients with cystic fibrosis to six commonly prescribed antimicrobial agents. Author(s): Pitt TL, Sparrow M, Warner M, Stefanidou M. Source: Thorax. 2003 September; 58(9): 794-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12947141&dopt=Abstract

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Survival effect of lung transplantation among patients with cystic fibrosis. Author(s): Liou TG, Adler FR, Cahill BC, FitzSimmons SC, Huang D, Hibbs JR, Marshall BC. Source: Jama : the Journal of the American Medical Association. 2001 December 5; 286(21): 2683-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11730443&dopt=Abstract

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Survival following Burkholderia cepacia sepsis in a patient with cystic fibrosis treated with corticosteroids. Author(s): Kazachkov M, Lager J, LiPuma J, Barker PM. Source: Pediatric Pulmonology. 2001 October; 32(4): 338-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11568995&dopt=Abstract

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Susceptibility of pseudomonas aeruginosa to cefepime versus ceftazidime in patients with cystic fibrosis. Author(s): Robinson CA, Kuhn RJ, Craigmyle J, Anstead MI, Kanga JE. Source: Pharmacotherapy. 2001 November; 21(11): 1320-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11714203&dopt=Abstract

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Susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration: lack of association in cystic fibrosis. Author(s): Smith AL, Fiel SB, Mayer-Hamblett N, Ramsey B, Burns JL. Source: Chest. 2003 May; 123(5): 1495-502. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12740266&dopt=Abstract

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Synergistic activities of macrolide antibiotics against Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, and Alcaligenes xylosoxidans isolated from patients with cystic fibrosis. Author(s): Saiman L, Chen Y, Gabriel PS, Knirsch C. Source: Antimicrobial Agents and Chemotherapy. 2002 April; 46(4): 1105-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11897598&dopt=Abstract

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Telephone use in primary care. Telephones have proved useful in managing cystic fibrosis. Author(s): Taccetti G, Festini F, de Martino M. Source: Bmj (Clinical Research Ed.). 2002 September 7; 325(7363): 547. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12224105&dopt=Abstract

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Terminal glycosylation in cystic fibrosis (CF): a review emphasizing the airway epithelial cell. Author(s): Rhim AD, Stoykova L, Glick MC, Scanlin TF. Source: Glycoconjugate Journal. 2001 September; 18(9): 649-59. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12386452&dopt=Abstract

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The cystic fibrosis therapeutics development network (CF TDN): a paradigm of a clinical trials network for genetic and orphan diseases. Author(s): Goss CH, Mayer-Hamblett N, Kronmal RA, Ramsey BW. Source: Advanced Drug Delivery Reviews. 2002 December 5; 54(11): 1505-28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458158&dopt=Abstract

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The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the HCO3- salvage transporter human Na+-HCO3- cotransport isoform 3. Author(s): Park M, Ko SB, Choi JY, Muallem G, Thomas PJ, Pushkin A, Lee MS, Kim JY, Lee MG, Muallem S, Kurtz I. Source: The Journal of Biological Chemistry. 2002 December 27; 277(52): 50503-9. Epub 2002 October 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12403779&dopt=Abstract

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The daily grind and how to stay sane as a mother of two children with cystic fibrosis. Author(s): Hunter V. Source: Journal of the Royal Society of Medicine. 2003; 96 Suppl 43: 51-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906326&dopt=Abstract

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The diffusing capacity in adult cystic fibrosis. Author(s): Espiritu JD, Ruppel G, Shrestha Y, Kleinhenz ME. Source: Respiratory Medicine. 2003 June; 97(6): 606-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814143&dopt=Abstract

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The effect of erythromycin on mucociliary transportability and rheology of cystic fibrosis and bronchiectasis sputum. Author(s): Shibuya Y, Wills PJ, Cole PJ. Source: Respiration; International Review of Thoracic Diseases. 2001; 68(6): 615-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11786718&dopt=Abstract

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The first case report in Saudi Arabia of diabetes mellitus and cystic fibrosis in two siblings. Author(s): Banjar H. Source: Annals of Tropical Paediatrics. 2002 December; 22(4): 383-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12530290&dopt=Abstract

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The heart in cystic fibrosis. Author(s): Bright-Thomas RJ, Webb AK. Source: Journal of the Royal Society of Medicine. 2002; 95 Suppl 41: 2-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12216270&dopt=Abstract

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The human DnaJ homologue (Hdj)-1/heat-shock protein (Hsp) 40 co-chaperone is required for the in vivo stabilization of the cystic fibrosis transmembrane conductance regulator by Hsp70. Author(s): Farinha CM, Nogueira P, Mendes F, Penque D, Amaral MD. Source: The Biochemical Journal. 2002 September 15; 366(Pt 3): 797-806. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12069690&dopt=Abstract

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The I148T CFTR allele occurs on multiple haplotypes: a complex allele is associated with cystic fibrosis. Author(s): Rohlfs EM, Zhou Z, Sugarman EA, Heim RA, Pace RG, Knowles MR, Silverman LM, Allitto BA. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2002 September-October; 4(5): 319-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12394343&dopt=Abstract

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The impact of cystic fibrosis on neonatal intestinal obstruction: the need for prenatal/neonatal screening. Author(s): Casaccia G, Trucchi A, Nahom A, Aite L, Lucidi V, Giorlandino C, Bagolan P. Source: Pediatric Surgery International. 2003 April; 19(1-2): 75-8. Epub 2003 January 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12721730&dopt=Abstract

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The impact of early cystic fibrosis diagnosis on pulmonary function in children. Author(s): Wang SS, O'Leary LA, Fitzsimmons SC, Khoury MJ. Source: The Journal of Pediatrics. 2002 December; 141(6): 804-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12461497&dopt=Abstract

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The interaction between syntaxin 1A and cystic fibrosis transmembrane conductance regulator Cl- channels is mechanistically distinct from syntaxin 1A-SNARE interactions. Author(s): Ganeshan R, Di A, Nelson DJ, Quick MW, Kirk KL. Source: The Journal of Biological Chemistry. 2003 January 31; 278(5): 2876-85. Epub 2002 November 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12446681&dopt=Abstract

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The pancreas in cystic fibrosis. Author(s): Taylor CJ, Aswani N. Source: Paediatric Respiratory Reviews. 2002 March; 3(1): 77-81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12065186&dopt=Abstract

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The PDZ-binding chloride channel ClC-3B localizes to the Golgi and associates with cystic fibrosis transmembrane conductance regulator-interacting PDZ proteins. Author(s): Gentzsch M, Cui L, Mengos A, Chang XB, Chen JH, Riordan JR. Source: The Journal of Biological Chemistry. 2003 February 21; 278(8): 6440-9. Epub 2002 December 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12471024&dopt=Abstract

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The PEST sequence does not contribute to the stability of the cystic fibrosis transmembrane conductance regulator. Author(s): Chen EY, Clarke DM. Source: Bmc Biochemistry [electronic Resource]. 2002 October 2; 3(1): 29. Epub 2002 Oct 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12361483&dopt=Abstract

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The Pseudomonas aeruginosa alternative sigma factor PvdS controls exotoxin A expression and is expressed in lung infections associated with cystic fibrosis. Author(s): Hunt TA, Peng WT, Loubens I, Storey DG. Source: Microbiology (Reading, England). 2002 October; 148(Pt 10): 3183-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12368452&dopt=Abstract

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The Pseudomonas aeruginosa genome: how do we use it to develop strategies for the treatment of patients with cystic fibrosis and Pseudomonas infections? Author(s): Erwin AL, VanDevanter DR. Source: Current Opinion in Pulmonary Medicine. 2002 November; 8(6): 547-51. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12394165&dopt=Abstract

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The pulmonary physician in critical care. Illustrative case 1: cystic fibrosis. Author(s): Thomas SR. Source: Thorax. 2003 April; 58(4): 357-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12668804&dopt=Abstract

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The relationship between genotype and exercise tolerance in children with cystic fibrosis. Author(s): Selvadurai HC, McKay KO, Blimkie CJ, Cooper PJ, Mellis CM, Van Asperen PP. Source: American Journal of Respiratory and Critical Care Medicine. 2002 March 15; 165(6): 762-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11897641&dopt=Abstract

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The relationship between insulin secretion, the insulin-like growth factor axis and growth in children with cystic fibrosis. Author(s): Ripa P, Robertson I, Cowley D, Harris M, Masters IB, Cotterill AM. Source: Clinical Endocrinology. 2002 March; 56(3): 383-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11940051&dopt=Abstract

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The revised German Cystic Fibrosis Questionnaire: validation of a disease-specific health-related quality of life instrument. Author(s): Wenninger K, Aussage P, Wahn U, Staab D; German Cystic Fibrosis Questionnaire study group. Source: Quality of Life Research : an International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation. 2003 February; 12(1): 77-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12625520&dopt=Abstract

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The role of hepatic stellate cells and transforming growth factor-beta(1) in cystic fibrosis liver disease. Author(s): Lewindon PJ, Pereira TN, Hoskins AC, Bridle KR, Williamson RM, Shepherd RW, Ramm GA. Source: American Journal of Pathology. 2002 May; 160(5): 1705-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12000722&dopt=Abstract

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The role of IDA scintigraphy in the follow-up of liver disease in patients with cystic fibrosis. Author(s): Foster JA, Ramsden WH, Conway SP, Taylor JM, Etherington C. Source: Nuclear Medicine Communications. 2002 July; 23(7): 673-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12089490&dopt=Abstract

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The role of supplemental oxygen during submaximal exercise in patients with cystic fibrosis. Author(s): McKone EF, Barry SC, FitzGerald MX, Gallagher CG. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 July; 20(1): 134-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12166561&dopt=Abstract

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The role of the C terminus and Na+/H+ exchanger regulatory factor in the functional expression of cystic fibrosis transmembrane conductance regulator in nonpolarized cells and epithelia. Author(s): Benharouga M, Sharma M, So J, Haardt M, Drzymala L, Popov M, Schwapach B, Grinstein S, Du K, Lukacs GL. Source: The Journal of Biological Chemistry. 2003 June 13; 278(24): 22079-89. Epub 2003 March 21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12651858&dopt=Abstract

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The role of the cystic fibrosis nurse specialist. Author(s): Cowlard J. Source: Nurs Times. 2002 March 21-27; 98(12): 62-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11933789&dopt=Abstract

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Therapy with macrolides in patients with cystic fibrosis. Author(s): Gaylor AS, Reilly JC. Source: Pharmacotherapy. 2002 February; 22(2): 227-39. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11837560&dopt=Abstract

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There is no evidence of a primary defect in energy metabolism in subjects with cystic fibrosis. Author(s): Pencharz PB, Jackson R. Source: The Journal of Pediatrics. 2002 May; 140(5): 498-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12032511&dopt=Abstract

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Three-minute step test to assess exercise capacity in children with cystic fibrosis with mild lung disease. Author(s): Narang I, Pike S, Rosenthal M, Balfour-Lynn IM, Bush A. Source: Pediatric Pulmonology. 2003 February; 35(2): 108-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12526071&dopt=Abstract

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Tidal expiratory flow limitation and chronic dyspnoea in patients with cystic fibrosis. Author(s): Goetghebeur D, Sarni D, Grossi Y, Leroyer C, Ghezzo H, Milic-Emiri J, Bellet M. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 March; 19(3): 492-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11936528&dopt=Abstract

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To the editor: Alcaligenes as a pathogen in airways chronic infection in cystic fibrosis. Author(s): Romano L, Bellodi S, Lugani F, Manno G. Source: Pediatric Pulmonology. 2003 May; 35(5): 412-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687601&dopt=Abstract

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To the editor: Bronchoalveolar lavage (BAL) in pediatric cystic fibrosis (CF): its clinical use modified by audit in a regional CF center. Author(s): Furness JC, Habeb A, Spencer DA, O'Brien CJ. Source: Pediatric Pulmonology. 2002 March; 33(3): 234. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11836806&dopt=Abstract

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To the editor: Is it safe to administer a continuous infusion of ceftazidime (Fortum) prepared for 24 hours in cystic fibrosis (CF) patients? Author(s): Plasse JC, Chabloz C, Terrier A, Bellon G. Source: Pediatric Pulmonology. 2002 March; 33(3): 232-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11836805&dopt=Abstract

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Totally implantable vascular access devices for cystic fibrosis. Author(s): A-Rahman A, Spencer D. Source: Cochrane Database Syst Rev. 2003; (3): Cd004111. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918004&dopt=Abstract

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Towards the pharmacogenomics of cystic fibrosis. Author(s): Sangiuolo F, D'Apice MR, Bruscia E, Lucidi V, Novelli G. Source: Pharmacogenomics. 2002 January; 3(1): 75-87. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11966405&dopt=Abstract

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Transcript analysis of the cystic fibrosis splicing mutation 1525-1G>A shows use of multiple alternative splicing sites and suggests a putative role of exonic splicing enhancers. Author(s): Ramalho AS, Beck S, Penque D, Gonska T, Seydewitz HH, Mall M, Amaral MD. Source: Journal of Medical Genetics. 2003 July; 40(7): E88. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843337&dopt=Abstract

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Transition in cystic fibrosis: much ado about nothing? A pediatrician's view. Author(s): Schidlow DV. Source: Pediatric Pulmonology. 2002 May; 33(5): 325-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11948975&dopt=Abstract

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Transition of adult patients with cystic fibrosis from paediatric to adult care--the patients' perspective before and after start-up of an adult clinic. Author(s): Steinkamp G, Ullrich G, Muller C, Fabel H, von der Hardt H. Source: European Journal of Medical Research. 2001 February 28; 6(2): 85-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11313196&dopt=Abstract

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Transition of care between paediatric and adult gastroenterology. Cystic fibrosis. Author(s): Jackson R, Pencharz PB. Source: Best Practice & Research. Clinical Gastroenterology. 2003 April; 17(2): 213-35. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12676116&dopt=Abstract

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Transition programs in cystic fibrosis centers: perceptions of patients. Author(s): Anderson DL, Flume PA, Hardy KK, Gray S. Source: Pediatric Pulmonology. 2002 May; 33(5): 327-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11948976&dopt=Abstract

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Transjugular intrahepatic portosystemic shunt in five children with cystic fibrosis: long-term results. Author(s): Pozler O, Krajina A, Vanicek H, Hulek P, Zizka J, Michl A, Elias P. Source: Hepatogastroenterology. 2003 July-August; 50(52): 1111-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12845992&dopt=Abstract

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Transmission of colistin-resistant Pseudomonas aeruginosa between patients attending a pediatric cystic fibrosis center. Author(s): Denton M, Kerr K, Mooney L, Keer V, Rajgopal A, Brownlee K, Arundel P, Conway S. Source: Pediatric Pulmonology. 2002 October; 34(4): 257-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12205566&dopt=Abstract

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Transplantation for cystic fibrosis: outcome following early liver transplantation. Author(s): Milkiewicz P, Skiba G, Kelly D, Weller P, Bonser R, Gur U, Mirza D, Buckels J, Stableforth D, Elias E. Source: Journal of Gastroenterology and Hepatology. 2002 February; 17(2): 208-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11966953&dopt=Abstract

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Treatment of children with cystic fibrosis: central, local or both? Author(s): van Koolwijk LM, Uiterwaal CS, van der Laag J, Hoekstra JH, Gulmans VA, van der Ent CK. Source: Acta Paediatrica (Oslo, Norway : 1992). 2002; 91(9): 972-7; Discussion 894-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12412875&dopt=Abstract

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Treatment of severe small airways disease in children with cystic fibrosis: alternatives to corticosteroids. Author(s): Jaffe A, Balfour-Lynn IM. Source: Paediatric Drugs. 2002; 4(6): 381-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12038874&dopt=Abstract

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Treatment options for cystic fibrosis: case study and panel discussion. Author(s): Kuhn RJ, Flume PA. Source: Pharmacotherapy. 2002 March; 22(3 Pt 2): 86S-87S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11898886&dopt=Abstract

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Typing of Pseudomonas aeruginosa strains in Turkish cystic fibrosis patients. Author(s): Yagci A, Ciragil P, Over U, Sener B, Erturan Z, Soyletir G. Source: New Microbiol. 2003 January; 26(1): 109-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12578318&dopt=Abstract

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Tyrosine kinase c-Src constitutes a bridge between cystic fibrosis transmembrane regulator channel failure and MUC1 overexpression in cystic fibrosis. Author(s): Gonzalez-Guerrico AM, Cafferata EG, Radrizzani M, Marcucci F, Gruenert D, Pivetta OH, Favaloro RR, Laguens R, Perrone SV, Gallo GC, Santa-Coloma TA. Source: The Journal of Biological Chemistry. 2002 May 10; 277(19): 17239-47. Epub 2002 February 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11872746&dopt=Abstract

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Ultrasound evaluation of liver disease in cystic fibrosis as part of an annual assessment clinic: a 9-year review. Author(s): Williams SM, Goodman R, Thomson A, McHugh K, Lindsell DR. Source: Clinical Radiology. 2002 May; 57(5): 365-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12014933&dopt=Abstract

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Unilateral air bronchogram in a patient with cystic fibrosis. Author(s): Huisman C, de Graaff CS, Boersma WG. Source: Chest. 2002 April; 121(4): 1343-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11948072&dopt=Abstract

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Unique presentations and chronic complications in adult cystic fibrosis: do they teach us anything about CFTR? Author(s): Boyle MP. Source: Respiratory Research. 2000; 1(3): 133-5. Epub 2000 November 16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11667976&dopt=Abstract

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Unusual respiratory bacterial flora in cystic fibrosis: microbiologic and clinical features. Author(s): Beringer PM, Appleman MD. Source: Current Opinion in Pulmonary Medicine. 2000 November; 6(6): 545-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11100967&dopt=Abstract

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Update on cystic fibrosis: selected aspects related to lung transplantation. Author(s): Boehler A. Source: Swiss Medical Weekly : Official Journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology. 2003 February 22; 133(7-8): 111-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12644957&dopt=Abstract

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Update: epidemiology of cystic fibrosis. Author(s): Krimsky WS, Parker HW. Source: Current Opinion in Pulmonary Medicine. 2002 November; 8(6): 552-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12394166&dopt=Abstract

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Updated assessment of cystic fibrosis mutation frequencies in non-Hispanic Caucasians. Author(s): Palomaki GE, Haddow JE, Bradley LA, FitzSimmons SC. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2002 March-April; 4(2): 90-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11882786&dopt=Abstract

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Up-regulation of acid-gated Na(+) channels (ASICs) by cystic fibrosis transmembrane conductance regulator co-expression in Xenopus oocytes. Author(s): Ji HL, Jovov B, Fu J, Bishop LR, Mebane HC, Fuller CM, Stanton BA, Benos DJ. Source: The Journal of Biological Chemistry. 2002 March 8; 277(10): 8395-405. Epub 2001 December 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11748227&dopt=Abstract

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Urinary excretion reflects lung deposition of aminoglycoside aerosols in cystic fibrosis. Author(s): Dequin PF, Faurisson F, Lemarie E, Delatour F, Marchand S, Valat C, Boissinot E, de Gialluly C, Diot P. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 August; 18(2): 316-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11529290&dopt=Abstract

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Urinary incontinence in female adolescents with cystic fibrosis. Author(s): Nixon GM, Glazner JA, Martin JM, Sawyer SM. Source: Pediatrics. 2002 August; 110(2 Pt 1): E22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12165621&dopt=Abstract

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Urogenital abnormalities in male children with cystic fibrosis. Author(s): Blau H, Freud E, Mussaffi H, Werner M, Konen O, Rathaus V. Source: Archives of Disease in Childhood. 2002 August; 87(2): 135-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12138064&dopt=Abstract

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Use of 16S rRNA gene sequencing for identification of nonfermenting gram-negative bacilli recovered from patients attending a single cystic fibrosis center. Author(s): Ferroni A, Sermet-Gaudelus I, Abachin E, Quesne G, Lenoir G, Berche P, Gaillard JL. Source: Journal of Clinical Microbiology. 2002 October; 40(10): 3793-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12354883&dopt=Abstract

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Use of amplified ribosomal DNA restriction analysis for identification of Ralstonia and Pandoraea species: interest in determination of the respiratory bacterial flora in patients with cystic fibrosis. Author(s): Segonds C, Paute S, Chabanon G. Source: Journal of Clinical Microbiology. 2003 July; 41(7): 3415-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843108&dopt=Abstract

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Use of computerized tomography and chest x-rays in evaluating efficacy of aerosolized recombinant human DNase in cystic fibrosis patients younger than age 5 years: a preliminary study. Author(s): Nasr SZ, Kuhns LR, Brown RW, Hurwitz ME, Sanders GM, Strouse PJ. Source: Pediatric Pulmonology. 2001 May; 31(5): 377-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11340684&dopt=Abstract

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Use of cough swabs in a cystic fibrosis clinic. Author(s): Equi AC, Pike SE, Davies J, Bush A. Source: Archives of Disease in Childhood. 2001 November; 85(5): 438-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11668115&dopt=Abstract

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Use of cyclosporin A as a steroid sparing agent in cystic fibrosis. Author(s): Bhal GK, Maguire SA, Bowler IM. Source: Archives of Disease in Childhood. 2001 January; 84(1): 89. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11213776&dopt=Abstract

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Use of nasal potential difference and sweat chloride as outcome measures in multicenter clinical trials in subjects with cystic fibrosis. Author(s): Ahrens RC, Standaert TA, Launspach J, Han SH, Teresi ME, Aitken ML, Kelley TJ, Hilliard KA, Milgram LJ, Konstan MW, Weatherly MR, McCarty NA. Source: Pediatric Pulmonology. 2002 February; 33(2): 142-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11802252&dopt=Abstract

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Use of random amplified polymorphic DNA PCR to examine epidemiology of Stenotrophomonas maltophilia and Achromobacter (Alcaligenes) xylosoxidans from patients with cystic fibrosis. Author(s): Krzewinski JW, Nguyen CD, Foster JM, Burns JL. Source: Journal of Clinical Microbiology. 2001 October; 39(10): 3597-602. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11574579&dopt=Abstract

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Use of rhDNase therapy and costs of respiratory-related care in patients with cystic fibrosis. Author(s): Ollendorf DA, McGarry LJ, Watrous ML, Oster G. Source: The Annals of Pharmacotherapy. 2000 March; 34(3): 304-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10917374&dopt=Abstract

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Use of selective medium for Burkholderia cepacia isolation in respiratory samples from cystic fibrosis patients. Author(s): da Silva Filho LV, Velloso Lde F, Bento CN, Gytin E, Tateno AF, Levi JE, Rodrigues JC, Ramos SR. Source: Revista Do Instituto De Medicina Tropical De Sao Paulo. 2002 July-August; 44(4): 203-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12219111&dopt=Abstract

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Use of subtractive hybridization to identify a diagnostic probe for a cystic fibrosis epidemic strain of Pseudomonas aeruginosa. Author(s): Parsons YN, Panagea S, Smart CH, Walshaw MJ, Hart CA, Winstanley C. Source: Journal of Clinical Microbiology. 2002 December; 40(12): 4607-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454160&dopt=Abstract

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Use of the E test to assess synergy of antibiotic combinations against isolates of Burkholderia cepacia-complex from patients with cystic fibrosis. Author(s): Manno G, Ugolotti E, Belli ML, Fenu ML, Romano L, Cruciani M. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2003 January; 22(1): 28-34. Epub 2003 January 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12582741&dopt=Abstract

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Use of the gas exchange threshold to noninvasively determine the lactate threshold in patients with cystic fibrosis. Author(s): Thin AG, Linnane SJ, McKone EF, Freaney R, FitzGerald MX, Gallagher CG, McLoughlin P. Source: Chest. 2002 June; 121(6): 1761-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12065336&dopt=Abstract

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Usefulness of 2D echo Doppler in the preoperative assessment of cystic fibrosis patients who are candidates for lung transplantation. Author(s): Vizza CD, Sciomer S, Della Rocca G, Di Roma A, Iacoboni C, Venuta F, Rendina EA, Di Giacomo T, Padovani D, Lavalle C, Quattrucci S, Flaishman I, Cimino G, Antonelli M, Coloni F, Fedele F. Source: Transplantation Proceedings. 2001 February-March; 33(1-2): 1628-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11267448&dopt=Abstract

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Utility of commercial systems for identification of Burkholderia cepacia complex from cystic fibrosis sputum culture. Author(s): Shelly DB, Spilker T, Gracely EJ, Coenye T, Vandamme P, LiPuma JJ. Source: Journal of Clinical Microbiology. 2000 August; 38(8): 3112-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10921992&dopt=Abstract

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Utility of gram staining for evaluation of the quality of cystic fibrosis sputum samples. Author(s): Nair B, Stapp J, Stapp L, Bugni L, Van Dalfsen J, Burns JL. Source: Journal of Clinical Microbiology. 2002 August; 40(8): 2791-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12149331&dopt=Abstract

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Validation of shuttle tests in children with cystic fibrosis. Author(s): Selvadurai HC, Cooper PJ, Meyers N, Blimkie CJ, Smith L, Mellis CM, Van Asperen PP. Source: Pediatric Pulmonology. 2003 February; 35(2): 133-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12526075&dopt=Abstract

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Valsalva retinopathy and optic nerve drusen in a patient with cystic fibrosis. Author(s): Gupta R, Singh S, Tang RA, Blackwell TA. Source: The American Journal of Medicine. 2002 February 15; 112(3): 246-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11893360&dopt=Abstract

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Variant cystic fibrosis phenotypes in the absence of CFTR mutations. Author(s): Couper RT. Source: The New England Journal of Medicine. 2002 December 5; 347(23): 1892-3; Author Reply 1892-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12466520&dopt=Abstract

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Variant cystic fibrosis phenotypes in the absence of CFTR mutations. Author(s): Groman JD, Meyer ME, Wilmott RW, Zeitlin PL, Cutting GR. Source: The New England Journal of Medicine. 2002 August 8; 347(6): 401-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12167682&dopt=Abstract

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Variations in the measurement of resting energy expenditure in children with cystic fibrosis. Author(s): Ashley MA, Broomhead L, Allen JR, Gaskin KJ. Source: European Journal of Clinical Nutrition. 2001 October; 55(10): 896-901. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11593352&dopt=Abstract

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Vertebral deformities and low bone mineral density in adults with cystic fibrosis: a cross-sectional study. Author(s): Elkin SL, Fairney A, Burnett S, Kemp M, Kyd P, Burgess J, Compston JE, Hodson ME. Source: Osteoporosis International : a Journal Established As Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the Usa. 2001; 12(5): 366-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11444084&dopt=Abstract

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Vertical infraclavicular brachial plexus block in a child with cystic fibrosis. Author(s): Zimmermann P, Papenfuss T, Schwemmer U, Greim CA. Source: Anesthesia and Analgesia. 2002 December; 95(6): 1825-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12456477&dopt=Abstract

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Vitamin K deficient bleeding in cystic fibrosis. Author(s): Verghese T, Beverley D. Source: Archives of Disease in Childhood. 2003 June; 88(6): 553. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765934&dopt=Abstract

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Wasting as an independent predictor of mortality in patients with cystic fibrosis. Author(s): Sharma R, Florea VG, Bolger AP, Doehner W, Florea ND, Coats AJ, Hodson ME, Anker SD, Henein MY. Source: Thorax. 2001 October; 56(10): 746-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11562511&dopt=Abstract

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Water-miscible tocopherol is not superior to fat-soluble preparation for vitamin E absorption in cystic fibrosis. Author(s): Soltani-Frisk S, Gronowitz E, Andersson H, Strandvik B. Source: Acta Paediatrica (Oslo, Norway : 1992). 2001 October; 90(10): 1112-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11697419&dopt=Abstract

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Ways of coping with cystic fibrosis: implications for treatment adherence. Author(s): Abbott J, Dodd M, Gee L, Webb K. Source: Disability and Rehabilitation. 2001 May 20; 23(8): 315-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11374521&dopt=Abstract

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What do children with cystic fibrosis and their parents know about nutrition and pancreatic enzymes? Author(s): Stapleton DR, Gurrin LC, Zubrick SR, Silburn SR, Sherriff JL, Sly PD. Source: Journal of the American Dietetic Association. 2000 December; 100(12): 1494-500. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11138442&dopt=Abstract

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What is cystic fibrosis? Author(s): Knowles MR, Durie PR. Source: The New England Journal of Medicine. 2002 August 8; 347(6): 439-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12167688&dopt=Abstract

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What is the cystic fibrosis clinician supposed to do with human recombinant dornase alfa? Author(s): Coates AL. Source: The Journal of Pediatrics. 2001 December; 139(6): 768-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11743499&dopt=Abstract

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Which factors account for renal stone formation in cystic fibrosis? Author(s): von der Heiden R, Balestra AP, Bianchetti MG, Casaulta Aebischer C, Mullis PE, Lippuner K, Jaeger P. Source: Clinical Nephrology. 2003 March; 59(3): 160-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12653257&dopt=Abstract

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Women with cystic fibrosis and their potential for reproduction. Author(s): Edenborough FP. Source: Thorax. 2001 August; 56(8): 649-55. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11462069&dopt=Abstract

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XV-2c/KM-19 haplotype analysis of cystic fibrosis mutations in Mexican patients. Author(s): Orozco L, Gonzalez L, Chavez M, Velazquez R, Lezana JL, Saldana Y, Villarreal T, Carnevale A. Source: American Journal of Medical Genetics. 2001 August 15; 102(3): 277-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11484207&dopt=Abstract

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CHAPTER 2. NUTRITION AND CYSTIC FIBROSIS Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and cystic fibrosis.

Finding Nutrition Studies on Cystic Fibrosis The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail: [email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “cystic fibrosis” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

7

Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

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The following is a typical result when searching for recently indexed consumer information on cystic fibrosis: •

Identification and treatment of cystic fibrosis-related diabetes. A survey of current medical practice in the U.S. Author(s): Department of Pediatrics, Tufts University School of Medicine, Boston, Massachusetts, USA. [email protected] Source: Allen, H F Gay, E C Klingensmith, G J Hamman, R F Diabetes-Care. 1998 June; 21(6): 943-8 0149-5992

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Insulin and glucose excursion following premeal insulin lispro or repaglinide in cystic fibrosis-related diabetes. Author(s): Division of Endocrinology, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota 55455, USA. [email protected] Source: Moran, A Phillips, J Milla, C Diabetes-Care. 2001 October; 24(10): 1706-10 01495992

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Nutrition in cystic fibrosis. Source: Schorah, C.J. Smithells, R.W. Nutr-Res-Rev. Cambridge [England] : Cambridge University Press. 1991. volume (4) page 51-67. 0954-4224

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Nutrition support in cystic fibrosis. Source: Gerson, W T Swan, P Walker, W A Nutr-Revolume 1987 December; 45(12): 35360 0029-6643

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Taurine supplementation in cystic fibrosis. Source: Anonymous Nutr-Revolume 1988 July; 46(7): 257-8 0029-6643

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Vitamin E therapy in cystic fibrosis. Source: Anonymous Nutr-Revolume 1988 August; 46(8): 289-90 0029-6643

The following information is typical of that found when using the “Full IBIDS Database” to search for “cystic fibrosis” (or a synonym): •

Abnormal bone turnover in cystic fibrosis adults. Author(s): Divisions of Pulmonary Medicine,The University of North Carolina at Chapel Hill, 27599-7524, USA. [email protected] Source: Aris, R M Ontjes, D A Buell, H E Blackwood, A D Lark, R K Caminiti, M Brown, S A Renner, J B Chalermskulrat, W Lester, G E Osteoporos-Int. 2002; 13(2): 151-7 0937941X

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Altered calcium homeostasis in adults with cystic fibrosis. Author(s): Division of Pulmonary Medicine, University of North Carolina, Chapel Hill 27599-7524, USA. [email protected] Source: Aris, R M Lester, G E Dingman, S Ontjes, D A Osteoporos-Int. 1999; 10(2): 102-8 0937-941X

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Anti-inflammatory approaches to the treatment of cystic fibrosis lung disease: past, present and future. Author(s): Pediatric Pulmonology Service, Baylor College of Medicine, TCH Feigin Center, Houston, TX, 77030 USA. [email protected] Source: Oermann, C M Curr-Opin-Investig-Drugs. 2001 July; 2(7): 900-6 1472-4472

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Antioxidant status in erythrocytes of cystic fibrosis children. Author(s): Department of Biochemistry, National Research Institute of Mother and Child, Warszawa, Poland. [email protected]

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Source: Laskowska Klita, T Chelchowska, M Acta-Biochim-Pol. 2001; 48(1): 283-5 0001527X •

Bisphosphonates for osteoporosis in people with cystic fibrosis (Cochrane Review). Author(s): Community Health and Epidemiology, Dalhousie University, 5849 University Avenue, Halifax, Nova Scotia, CANADA, B3H 4H7. [email protected] Source: Brenckmann, C Papaioannou, A Cochrane-Database-Syst-Revolume 2001; 4: CD002010 1469-493X

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Combined lung and liver transplantation in a girl with cystic fibrosis. Author(s): Department of Anesthesiology, Washington University School of Medicine and St. Louis Children's Hospital, Missouri, USA. [email protected] Source: Zimmerman, A A Howard, T K Huddleston, C B Can-J-Anaesth. 1999 June; 46(6): 571-5 0832-610X

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Control of malabsorption in cystic fibrosis. Author(s): Regional Paediatric Cystic Fibrosis Unit, St James Hospital, Leeds, England. [email protected] Source: Littlewood, J M Wolfe, S P Paediatr-Drugs. 2000 May-June; 2(3): 205-22 11745878

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Cystic fibrosis with fibrosing colonopathy in the absence of pancreatic enzymes. Author(s): Department of Pathology and Laboratory Medicine, Fletcher Allen Health Care, Burlington, VT 05401, USA. Source: Waters, B L Pediatr-Dev-Pathol. 1998 Jan-February; 1(1): 74-8 1093-5266

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Detection of Pseudomonas aeruginosa cell-to-cell signals in lung tissue of cystic fibrosis patients. Author(s): Department of Genetics and Microbiology, Medical School, CH-1211 Geneva 4, Switzerland. Source: Favre Bonte, Sabine Pache, Jean Claude Robert, John Blanc, Dominique Pechere, Jean Claude van Delden, Christian Microb-Pathog. 2002 March; 32(3): 143-7 0882-4010

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Different activation mechanisms of cystic fibrosis transmembrane conductance regulator expressed in Xenopus laevis oocytes. Author(s): Laboratory of Physiology, K U Leuven, Belgium. [email protected] Source: Webe W, M Segal, A Vankeerberghen, A Cassiman J, J Van Driessche, W CompBiochem-Physiol-A-Mol-Integr-Physiol. 2001 October; 130(3): 521-31 1095-6433

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Effect of phenol red and steroid hormones on cystic fibrosis transmembrane conductance regulator in mouse endometrial epithelial cells. Author(s): Epithelial Cell Biology Research Center, Department of Physiology, The Chinese University of Hong Kong. Source: Tsang, L L Chan, L N Liu, C Q Chan, H C Cell-Biol-Int. 2001; 25(10): 1021-4 10656995

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Endoscopic sinus surgery in cystic fibrosis: do patients benefit from surgery? Author(s): Southern California Permanente Medical Group, Department of Head and Neck Surgery, 6th Floor, 4900 Sunset Boulevard, Los Angeles, CA 90027, USA. Source: Rosbe, K W Jones, D T Rahbar, R Lahiri, T Auerbach, A D Int-J-PediatrOtorhinolaryngol. 2001 November 1; 61(2): 113-9 0165-5876

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Enteral tube feeding for cystic fibrosis. Author(s): Cystic Fibrosis Department, Seacroft Hospital, York Road, Leeds, Yorkshire, UK, LS14 6UH.

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Source: Conway, S P Morton, A Wolfe, S Cochrane-Database-Syst-Revolume 2000; (2): CD001198 1469-493X •

Fatty acids in cystic fibrosis. Author(s): Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. [email protected] Source: Freedman, S D Shea, J C Blanco, P G Alvarez, J G Curr-Opin-Pulm-Med. 2000 November; 6(6): 530-2 1070-5287

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Frequency, consequences and pharmacological treatment of gastroesophageal reflux in children with cystic fibrosis. Author(s): Department of Pediatrics, Gastroenterology and Paediatric Oncology, Medical University of Gdansk, Poland. Source: Brodzicki, J Trawinska Bartnicka, M Korzon, M Med-Sci-Monit. 2002 July; 8(7): CR529-37 1234-1010

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Future pharmacological treatment of cystic fibrosis. Author(s): Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. [email protected] Source: Zeitlin, P L Respiration. 2000; 67(4): 351-7 0025-7931

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Gadolinium as an opener of the outwardly rectifying Cl(-) channel (ORCC). Is there relevance for cystic fibrosis therapy? Author(s): Max-Planck-Institut fur Experimentelle Medizin, Abteilung Immunchemie, Hermann-Rein-Strasse 3, 37075 Gottingen, Germany. [email protected] Source: Thinnes, F P Walter, G Hellmann, K P Hellmann, T Merker, R Kiafard, Z Eben Brunnen, J Schwarzer, C Gotz, H Hilschmann, N Pflugers-Arch. 2001; 443 Suppl 1: S1116 0031-6768

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Gene complementation of airway epithelium in the cystic fibrosis mouse is necessary and sufficient to correct the pathogen clearance and inflammatory abnormalities. Author(s): Institute for Molecular Biosciences, Imperial College of Medicine at the National Heart and Lung Institute, Manresa Road, London SW3 6LR, UK. Source: Oceandy, D McMorran, B J Smith, S N Schreiber, R Kunzelmann, K Alton, E W Hume, D A Wainwright, B J Hum-Mol-Genet. 2002 May 1; 11(9): 1059-67 0964-6906

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Gene therapy for cystic fibrosis with aerosolized adenovirus-CFTR: characterization of the aerosol and scintigraphic determination of lung deposition in baboons. Author(s): INSERM EMI-U 0010, Faculte de Medecine, Tours, France. [email protected] Source: Lerondel, S Vecellio None, L Faure, L Sizaret, P Y Sene, C Pavirani, A Diot, P Le Pape, A J-Aerosol-Med. 2001 Spring; 14(1): 95-105 0894-2684

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Glucose intolerance in cystic fibrosis patients. Author(s): Department of Paediatrics, Rigshospitalet, CF Centre Copenhagen, Copenhagen, Denmark. [email protected] Source: Lanng, S Paediatr-Respir-Revolume 2001 September; 2(3): 253-9 1526-0542

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Growth and nutrition in South African children with cystic fibrosis. Author(s): Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital. Source: Westwood, A T Saitowitz, R S-Afr-Med-J. 1999 December; 89(12): 1276-8 00382469

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Growth hormone improves weight velocity and height velocity in prepubertal children with cystic fibrosis. Author(s): University of Texas Health Science Center, Houston 77030, USA. [email protected] Source: Hardin, D S Stratton, R Kramer, J C Reyes de la Rocha, S Govaerts, K Wilson, D P Horm-Metab-Res. 1998 October; 30(10): 636-41 0018-5043

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Growth problems and growth hormone treatment in children with cystic fibrosis. Author(s): Department of Pediatrics, University of Texas Southwestern Medical School, Dallas 75390-9063, USA. [email protected] Source: Hardin, D S J-Pediatr-Endocrinol-Metab. 2002 May; 15 Suppl 2: 731-5

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Guidelines for the diagnosis and therapy of diabetes mellitus in cystic fibrosis. Author(s): Department of Pediatrics, University of Minnesota, Minneapolis 55455, USA. Source: Riggs, A C Seaquist, E R Moran, A Curr-Opin-Pulm-Med. 1999 November; 5(6): 378-82 1078-1641

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Intracellular cysteines of the cystic fibrosis transmembrane conductance regulator (CFTR) modulate channel gating. Author(s): Department of Physiology, Johns Hopkins University School of Medicine, Baltimore MD 21205, USA. Source: Ketchum, Christian J Yue, Hongwen Alessi, Karen A Devidas, Shreenivas Guggino, William B Maloney, Peter C Cell-Physiol-Biochem. 2002; 12(1): 1-8 1015-8987

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Intracellular rate-limiting steps of gene transfer using glycosylated polylysines in cystic fibrosis airway epithelial cells. Author(s): Laboratoire de Physiologie Respiratoire, CHU Cochin, AP-HP-Universite Paris V, France. Source: Grosse, S Tremeau Bravard, A Aron, Y Briand, P Fajac, I Gene-Ther. 2002 August; 9(15): 1000-7 0969-7128

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Lundh meal: a single non-invasive challenge test for evaluation of exocrine and endocrine pancreatic function in cystic fibrosis patients. Author(s): National Cystic Fibrosis Center, The Chaim Sheba Medical Center, TelHashomer, Israel. Source: Augarten, A Dubenbaum, L Yahav, Y Katznelson, D Szeinberg, A Blank, A Sack, J Int-J-Clin-Lab-Res. 1999; 29(3): 114-6 0940-5437

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Multifocal myocardial necrosis: a distinctive cardiac lesion in cystic fibrosis, lipomatous pancreatic atrophy, and Keshan disease. Author(s): Department of Pathology, Hjpital Edouard Herriot, Lyon, France. Source: Nezelof, C Bouvier, R Dijoud, F Pediatr-Pathol-Mol-Med. 2002 May-June; 21(3): 343-52 1522-7952

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New developments in cystic fibrosis. Author(s): Department of Pediatrics, Medical College of Georgia, Augusta 30912, USA. Source: Hudson, V L Guill, M F Pediatr-Ann. 1998 August; 27(8): 515-20 0090-4481

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Nutritional imperatives in cystic fibrosis therapy. Author(s): Department of Pediatrics, Steele Memorial Research Center, University of Arizona Health Sciences Center, Tucson 85724-5073, USA. Source: Erdman, S H Pediatr-Ann. 1999 February; 28(2): 129-36 0090-4481

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Nutritional management in cystic fibrosis--an alternative perspective gastrointestinal function. Author(s): Institute of Human Nutrition, University of Southampton, UK.

in

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Source: Murphy, J L Wootton, S A Disabil-Rehabil. 1998 Jun-July; 20(6-7): 226-34 09638288 •

Omega-3 fatty acids (from fish oils) for cystic fibrosis. Author(s): Department of Nutrition and Dietetics, Sheffield Children's Hospital NHS Trust, Western Bank, Sheffield, UK, S10 2TH. [email protected] Source: Beckles, W I Elliott, T M Everard, M L Cochrane-Database-Syst-Revolume 2002; (3): CD002201 1469-493X

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Oral calorie supplements for cystic fibrosis. Author(s): Institute of Child health, University of Liverpool, Alder Hey Children's Hospital, Eaton Road, Liverpool, Merseyside, UK, L12 2AP. [email protected] Source: Smyth, R Walters, S Cochrane-Database-Syst-Revolume 2000; (2): CD000406 1469-493X

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Osteoporosis in patients with cystic fibrosis. Author(s): Division of Metabolism, University of Washington, Seattle, USA. Source: Ott, S M Aitken, M L Clin-Chest-Med. 1998 September; 19(3): 555-67 0272-5231

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Parent relationships and compliance in cystic fibrosis. Author(s): Kosair Children's Hospital, Louisville, KY 40202, USA. Source: Eddy, M E Carter, B D Kronenberger, W G Conradsen, S Eid, N S Bourland, S L Adams, G J-Pediatr-Health-Care. 1998 Jul-August; 12(4): 196-202 0891-5245

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Phagocyte oxidants and nitric oxide in cystic fibrosis: new therapeutic targets? Author(s): Division of Pulmonary Critical Care Medicine, Center for Comparative Lung Cell Biology and Medicine, University of California, Davis School of Medicine, USA. [email protected] Source: van der Vliet, A Cross, C E Curr-Opin-Pulm-Med. 2000 November; 6(6): 533-9 1070-5287

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Pharmacokinetic assessment of oral ganciclovir in lung transplant recipients with cystic fibrosis. Author(s): Lung and Heart Transplant Service, Departments of Clinical Pharmacology, Pharmacy and Clinical Biochemistry, Alfred Hospital, Prahran 3181, Australia. Source: Snell, G I Kotsimbos, T C Levvey, B J Skiba, M Rutherford, D M Kong, D C Williams, T J Krum, H J-Antimicrob-Chemother. 2000 April; 45(4): 511-6 0305-7453

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Prolonged airway retention of insoluble particles in cystic fibrosis versus primary ciliary dyskinesia. Author(s): Department of Medicine, University of North Carolina at Chapel Hill, USA. Source: Regnis, J A Zeman, K L Noone, P G Knowles, M R Bennett, W D Exp-Lung-Res. 2000 Apr-May; 26(3): 149-62 0190-2148

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Regulation and properties of KCNQ1 (K(V)LQT1) and impact of the cystic fibrosis transmembrane conductance regulator. Author(s): Department of Physiology & Pharmacology, University of Queensland, St. Lucia, QLD 4072, Australia. Source: Boucherot, A Schreiber, R Kunzelmann, K J-Membr-Biol. 2001 July 1; 182(1): 3947 0022-2631

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Repeatability and methodology of resting energy expenditure in patients with cystic fibrosis. Author(s): Section of Respiratory Medicine, University of Wales College of Medicine, Llandough Hospital and Community NHS Trust, Penarth, South Glamorgan, UK. [email protected]

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Source: Bell, S C Elborn, J S Nixon, L E Macdonald, I A Shale, D J Respir-Physiol. 1999 May 3; 115(3): 301-7 0034-5687 •

Retrospective clinical comparison of Celsior solution to modified blood Wallwork solution in lung transplantation for cystic fibrosis. Author(s): Thoracic Transplantation Unit, Cardiovascular Surgery Department, Laennec Hospital, Nantes, France. Source: Baron, O Fabre, S Haloun, A Treilhaud, M al Habasch, O Duveau, D Michaud, J L Despins, P Prog-Transplant. 2002 September; 12(3): 176-80 1526-9248

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Role of enteral nutrition in the pathophysiology and treatment of pancreatitis and cystic fibrosis. Author(s): Pancreas Center, Beth Israel Deaconess Medical Center, Boston, Mass., USA. Source: Freedman, S D Nestle-Nutr-Workshop-Ser-Clin-Perform-Programme. 2000; 3: 239-43; discussion 243-6 1422-7584

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'Semper aliquod novi cystic fibrosis adferre'. Cystic fibrosis always brings us something new--with apologies to Pliny the Elder. Source: Bush, A Respiration. 2000; 67(3): 251-2 0025-7931

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Serum lipase levels pre and post Lundh meal: evaluation of exocrine pancreatic status in cystic fibrosis. Author(s): Cystic Fibrosis Center, Chaim Sheba Medical Center, Tel-Hashomer, Israel. Source: Augarten, A Katznelson, D Dubenbaum, L Doolman, R Sela, B A Lusky, A Szeinberg, A Kerem, B S Paret, G Gazit, E Sack, J Yahav, Y Int-J-Clin-Lab-Res. 1998; 28(4): 226-9 0940-5437

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Studies of the molecular basis for cystic fibrosis using purified reconstituted CFTR protein. Author(s): Programme in Cell Biology, Research Institute, Hospital for Sick Children, Department of Physiology, Faculty of Medicine, Toronto, Ontario, Canada. Source: Kogan, Ilana Ramjeesingh, Mohabir Li, Canhui Bear, Christine E Methods-MolMed. 2002; 70: 143-57

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Successful endoscopic therapy of cholangitis associated with intrahepatic cholangiectasis in adult cystic fibrosis. Author(s): Departments of Gastroenterology, Pulmonology, Pediatrics, and Radiology, Wilford Hall Medical Center, Lackland AFB, Texas, USA. Source: Baldwin, T L Schutz, S M Owens, G Olivier, K Little, C Abbott, R GastrointestEndosc. 1999 February; 49(2): 249-51 0016-5107

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Taurocholic acid-induced secretion in normal and cystic fibrosis mouse ileum. Author(s): Department of Biomedical Science, University of Sheffield, UK. [email protected] Source: Hardcastle, J Hardcastle, P T Chapman, J Taylor, C J J-Pharm-Pharmacol. 2001 May; 53(5): 711-9 0022-3573

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The cystic fibrosis transmembrane conductance regulator (CFTR) inhibits ENaC through an increase in the intracellular Cl- concentration. Author(s): School of Biomedical Sciences, Department of Physiology and Pharmacology, University of Queensland, St Lucia, Queensland 4072, Brisbane, Australia. Source: Konig, J Schreiber, R Voelcker, T Mall, M Kunzelmann, K EMBO-Repage 2001 November; 2(11): 1047-51 1469-221X

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The effect of alginate on the invasion of cystic fibrosis respiratory epithelial cells by clinical isolates of Pseudomonas aeruginosa. Author(s): Department of Microbiology, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, USA. [email protected] Source: Massengale, A R Quinn, F J Williams, A Gallagher, S Aronoff, S C Exp-LungRes. 2000 Apr-May; 26(3): 163-78 0190-2148

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The use of dual-isotope imaging to compare the gastrointestinal transit of food and pancreatic enzyme pellets in cystic fibrosis patients. Author(s): Department of Medical Physics and Clinical Engineering, Royal Hallamshire Hospital, Sheffield, UK. Source: Hillel, P G Tindale, W B Taylor, C J Frier, M Senior, S Ghosal, S Nucl-MedCommun. 1998 August; 19(8): 761-9 0143-3636

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Therapies aimed at airway inflammation in cystic fibrosis. Author(s): Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. Source: Konstan, M W Clin-Chest-Med. 1998 September; 19(3): 505-13, vi 0272-5231

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Treatment of severe small airways disease in children with cystic fibrosis: alternatives to corticosteroids. Author(s): Department of Respiratory Medicine, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom. [email protected] Source: Jaffe, A Balfour Lynn, I M Paediatr-Drugs. 2002; 4(6): 381-9 1174-5878

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Upregulation of cystic fibrosis transmembrane conductance regulator expression by oestrogen and Bak Foong Pill in mouse uteri. Author(s): Epithelial Cell Biology Research Center, Department of Physiology, Chinese University of Hong Kong, Shatin, Hong Kong. Source: Rowlands, D K Tsang, L L Cui, Y G Chung, Y W Chan, L N Liu, C Q James, T Chan, H C Cell-Biol-Int. 2001; 25(10): 1033-5 1065-6995

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Ways of coping with cystic fibrosis: implications for treatment adherence. Author(s): Postgraduate School of Medicine and Health, University of Central Lancashire, Preston, UK. [email protected] Source: Abbott, J Dodd, M Gee, L Webb, K Disabil-Rehabil. 2001 May 20; 23(8): 315-24 0963-8288

Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

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Google: http://directory.google.com/Top/Health/Nutrition/

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Healthnotes: http://www.healthnotes.com/

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Open Directory Project: http://dmoz.org/Health/Nutrition/

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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/

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WebMD®Health: http://my.webmd.com/nutrition

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,,00.html

The following is a specific Web list relating to cystic fibrosis; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation (some Web sites are subscription based): •

Vitamins Vitamin B12 Source: Healthnotes, Inc. www.healthnotes.com Vitamin D Source: Healthnotes, Inc. www.healthnotes.com Vitamin E Source: Healthnotes, Inc. www.healthnotes.com Vitamin K Source: Healthnotes, Inc. www.healthnotes.com

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Minerals Zinc Source: Healthnotes, Inc. www.healthnotes.com

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Food and Diet Low-Salt Diet Source: Healthnotes, Inc. www.healthnotes.com Polyunsaturated Fats Source: Healthnotes, Inc. www.healthnotes.com

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CHAPTER 3. ALTERNATIVE MEDICINE AND CYSTIC FIBROSIS Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to cystic fibrosis. At the conclusion of this chapter, we will provide additional sources.

The Combined Health Information Database The Combined Health Information Database (CHID) is a bibliographic database produced by health-related agencies of the U.S. federal government (mostly from the National Institutes of Health) that can offer concise information for a targeted search. The CHID database is updated four times a year at the end of January, April, July, and October. Check the titles, summaries, and availability of CAM-related information by using the “Simple Search” option at the following Web site: http://chid.nih.gov/simple/simple.html. In the drop box at the top, select “Complementary and Alternative Medicine.” Then type “cystic fibrosis” (or synonyms) in the second search box. We recommend that you select 100 “documents per page” and to check the “whole records” options. The following was extracted using this technique: •

Alternative Medicine Update Source: Alternative Health Practitioner. 3(3): 157-160. Fall/Winter 1997. Summary: This journal article reports the results of 12 studies funded by the Office of Alternative Medicine in 1993 and 1994. The studies were classified as either mind/body interventions or as pharmacological or biological treatments. The 10 mind/body intervention studies include the following therapies: biofeedback, dance movement therapy, guided imagery, hypnotic imagery, music therapy, prayer, and yoga. Conditions studied include pain, diabetes mellitus, cystic fibrosis, asthma, immunity, cancer, AIDS, brain injury, and drug abuse. The two pharmacological and biological studies were 'Enzyme Therapy and Experimental Memory Metastasis' and 'Pharmacological Treatment of Cancer by Antioxidants.'.

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National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to cystic fibrosis and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “cystic fibrosis” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to cystic fibrosis: •

A common mechanism for cystic fibrosis transmembrane conductance regulator protein activation by genistein and benzimidazolone analogs. Author(s): Al-Nakkash L, Hu S, Li M, Hwang TC. Source: The Journal of Pharmacology and Experimental Therapeutics. 2001 February; 296(2): 464-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11160632&dopt=Abstract

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A comprehensive exercise program for persons with cystic fibrosis. Author(s): Rose J, Jay S. Source: Journal of Pediatric Nursing. 1986 October; 1(5): 323-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3639937&dopt=Abstract

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A controlled trial using intravenous infusion of soya oil emulsion in the treatment of children with cystic fibrosis. Author(s): Davidson GP, Phelan PD, Townley RR. Source: Aust Paediatr J. 1978 June; 14(2): 80-2. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=356838&dopt=Abstract

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A disciplined approach to spiritual care giving for adults living with cystic fibrosis. Author(s): Palmer C. Source: J Health Care Chaplain. 2001; 11(1): 95-102. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11398539&dopt=Abstract

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A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr(-/-) mice. Author(s): Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY, Alvarez JG. Source: Proceedings of the National Academy of Sciences of the United States of America. 1999 November 23; 96(24): 13995-4000. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10570187&dopt=Abstract

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A model for group intervention with the chronically ill: cystic fibrosis and the family. Author(s): Brown DG, Krieg K, Belluck F.

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Source: Soc Work Health Care. 1995; 21(1): 81-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8553194&dopt=Abstract •

A therapeutic trial of fatty acid supplementation in cystic fibrosis. Author(s): Elliott RB. Source: Pediatrics. 1976 April; 57(4): 474-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1264542&dopt=Abstract

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Absorption of safflower oil and structured lipid preparations in patients with cystic fibrosis. Author(s): Hubbard VS, McKenna MC. Source: Lipids. 1987 June; 22(6): 424-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3613873&dopt=Abstract

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Actions of genistein on cystic fibrosis transmembrane conductance regulator channel gating. Evidence for two binding sites with opposite effects. Author(s): Wang F, Zeltwanger S, Yang IC, Nairn AC, Hwang TC. Source: The Journal of General Physiology. 1998 March; 111(3): 477-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9482713&dopt=Abstract

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Activation of cystic fibrosis transmembrane conductance regulator in rat epididymal epithelium by genistein. Author(s): Leung GP, Wong PY. Source: Biology of Reproduction. 2000 January; 62(1): 143-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10611078&dopt=Abstract

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Activation of deltaF508 CFTR in a cystic fibrosis respiratory epithelial cell line by 4phenylbutyrate, genistein and CPX. Author(s): Andersson C, Roomans GM. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2000 May; 15(5): 937-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10853862&dopt=Abstract

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Acute lymphoblastic leukaemia in a child with cystic fibrosis. Author(s): Rizzari C, Conter V, Jankovic M, D'Angelo P, Masera G, Costantini D, Bettinelli ME, Giunta AM. Source: Haematologica. 1992 September-October; 77(5): 427-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1483594&dopt=Abstract

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Acute respiratory distress due to vocal cord dysfunction in cystic fibrosis. Author(s): Rusakow LS, Blager FB, Barkin RC, White CW.

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Source: The Journal of Asthma : Official Journal of the Association for the Care of Asthma. 1991; 28(6): 443-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1744030&dopt=Abstract •

Acute respiratory infection in patients with cystic fibrosis with mild pulmonary impairment: comparison of two physiotherapy regimens. Author(s): Williams MT, Parsons DW, Frick RA, Ellis ER, Martin AJ, Giles SE, Grant ER. Source: The Australian Journal of Physiotherapy. 2001; 47(4): 227-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11722291&dopt=Abstract

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Airway clearance techniques in the treatment of cystic fibrosis. Author(s): McIlwaine MP, Davidson AG. Source: Current Opinion in Pulmonary Medicine. 1996 November; 2(6): 447-51. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9363183&dopt=Abstract

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Allergy in cystic fibrosis nurses to pancreatic extract. Author(s): Lipkin GW, Vickers DW. Source: Lancet. 1987 February 14; 1(8529): 392. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2880202&dopt=Abstract

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Altered calcium homeostasis in adults with cystic fibrosis. Author(s): Aris RM, Lester GE, Dingman S, Ontjes DA. Source: Osteoporosis International : a Journal Established As Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the Usa. 1999; 10(2): 102-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10501788&dopt=Abstract

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Altered channel properties of porins from Haemophilus influenzae: isolates from cystic fibrosis patients. Author(s): Arbing MA, Hanrahan JW, Coulton JW. Source: The Journal of Membrane Biology. 2002 September 15; 189(2): 131-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12235488&dopt=Abstract

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Assessment of CFTR chloride channel openers in intact normal and cystic fibrosis murine epithelia. Author(s): Cuthbert AW. Source: British Journal of Pharmacology. 2001 February; 132(3): 659-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11159718&dopt=Abstract

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Autogenic drainage: a modern approach to physiotherapy in cystic fibrosis. Author(s): Schoni MH.

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Source: Journal of the Royal Society of Medicine. 1989; 82 Suppl 16: 32-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2657053&dopt=Abstract •

Bak Foong Pills stimulate anion secretion across normal and cystic fibrosis pancreatic duct epithelia. Author(s): Zhu JX, Lo PS, Zhao WC, Tang N, Zhou Q, Rowlands DK, Gou YL, Chung YW, Chan HC. Source: Cell Biology International. 2002; 26(12): 1011-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12468376&dopt=Abstract

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Behavioral interventions and stress management training for hospitalized adolescents and young adults with cystic fibrosis. Author(s): Spirito A, Russo DC, Masek BJ. Source: General Hospital Psychiatry. 1984 July; 6(3): 211-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6378718&dopt=Abstract

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Benefits of music therapy as an adjunct to chest physiotherapy in infants and toddlers with cystic fibrosis. Author(s): Grasso MC, Button BM, Allison DJ, Sawyer SM. Source: Pediatric Pulmonology. 2000 May; 29(5): 371-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10790249&dopt=Abstract

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Beta-carotene supplementation in cystic fibrosis. Author(s): Winklhofer-Roob BM. Source: The Journal of Pediatrics. 1996 July; 129(1): 181-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8757591&dopt=Abstract

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Bronchial asthma due to allergy to pancreatic extract: a hazard in the treatment of cystic fibrosis. Author(s): Sakula A. Source: Br J Dis Chest. 1977 October; 71(4): 295-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=588432&dopt=Abstract

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Changes in body composition and muscle protein degradation during nutritional supplementation in nutritionally growth-retarded children with cystic fibrosis. Author(s): Shepherd RW, Thomas BJ, Bennett D, Cooksley WG, Ward LC. Source: Journal of Pediatric Gastroenterology and Nutrition. 1983; 2(3): 439-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6620051&dopt=Abstract

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Chest physiotherapy in cystic fibrosis: a comparative study of autogenic drainage and the active cycle of breathing techniques with postural drainage. Author(s): Miller S, Hall DO, Clayton CB, Nelson R.

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Source: Thorax. 1995 February; 50(2): 165-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7701456&dopt=Abstract •

Chest physiotherapy in cystic fibrosis: improved tolerance with nasal pressure support ventilation. Author(s): Fauroux B, Boule M, Lofaso F, Zerah F, Clement A, Harf A, Isabey D. Source: Pediatrics. 1999 March; 103(3): E32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10049988&dopt=Abstract

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Chest physiotherapy--the mechanical approach to antiinfective therapy in cystic fibrosis. Author(s): Zach MS, Oberwaldner B. Source: Infection. 1987; 15(5): 381-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3319913&dopt=Abstract

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Children with cystic fibrosis benefit from massage therapy. Author(s): Hernandez-Reif M, Field T, Krasnegor J, Martinez E, Schwartzman M, Mavunda K. Source: Journal of Pediatric Psychology. 1999 April; 24(2): 175-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10361400&dopt=Abstract

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Cholesterol esterase activities in commercial pancreatic enzyme preparations and implications for use in pancreatic insufficient cystic fibrosis. Author(s): Walters MP, Conway SP. Source: Journal of Clinical Pharmacy and Therapeutics. 2001 December; 26(6): 425-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11722679&dopt=Abstract

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Cimetidine as an adjunct to oral enzymes in the treatment of malabsorption due to cystic fibrosis. Author(s): de Bieville F, Neijens HJ, Fernandes J, van Caillie M, Kerrebijn KF. Source: Acta Paediatr Scand. 1981 January; 70(1): 33-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6908433&dopt=Abstract

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Colloid and crystal formation in parotid saliva of cystic fibrosis patients and noncystic fibrosis subjects. I. Physicochemistry. Author(s): Allars HM, Blomfield J, Rush AR, Brown JM. Source: Pediatric Research. 1976 June; 10(6): 578-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=818608&dopt=Abstract

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Colloid and crystal formation in parotid saliva of cystic fibrosis patients and noncystic fibrosis subjects. II. Electron microscopy and electrophoresis. Author(s): Allars HM, Cockayne DJ, Blomfield J, Rush AR, Van Lennep EW, Brown JM.

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Source: Pediatric Research. 1976 June; 10(6): 584-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=818609&dopt=Abstract •

Comparison of a high lipase pancreatic enzyme extract with a regular pancreatin preparation in adult cystic fibrosis patients. Author(s): Gan KH, Heijerman HG, Geus WP, Bakker W, Lamers CB. Source: Alimentary Pharmacology & Therapeutics. 1994 December; 8(6): 603-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7696449&dopt=Abstract

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Correction of linoleic acid deficiency in cystic fibrosis. Author(s): Mischler EH, Parrell SW, Farrell PM, Raynor WJ, Lemen RJ. Source: Pediatric Research. 1986 January; 20(1): 36-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3456148&dopt=Abstract

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Current knowledge on fatty acids in cystic fibrosis. Author(s): Biochemistry. 1997 Nov 11;36(45):13972 Source: Prostaglandins, Leukotrienes, and Essential Fatty Acids. 1996 September; 55(3): 129-38. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9546810

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Cystic fibrosis and the role of the physical therapist in its management. Author(s): Tecklin JS, Holsclaw DS. Source: Physical Therapy. 1973 April; 53(4): 386-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4693291&dopt=Abstract

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Cystic fibrosis in Russia: background and a model for future collaboration with the West. Author(s): Kapranov N, Ginter E, Kashirskaja N, Hill CM, Ilangovan P, Rolles CJ. Source: Journal of the Royal Society of Medicine. 1996; 89 Suppl 27: 44-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8778450&dopt=Abstract

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Cystic fibrosis transmembrane conductance regulator activation by cAMPindependent mechanisms. Author(s): He Z, Raman S, Guo Y, Reenstra WW. Source: The American Journal of Physiology. 1998 October; 275(4 Pt 1): C958-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9755049&dopt=Abstract

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Cystic fibrosis. Author(s): Morony T. Source: Prog Phys Ther. 1970; 1(3): 220-31. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5523596&dopt=Abstract

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Cystic fibrosis: what is involved in the home treatment program for these children, adolescents and young adults? Author(s): Selekman J. Source: Pediatric Nursing. 1977 March-April; 3(2): 32-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=584356&dopt=Abstract

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Defective essential-fatty-acid metabolism in cystic fibrosis. Author(s): Rivers JP, Hassam AG. Source: Lancet. 1975 October 4; 2(7936): 642-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=52009&dopt=Abstract

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Defective function of the cystic fibrosis-causing missense mutation G551D is recovered by genistein. Author(s): Illek B, Zhang L, Lewis NC, Moss RB, Dong JY, Fischer H. Source: The American Journal of Physiology. 1999 October; 277(4 Pt 1): C833-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10516113&dopt=Abstract

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Deficiency of vitamins E and A in cystic fibrosis is independent of pancreatic function and current enzyme and vitamin supplementation. Author(s): Lancellotti L, D'Orazio C, Mastella G, Mazzi G, Lippi U. Source: European Journal of Pediatrics. 1996 April; 155(4): 281-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8777920&dopt=Abstract

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Detection of cystic fibrosis delta F508 mutation by anti-double-stranded DNA antibody. Author(s): Hopfer SM, Makowski GS, Davis EL, Aslanzadeh J. Source: Ann Clin Lab Sci. 1995 November-December; 25(6): 475-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8572556&dopt=Abstract

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Development and evaluation of a multi-family psychoeducational program for cystic fibrosis. Author(s): Goldbeck L, Babka C. Source: Patient Education and Counseling. 2001 August; 44(2): 187-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11479059&dopt=Abstract

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Development of the role-play inventory of situations and coping strategies for parents of children with cystic fibrosis. Author(s): Quittner AL, Tolbert VE, Regoli MJ, Orenstein DM, Hollingsworth JL, Eigen H. Source: Journal of Pediatric Psychology. 1996 April; 21(2): 209-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8920154&dopt=Abstract

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Diet for cystic fibrosis. Nutritional requirements and prescriptions. Author(s): Warwick WJ. Source: Postgraduate Medicine. 1987 December; 82(8): 121-6, 129-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3684818&dopt=Abstract

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Dietary essential fatty acids in cystic fibrosis. Author(s): Rosenlund ML, Selekman JA, Kim HK, Kritchevsky D. Source: Pediatrics. 1977 March; 59(3): 428-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=840562&dopt=Abstract

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Dietary fat in cystic fibrosis. Author(s): Dodge JA. Source: The Journal of Pediatrics. 1994 November; 125(5 Pt 1): 844-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7965447&dopt=Abstract

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Dietary supplement and nutrition in children with cystic fibrosis. Author(s): Berry HK, Kellogg FW, Hunt MM, Ingberg RL, Richter L, Gutjahr C. Source: Am J Dis Child. 1975 February; 129(2): 165-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1091138&dopt=Abstract

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Dietary supplements in cystic fibrosis. Author(s): Warwick WJ. Source: The Journal of Pediatrics. 1984 December; 105(6): 1007-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6438289&dopt=Abstract

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Differential stimulation of cytosolic phospholipase A2 by bradykinin in human cystic fibrosis cell lines. Author(s): Berguerand M, Klapisz E, Thomas G, Humbert L, Jouniaux AM, Olivier JL, Bereziat G, Masliah J. Source: American Journal of Respiratory Cell and Molecular Biology. 1997 October; 17(4): 481-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9376123&dopt=Abstract

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Directed modification instead of normalization of fatty acid patterns in cystic fibrosis: an emerging concept. Author(s): Christophe A, Robberecht E. Source: Current Opinion in Clinical Nutrition and Metabolic Care. 2001 March; 4(2): 1113. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11224654&dopt=Abstract

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Duodenal pH in cystic fibrosis and its relationship to fat malabsorption. Author(s): Robinson PJ, Smith AL, Sly PD.

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Source: Digestive Diseases and Sciences. 1990 October; 35(10): 1299-304. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2120019&dopt=Abstract •

Edetate sodium aerosol in Pseudomonas lung infection in cystic fibrosis. Author(s): Brown J, Mellis CM, Wood RE. Source: Am J Dis Child. 1985 August; 139(8): 836-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3927708&dopt=Abstract

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Effect of a medium dose of ursodeoxycholic acid with or without taurine supplementation on the nutritional status of patients with cystic fibrosis: a randomized, placebo-controlled, crossover trial. Author(s): Merli M, Bertasi S, Servi R, Diamanti S, Martino F, De Santis A, Goffredo F, Quattrucci S, Antonelli M, Angelico M. Source: Journal of Pediatric Gastroenterology and Nutrition. 1994 August; 19(2): 198-203. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7815243&dopt=Abstract

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Effect of abnormal liver function on vitamin E status and supplementation in adults with cystic fibrosis. Author(s): Stead RJ, Muller DP, Matthews S, Hodson ME, Batten JC. Source: Gut. 1986 June; 27(6): 714-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3721295&dopt=Abstract

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Effect of an 8-month treatment with omega-3 fatty acids (eicosapentaenoic and docosahexaenoic) in patients with cystic fibrosis. Author(s): De Vizia B, Raia V, Spano C, Pavlidis C, Coruzzo A, Alessio M. Source: Jpen. Journal of Parenteral and Enteral Nutrition. 2003 January-February; 27(1): 52-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12549599&dopt=Abstract

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Effect of an organized lipid matrix on lipid absorption and clinical outcomes in patients with cystic fibrosis. Author(s): Lepage G, Yesair DW, Ronco N, Champagne J, Bureau N, Chemtob S, Berube D, Roy CC. Source: The Journal of Pediatrics. 2002 August; 141(2): 178-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12183711&dopt=Abstract

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Effect of double-blind crossover selenium supplementation on biological indices of selenium status in cystic fibrosis patients. Author(s): Portal B, Richard MJ, Ducros V, Aguilaniu B, Brunel F, Faure H, Gout JP, Bost M, Favier A. Source: Clinical Chemistry. 1993 June; 39(6): 1023-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8504531&dopt=Abstract

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Effect of double-blind cross-over selenium supplementation on lipid peroxidation markers in cystic fibrosis patients. Author(s): Portal B, Richard MJ, Coudray C, Arnaud J, Favier A. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 1995 January 31; 234(1-2): 137-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7758213&dopt=Abstract

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Effect of misoprostol on fat malabsorption in cystic fibrosis. Author(s): Robinson PJ, Sly PD, Smith AL. Source: Archives of Disease in Childhood. 1988 September; 63(9): 1081-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3140739&dopt=Abstract

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Effect of pancreatic extracts on the faecal excretion and on the serum concentration of cobalamin and cobalamin analogues in cystic fibrosis. Author(s): Gueant JL, Vidailhet M, Pasquet C, Djalali M, Nicolas JP. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 1984 February 14; 137(1): 33-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6697525&dopt=Abstract

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Effect of supplementing medium chain triglycerides with linoleic acid-rich monoglycerides on severely disturbed serum lipid fatty acid patterns in patients with cystic fibrosis. Author(s): Christophe A, Verdonk G, Robberecht E, Mahathanakhun R. Source: Annals of Nutrition & Metabolism. 1985; 29(4): 239-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4026204&dopt=Abstract

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Effect of taurine supplementation on fat and bile acid absorption in patients with cystic fibrosis. Author(s): Colombo C, Arlati S, Curcio L, Maiavacca R, Garatti M, Ronchi M, Corbetta C, Giunta A. Source: Scand J Gastroenterol Suppl. 1988; 143: 151-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3164502&dopt=Abstract

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Effect of taurine supplementation on fat and energy absorption in cystic fibrosis. Author(s): De Curtis M, Santamaria F, Ercolini P, Vittoria L, De Ritis G, Garofalo V, Ciccimarra F. Source: Archives of Disease in Childhood. 1992 September; 67(9): 1082-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1417050&dopt=Abstract

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Effect of taurine supplements on fat absorption in cystic fibrosis. Author(s): Darling PB, Lepage G, Leroy C, Masson P, Roy CC.

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Source: Pediatric Research. 1985 June; 19(6): 578-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4011338&dopt=Abstract •

Effect of taurine supplements on growth, fat absorption and bile acid on cystic fibrosis. Author(s): Carrasco S, Codoceo R, Prieto G, Lama R, Polanco I. Source: Acta Univ Carol [med] (Praha). 1990; 36(1-4): 152-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2130680&dopt=Abstract

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Effect of the addition of protease inhibitors to sputa from cystic fibrosis patients. Author(s): Costello CM, McQuaid K, O'Connor CM, Fitzgerald MX. Source: Biochemical Society Transactions. 1994 February; 22(1): 53S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8206281&dopt=Abstract

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Effect of vitamin K1 supplementation on vitamin K status in cystic fibrosis patients. Author(s): Beker LT, Ahrens RA, Fink RJ, O'Brien ME, Davidson KW, Sokoll LJ, Sadowski JA. Source: Journal of Pediatric Gastroenterology and Nutrition. 1997 May; 24(5): 512-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9161943&dopt=Abstract

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Effect on renal function of essential fatty acid supplementation in cystic fibrosis. Author(s): Strandvik B, Berg U, Kallner A, Kusoffsky E. Source: The Journal of Pediatrics. 1989 August; 115(2): 242-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2754552&dopt=Abstract

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Effects of beta-carotene supplementation for six months on clinical and laboratory parameters in patients with cystic fibrosis. Author(s): Renner S, Rath R, Rust P, Lehr S, Frischer T, Elmadfa I, Eichler I. Source: Thorax. 2001 January; 56(1): 48-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11120904&dopt=Abstract

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Effects of calcium on intestinal mucin: implications for cystic fibrosis. Author(s): Forstner JF, Forstner GG. Source: Pediatric Research. 1976 June; 10(6): 609-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1272637&dopt=Abstract

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Effects of long-term oral beta-carotene supplementation on lipid peroxidation in patients with cystic fibrosis. Author(s): Rust P, Eichler I, Renner S, Elmadfa I. Source: Int J Vitam Nutr Res. 1998; 68(2): 83-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9565821&dopt=Abstract

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Eicosapentaenoic acid in cystic fibrosis: evidence of a pathogenetic role for leukotriene B4. Author(s): Lawrence R, Sorrell T. Source: Lancet. 1993 August 21; 342(8869): 465-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8102430&dopt=Abstract

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Eicosapentaenoic acid modulates neutrophil leukotriene B4 receptor expression in cystic fibrosis. Author(s): Lawrence RH, Sorrell TC. Source: Clinical and Experimental Immunology. 1994 October; 98(1): 12-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7923869&dopt=Abstract

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End of life issues in a palliative care framework for a critically ill adult African American with cystic fibrosis: a case study. Author(s): McNeal GJ. Source: J Cult Divers. 2002 Winter; 9(4): 118-28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12674889&dopt=Abstract

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Energy supplements rich in linoleic acid improve body weight and essential fatty acid status of cystic fibrosis patients. Author(s): Steinkamp G, Demmelmair H, Ruhl-Bagheri I, von der Hardt H, Koletzko B. Source: Journal of Pediatric Gastroenterology and Nutrition. 2000 October; 31(4): 418-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11045840&dopt=Abstract

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Enhanced resistance to oxidation of low density lipoproteins and decreased lipid peroxide formation during beta-carotene supplementation in cystic fibrosis. Author(s): Winklhofer-Roob BM, Puhl H, Khoschsorur G, van't Hof MA, Esterbauer H, Shmerling DH. Source: Free Radical Biology & Medicine. 1995 May; 18(5): 849-59. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7797092&dopt=Abstract

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Enteral tube feeding for cystic fibrosis. Author(s): Conway SP, Morton A, Wolfe S. Source: Cochrane Database Syst Rev. 2000; (2): Cd001198. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10796753&dopt=Abstract

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Epithelial cell specific properties and genetic complementation in a delta F508 cystic fibrosis nasal polyp cell line. Author(s): Kunzelmann K, Lei DC, Eng K, Escobar LC, Koslowsky T, Gruenert DC. Source: In Vitro Cellular & Developmental Biology. Animal. 1995 September; 31(8): 61724. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8528517&dopt=Abstract

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Erythrocyte sodium-potassium transport in cystic fibrosis. Author(s): Sigstrom L, Strandvik B. Source: Pediatric Research. 1992 May; 31(5): 425-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1318537&dopt=Abstract

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Essential fatty acid deficiency and nutritional supplementation in cystic fibrosis. Author(s): Lloyd-Still JD. Source: The Journal of Pediatrics. 2002 August; 141(2): 157-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12183705&dopt=Abstract

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Essential fatty acid deficiency in relation to genotype in patients with cystic fibrosis. Author(s): Strandvik B, Gronowitz E, Enlund F, Martinsson T, Wahlstrom J. Source: The Journal of Pediatrics. 2001 November; 139(5): 650-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11713441&dopt=Abstract

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Essential fatty acid status in cystic fibrosis and the effects of safflower oil supplementation. Author(s): Lloyd-Still JD, Johnson SB, Holman RT. Source: The American Journal of Clinical Nutrition. 1981 January; 34(1): 1-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7446449&dopt=Abstract

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Estrogen inhibition of cystic fibrosis transmembrane conductance regulator-mediated chloride secretion. Author(s): Singh AK, Schultz BD, Katzenellenbogen JA, Price EM, Bridges RJ, Bradbury NA. Source: The Journal of Pharmacology and Experimental Therapeutics. 2000 October; 295(1): 195-204. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10991979&dopt=Abstract

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Evaluation of the forced expiration technique as an adjunct to postural drainage in treatment of cystic fibrosis. Author(s): Pryor JA, Webber BA, Hodson ME, Batten JC. Source: British Medical Journal. 1979 August 18; 2(6187): 417-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=486968&dopt=Abstract

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Evidence that endoplasmic reticulum (ER)-associated degradation of cystic fibrosis transmembrane conductance regulator is linked to retrograde translocation from the ER membrane. Author(s): Xiong X, Chong E, Skach WR. Source: The Journal of Biological Chemistry. 1999 January 29; 274(5): 2616-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9915789&dopt=Abstract

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External ATP and its analogs activate the cystic fibrosis transmembrane conductance regulator by a cyclic AMP-independent mechanism. Author(s): Cantiello HF, Prat AG, Reisin IL, Ercole LB, Abraham EH, Amara JF, Gregory RJ, Ausiello DA. Source: The Journal of Biological Chemistry. 1994 April 15; 269(15): 11224-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7512560&dopt=Abstract

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Extracellular neuraminidase production by a strain of Pseudomonas aeruginosa isolated from cystic fibrosis. Author(s): Leprat R, Michel-Briand Y. Source: Ann Microbiol (Paris). 1980 November-December; 131B(3): 209-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6781392&dopt=Abstract

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Faecal elastase-1 and fat-soluble vitamin profiles in patients with cystic fibrosis in Western Norway. Author(s): Dorlochter L, Aksnes L, Fluge G. Source: European Journal of Nutrition. 2002 August; 41(4): 148-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12242582&dopt=Abstract

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Fat malabsorption in cystic fibrosis patients receiving enzyme replacement therapy is due to impaired intestinal uptake of long-chain fatty acids. Author(s): Kalivianakis M, Minich DM, Bijleveld CM, van Aalderen WM, Stellaard F, Laseur M, Vonk RJ, Verkade HJ. Source: The American Journal of Clinical Nutrition. 1999 January; 69(1): 127-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9925134&dopt=Abstract

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Fat malabsorption in cystic fibrosis patients. Author(s): Murphy J, Laiho K, Wootton S. Source: The American Journal of Clinical Nutrition. 1999 November; 70(5): 943-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10539762&dopt=Abstract

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Fatty acids composition of plasma phospholipids and triglycerides in children with cystic fibrosis. The effect of dietary supplementation with an olive and soybean oils mixture. Author(s): Caramia G, Cocchi M, Gagliardini R, Malavolta M, Mozzon M, Frega NG. Source: Pediatr Med Chir. 2003 January-February; 25(1): 42-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12920976&dopt=Abstract

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Fatty acids in cystic fibrosis. Author(s): Freedman SD, Shea JC, Blanco PG, Alvarez JG. Source: Current Opinion in Pulmonary Medicine. 2000 November; 6(6): 530-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11100964&dopt=Abstract

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Fatty acids, alpha-fetoprotein, and cystic fibrosis. Author(s): Mizejewski GJ, Pass KA. Source: Pediatrics. 2001 December; 108(6): 1370-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11731663&dopt=Abstract

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Fibrosing colonopathy revealing cystic fibrosis in a neonate before any pancreatic enzyme supplementation. Author(s): Serban DE, Florescu P, Miu N. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002 September; 35(3): 3569. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12352527&dopt=Abstract

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Flow-dependency of exhaled nitric oxide in children with asthma and cystic fibrosis. Author(s): Kroesbergen A, Jobsis Q, Bel EH, Hop WC, de Jongste JC. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1999 October; 14(4): 871-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10573235&dopt=Abstract

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Framework for a proactive parent support group: the Syracuse cystic fibrosis model. Author(s): Matloff ET, Zimmerman SJ. Source: Journal of Pediatric Health Care : Official Publication of National Association of Pediatric Nurse Associates & Practitioners. 1996 November-December; 10(6): 264-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9052117&dopt=Abstract

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Future pharmacological treatment of cystic fibrosis. Author(s): Zeitlin PL. Source: Respiration; International Review of Thoracic Diseases. 2000; 67(4): 351-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10940786&dopt=Abstract

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Genistein improves regulatory interactions between G551D-cystic fibrosis transmembrane conductance regulator and the epithelial sodium channel in Xenopus oocytes. Author(s): Suaud L, Carattino M, Kleyman TR, Rubenstein RC. Source: The Journal of Biological Chemistry. 2002 December 27; 277(52): 50341-7. Epub 2002 October 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12386156&dopt=Abstract

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Genistein inhibits constitutive and inducible NFkappaB activation and decreases IL-8 production by human cystic fibrosis bronchial gland cells. Author(s): Tabary O, Escotte S, Couetil JP, Hubert D, Dusser D, Puchelle E, Jacquot J.

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Glycemic response to dietary supplements in cystic fibrosis is dependent on the carbohydrate content of the formula. Author(s): Milla C, Doherty L, Raatz S, Schwarzenberg SJ, Regelmann W, Moran A. Source: Jpen. Journal of Parenteral and Enteral Nutrition. 1996 May-June; 20(3): 182-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8776690&dopt=Abstract

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Granulocyte elastase-mediated proteolysis of alpha 1-antitrypsin in cystic fibrosis bronchopulmonary secretions. Author(s): Cantin A, Bilodeau G, Begin R. Source: Pediatric Pulmonology. 1989; 7(1): 12-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2788857&dopt=Abstract

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Growing up with chronic illness: the experience of growing up with cystic fibrosis. Author(s): Tracy JP. Source: Holistic Nursing Practice. 1997 October; 12(1): 27-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9384068&dopt=Abstract

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Growing up with cystic fibrosis. Author(s): Helms PJ. Source: Br J Hosp Med. 1993 September 15-October 5; 50(6): 326-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8080484&dopt=Abstract

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HCO(3)(-)-dependent soluble adenylyl cyclase activates cystic fibrosis transmembrane conductance regulator in corneal endothelium. Author(s): Sun XC, Zhai CB, Cui M, Chen Y, Levin LR, Buck J, Bonanno JA. Source: American Journal of Physiology. Cell Physiology. 2003 May; 284(5): C1114-22. Epub 2003 January 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12519749&dopt=Abstract

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Holistic approach of a child with cystic fibrosis: a case report. Author(s): da Costa CC, Cardoso L, de Carvalho Rocha MJ. Source: J Dent Child (Chic). 2003 January-April; 70(1): 86-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12762618&dopt=Abstract

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Hopkins Teen Central: Assessment of an internet-based support system for children with cystic fibrosis. Author(s): Johnson KB, Ravert RD, Everton A.

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Source: Pediatrics. 2001 February; 107(2): E24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11158498&dopt=Abstract •

Hydrogen peroxide and nitric oxide in exhaled air of children with cystic fibrosis during antibiotic treatment. Author(s): Jobsis Q, Raatgeep HC, Schellekens SL, Kroesbergen A, Hop WC, de Jongste JC. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2000 July; 16(1): 95-100. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10933092&dopt=Abstract

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Hyperuricosuria due to high-dose pancreatic extract therapy in cystic fibrosis. Author(s): Stapleton FB, Kennedy J, Nousia-Arvanitakis S, Linshaw MA. Source: The New England Journal of Medicine. 1976 July 29; 295(5): 246-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=934188&dopt=Abstract

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Hypnosis, Theodore Roosevelt, and the patient with cystic fibrosis. Author(s): Anbar RD. Source: Pediatrics. 2000 August; 106(2 Pt 1): 339-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10920161&dopt=Abstract

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Hypoproteinemia and anemia in infants with cystic fibrosis. A presenting symptom complex often misdiagnosed. Author(s): Lee PA, Roloff DW, Howatt WF. Source: Jama : the Journal of the American Medical Association. 1974 April 29; 228(5): 585-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4406186&dopt=Abstract

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Hypovitaminosis D and response to supplementation in older patients with cystic fibrosis. Author(s): Hanly JG, McKenna MJ, Quigley C, Freaney R, Muldowney FP, FitzGerald MX. Source: The Quarterly Journal of Medicine. 1985 July; 56(219): 377-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4095249&dopt=Abstract

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IgE mediated hypersensitivity to pancreatic extract (PE) in parents of cystic fibrosis (CF) children. Author(s): Ganier M, Lieberman P. Source: Clin Allergy. 1979 March; 9(2): 125-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=87285&dopt=Abstract

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IgG proteolytic activity of Pseudomonas aeruginosa in cystic fibrosis. Author(s): Fick RB Jr, Baltimore RS, Squier SU, Reynolds HY.

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Source: The Journal of Infectious Diseases. 1985 April; 151(4): 589-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3919115&dopt=Abstract •

Impaired resistance to oxidation of low density lipoprotein in cystic fibrosis: improvement during vitamin E supplementation. Author(s): Winklhofer-Roob BM, Ziouzenkova O, Puhl H, Ellemunter H, Greiner P, Muller G, van't Hof MA, Esterbauer H, Shmerling DH. Source: Free Radical Biology & Medicine. 1995 December; 19(6): 725-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8582644&dopt=Abstract

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Improved antioxidant and fatty acid status of patients with cystic fibrosis after antioxidant supplementation is linked to improved lung function. Author(s): Wood LG, Fitzgerald DA, Lee AK, Garg ML. Source: The American Journal of Clinical Nutrition. 2003 January; 77(1): 150-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12499335&dopt=Abstract

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Improved growth and clinical, nutritional, and respiratory changes in response to nutritional therapy in cystic fibrosis. Author(s): Shepherd R, Cooksley WG, Cooke WD. Source: The Journal of Pediatrics. 1980 September; 97(3): 351-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6774070&dopt=Abstract

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Improved pulmonary function and exercise tolerance with inspiratory muscle conditioning in children with cystic fibrosis. Author(s): Sawyer EH, Clanton TL. Source: Chest. 1993 November; 104(5): 1490-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8222813&dopt=Abstract

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Increase of long chain omega-3 fatty acids in the major serum lipid classes of patients with cystic fibrosis. Author(s): Christophe A, Robberecht E, De Baets F, Franckx H. Source: Annals of Nutrition & Metabolism. 1992; 36(5-6): 304-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1492758&dopt=Abstract

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Influence of antacid and formulation on effectiveness of pancreatic enzyme supplementation in cystic fibrosis. Author(s): Braggion C, Borgo G, Faggionato P, Mastella G. Source: Archives of Disease in Childhood. 1987 April; 62(4): 349-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3036018&dopt=Abstract

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Inhibition of ATPase, GTPase and adenylate kinase activities of the second nucleotide-binding fold of the cystic fibrosis transmembrane conductance regulator

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by genistein. Author(s): Randak C, Auerswald EA, Assfalg-Machleidt I, Reenstra WW, Machleidt W. Source: The Biochemical Journal. 1999 May 15; 340 ( Pt 1): 227-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10229679&dopt=Abstract •

Inhibition of sugar transport by cystic fibrosis plasma. Author(s): Brown GA, Oshin A, Goodchild MC, Anderson CM. Source: Gut. 1971 October; 12(10): 856. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5166269&dopt=Abstract

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Inspiratory muscle training in patients with cystic fibrosis. Author(s): de Jong W, van Aalderen WM, Kraan J, Koeter GH, van der Schans CP. Source: Respiratory Medicine. 2001 January; 95(1): 31-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11207014&dopt=Abstract

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Intestinal permeability to [51Cr]EDTA in children with cystic fibrosis. Author(s): Leclercq-Foucart J, Forget P, Sodoyez-Goffaux F, Zappitelli A. Source: Journal of Pediatric Gastroenterology and Nutrition. 1986 May-June; 5(3): 384-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3088249&dopt=Abstract

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Intestinal permeability to 51Cr-EDTA and orocecal transit time in cystic fibrosis. Author(s): Escobar H, Perdomo M, Vasconez F, Camarero C, del Olmo MT, Suarez L. Source: Journal of Pediatric Gastroenterology and Nutrition. 1992 February; 14(2): 204-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1593376&dopt=Abstract

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Intravenous linoleic acid supplementation in children with cystic fibrosis. Author(s): Chase HP, Cotton EK, Elliott RB. Source: Pediatrics. 1979 August; 64(2): 207-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=382082&dopt=Abstract

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Linoleic acid absorption from lipid supplements in patients with cystic fibrosis with pancreatic insufficiency and in control subjects. Author(s): McKenna MC, Hubbard VS, Bieri JG. Source: Journal of Pediatric Gastroenterology and Nutrition. 1985 February; 4(1): 45-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3981368&dopt=Abstract

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Linoleic acid absorption in children with cystic fibrosis. Author(s): Chase HP, Welch NN, Rabaglia ME, Dupont J. Source: Journal of Pediatric Gastroenterology and Nutrition. 1982; 1(1): 49-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7186027&dopt=Abstract

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Lipids in cystic fibrosis. Author(s): Rosenlund ML, Walsh EP, Scott DA, Kritchevsky D. Source: Curr Concepts Nutr. 1979; 8: 219-27. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=393469&dopt=Abstract

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Liver function in patients with cystic fibrosis ingesting fish oil. Author(s): Henderson WR Jr, Astley SJ, Ramsey BW. Source: The Journal of Pediatrics. 1994 September; 125(3): 504-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8071770&dopt=Abstract

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Long-term oral beta-carotene supplementation in patients with cystic fibrosis - effects on antioxidative status and pulmonary function. Author(s): Rust P, Eichler I, Renner S, Elmadfa I. Source: Annals of Nutrition & Metabolism. 2000; 44(1): 30-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10838464&dopt=Abstract

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Long-term oral vitamin E supplementation in cystic fibrosis patients: RRR-alphatocopherol compared with all-rac-alpha-tocopheryl acetate preparations. Author(s): Winklhofer-Roob BM, van't Hof MA, Shmerling DH. Source: The American Journal of Clinical Nutrition. 1996 May; 63(5): 722-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8615355&dopt=Abstract

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Malabsorption of medium-chain triglycerides in infants with cystic fibrosis: correction with pancreatic enzyme supplement. Author(s): Durie PR, Newth CJ, Forstner GG, Gall DG. Source: The Journal of Pediatrics. 1980 May; 96(5): 862-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7365588&dopt=Abstract

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Massive hepatomegaly, steatosis, and secondary plasma carnitine deficiency in an infant with cystic fibrosis. Author(s): Treem WR, Stanley CA. Source: Pediatrics. 1989 June; 83(6): 993-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2726354&dopt=Abstract

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Meconium ileus equivalent in a child with cystic fibrosis taking cimetidine. Author(s): Mitchell EA, White PR, Elliott RB. Source: N Z Med J. 1980 August 27; 92(666): 155-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6933350&dopt=Abstract

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Mediation of the killing of rough, mucoid isolates of Pseudomonas aeruginosa from patients with cystic fibrosis by the alternative pathway of complement. Author(s): Pier GB, Ames P.

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Molecular diagnosis of cystic fibrosis in Indian patients--a preliminary report. Author(s): Ashavaid TF, Dherai AJ, Kondkar AA, Raghavan R, Udani SV, Udwadia ZF, Desai D. Source: J Assoc Physicians India. 2003 April; 51: 345-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12723646&dopt=Abstract

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Mucus clearance with three chest physiotherapy regimes in cystic fibrosis: a comparison between postural drainage, PEP and physical exercise. Author(s): Lannefors L, Wollmer P. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1992 June; 5(6): 748-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1628733&dopt=Abstract

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Mutations in the nucleotide binding domain 1 signature motif region rescue processing and functional defects of cystic fibrosis transmembrane conductance regulator delta f508. Author(s): DeCarvalho AC, Gansheroff LJ, Teem JL. Source: The Journal of Biological Chemistry. 2002 September 27; 277(39): 35896-905. Epub 2002 July 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12110684&dopt=Abstract

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Negative effects of oral fatty acid supplementation on sweat chloride in cystic fibrosis. Author(s): Lloyd-Still JD, Simon SH, Wessel HU, Gibson LE. Source: Pediatrics. 1979 July; 64(1): 50-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=450561&dopt=Abstract

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Neutrophil elastase/alpha 1-proteinase inhibitor complex levels decrease in plasma of cystic fibrosis patients during long-term oral beta-carotene supplementation. Author(s): Winklhofer-Roob BM, Schlegel-Haueter SE, Khoschsorur G, van't Hof MA, Suter S, Shmerling DH. Source: Pediatric Research. 1996 July; 40(1): 130-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8798258&dopt=Abstract

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New and emerging therapies for pulmonary complications of cystic fibrosis. Author(s): Tonelli MR, Aitken ML. Source: Drugs. 2001; 61(10): 1379-85. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11558827&dopt=Abstract

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Nutrition and growth in cystic fibrosis. Author(s): Hankard R, Munck A, Navarro J. Source: Hormone Research. 2002; 58 Suppl 1: 16-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12373008&dopt=Abstract

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Nutrition intervention for weight gain in cystic fibrosis: a meta analysis. Author(s): Jelalian E, Stark LJ, Reynolds L, Seifer R. Source: The Journal of Pediatrics. 1998 March; 132(3 Pt 1): 486-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9544906&dopt=Abstract

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Nutritional assessment and management in cystic fibrosis: a consensus report. The Consensus Committee. Author(s): Ramsey BW, Farrell PM, Pencharz P. Source: The American Journal of Clinical Nutrition. 1992 January; 55(1): 108-16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1728810&dopt=Abstract

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Nutritional effects of long-term gastrostomy feedings in children with cystic fibrosis. Author(s): Rosenfeld M, Casey S, Pepe M, Ramsey BW. Source: Journal of the American Dietetic Association. 1999 February; 99(2): 191-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9972186&dopt=Abstract

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Nutritional imperatives in cystic fibrosis therapy. Author(s): Erdman SH. Source: Pediatric Annals. 1999 February; 28(2): 129-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10036689&dopt=Abstract

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Nutritional status of patients with cystic fibrosis with meconium ileus: a comparison with patients without meconium ileus and diagnosed early through neonatal screening. Author(s): Lai HC, Kosorok MR, Laxova A, Davis LA, FitzSimmon SC, Farrell PM. Source: Pediatrics. 2000 January; 105(1 Pt 1): 53-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10617704&dopt=Abstract

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Nutritional supplementation in treatment of cystic fibrosis of the pancreas. Author(s): Allan JD, Mason A, Moss AD. Source: Am J Dis Child. 1973 July; 126(1): 22-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4723167&dopt=Abstract

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Ocular findings in cystic fibrosis patients receiving vitamin A supplementation. Author(s): Morkeberg JC, Edmund C, Prause JU, Lanng S, Koch C, Michaelsen KF.

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Ocular signs and symptoms and vitamin A status in patients with cystic fibrosis treated with daily vitamin A supplements. Author(s): Ansari EA, Sahni K, Etherington C, Morton A, Conway SP, Moya E, Littlewood JM. Source: The British Journal of Ophthalmology. 1999 June; 83(6): 688-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10340977&dopt=Abstract

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Omega-3 fatty acids (from fish oils) for cystic fibrosis. Author(s): Beckles Willson N, Elliott TM, Everard ML. Source: Cochrane Database Syst Rev. 2002; (3): Cd002201. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12137649&dopt=Abstract

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Omega-3 fatty acids suppress the enhanced production of 5-lipoxygenase products from polymorph neutrophil granulocytes in cystic fibrosis. Author(s): Keicher U, Koletzko B, Reinhardt D. Source: European Journal of Clinical Investigation. 1995 December; 25(12): 915-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8719931&dopt=Abstract

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One breath at a time: a family teaching program for children with cystic fibrosis. Author(s): Sams CA. Source: Can Nurse. 1979 September; 75(8): 20-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=256764&dopt=Abstract

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Oral absorption of omega-3 fatty acids in patients with cystic fibrosis who have pancreatic insufficiency and in healthy control subjects. Author(s): Henderson WR Jr, Astley SJ, McCready MM, Kushmerick P, Casey S, Becker JW, Ramsey BW. Source: The Journal of Pediatrics. 1994 March; 124(3): 400-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8120709&dopt=Abstract

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Oral calorie supplements for cystic fibrosis. Author(s): Smyth R, Walters S. Source: Cochrane Database Syst Rev. 2000; (2): Cd000406. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10796716&dopt=Abstract

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Oral supplementation with a high-fat, high-energy product improves nutritional status and alters serum lipids in patients with cystic fibrosis. Author(s): Rettammel AL, Marcus MS, Farrell PM, Sondel SA, Koscik RE, Mischler EH.

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Overexpression of the cystic fibrosis transmembrane conductance regulator in NIH 3T3 cells lowers membrane potential and intracellular pH and confers a multidrug resistance phenotype. Author(s): Wei LY, Stutts MJ, Hoffman MM, Roepe PD. Source: Biophysical Journal. 1995 September; 69(3): 883-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8519988&dopt=Abstract

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Paradoxical effects of essential fatty acid supplementation on lipid profiles and sweat electrolytes in cystic fibrosis. Author(s): Dodge JA, Custance JM, Goodchild MC, Laing SC, Vaughan M. Source: The British Journal of Nutrition. 1990 March; 63(2): 259-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2185826&dopt=Abstract

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Partial purification and characterization of a polymannuronic acid depolymerase produced by a mucoid strain of Pseudomonas aeruginosa isolated from a patient with cystic fibrosis. Author(s): Dunne WM Jr, Buckmire FL. Source: Applied and Environmental Microbiology. 1985 September; 50(3): 562-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3935048&dopt=Abstract

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Pharmacological treatment of the ion transport defect in cystic fibrosis. Author(s): Roomans GM. Source: Expert Opinion on Investigational Drugs. 2001 January; 10(1): 1-19. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11116277&dopt=Abstract

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Pharmacotherapy of the ion transport defect in cystic fibrosis. Author(s): Kunzelmann K, Mall M. Source: Clinical and Experimental Pharmacology & Physiology. 2001 November; 28(11): 857-67. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11703384&dopt=Abstract

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Physiotherapy and cystic fibrosis. Author(s): Rubin S. Source: Physiotherapy. 1967 February; 53(2): 51-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6045287&dopt=Abstract

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Physiotherapy for adolescents and adults with cystic fibrosis. Author(s): Gaskell D.

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Physiotherapy in cystic fibrosis. Author(s): Prasad SA, Tannenbaum EL, Mikelsons C. Source: Journal of the Royal Society of Medicine. 2000; 93 Suppl 38: 27-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10911816&dopt=Abstract

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Plant sources of acid stable lipases: potential therapy for cystic fibrosis. Author(s): Tursi JM, Phair PG, Barnes GL. Source: Journal of Paediatrics and Child Health. 1994 December; 30(6): 539-43. Erratum In: http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7865271&dopt=Abstract

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Posture and cystic fibrosis. Author(s): Tattersall R, Walshaw MJ. Source: Journal of the Royal Society of Medicine. 2003; 96 Suppl 43: 18-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12906321&dopt=Abstract

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Probe of the (Ca2+ + Mg2+)-ATPase in erythrocyte membranes of cystic fibrosis patients. Author(s): Hunsinger RN, Cheung HC. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 1986 April 30; 156(2): 165-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2940033&dopt=Abstract

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Protein metabolism in cystic fibrosis: responses to malnutrition and taurine supplementation. Author(s): Thompson GN, Tomas FM. Source: The American Journal of Clinical Nutrition. 1987 October; 46(4): 606-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3661477&dopt=Abstract

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Psychological interventions for cystic fibrosis. Author(s): Glasscoe CA, Quittner AL. Source: Cochrane Database Syst Rev. 2003; (3): Cd003148. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917948&dopt=Abstract

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Psychosocial support for adults with cystic fibrosis: a group approach. Author(s): Strauss GD, Pedersen S, Dudovitz D. Source: Am J Dis Child. 1979 March; 133(3): 301-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=425945&dopt=Abstract

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Quality of life in children and adolescents with cystic fibrosis: implications for optimizing treatments and clinical trial design. Author(s): Abbott J, Gee L. Source: Paediatric Drugs. 2003; 5(1): 41-56. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12513105&dopt=Abstract

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Ranitidine in children with peptic ulcer and patients with pancreatic cystic fibrosis. Author(s): Scorza A, Conti-Nibali S, Sferlazzas C, Saitta G, Tedeschi A. Source: Int J Clin Pharmacol Res. 1990; 10(3): 179-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2228343&dopt=Abstract

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Relationships among nutritional status and skeletal and respiratory muscle function in cystic fibrosis: does early dietary supplementation make a difference? Author(s): Hanning RM, Blimkie CJ, Bar-Or O, Lands LC, Moss LA, Wilson WM. Source: The American Journal of Clinical Nutrition. 1993 April; 57(4): 580-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8460615&dopt=Abstract

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Relationships between essential fatty acid levels, pulmonary function and fat absorption in pre-adolescent cystic fibrosis children with good clinical scores. Author(s): Thompson GN. Source: European Journal of Pediatrics. 1989 January; 148(4): 327-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2707278&dopt=Abstract

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Religious/spiritual coping in childhood cystic fibrosis: a qualitative study. Author(s): Pendleton SM, Cavalli KS, Pargament KI, Nasr SZ. Source: Pediatrics. 2002 January; 109(1): E8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11773576&dopt=Abstract

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Response to oral beta-carotene supplementation in patients with cystic fibrosis: a 16month follow-up study. Author(s): Winklhofer-Roob BM, van't Hof MA, Shmerling DH. Source: Acta Paediatrica (Oslo, Norway : 1992). 1995 October; 84(10): 1132-6. Erratum In: Acta Paediatr 1996 January; 85(1): 124. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8563224&dopt=Abstract

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Riboflavin deficiency in cystic fibrosis: three case reports. Author(s): McCabe H. Source: Journal of Human Nutrition and Dietetics : the Official Journal of the British Dietetic Association. 2001 October; 14(5): 365-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11906577&dopt=Abstract

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Scotopic thresholds and plasma retinol in cystic fibrosis. Author(s): Fulton AB, Hansen RM, Underwood BA, Shwachman H, Barg DC.

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Selenium: childhood poisoning and cystic fibrosis. Author(s): Snodgrass W, Rumack BH, Sullivan JB Jr, Peterson RG, Chase HP, Cotton EK, Sokol R. Source: Clin Toxicol. 1981 February; 18(2): 211-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7226733&dopt=Abstract

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Self-administered chest physiotherapy in cystic fibrosis: a comparative study of highpressure PEP and autogenic drainage. Author(s): Pfleger A, Theissl B, Oberwaldner B, Zach MS. Source: Lung. 1992; 170(6): 323-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1434782&dopt=Abstract

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Self-hypnosis for patients with cystic fibrosis. Author(s): Anbar RD. Source: Pediatric Pulmonology. 2000 December; 30(6): 461-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11109057&dopt=Abstract

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Sex differences in weight perception and nutritional behaviour in adults with cystic fibrosis. Author(s): Walters S. Source: Journal of Human Nutrition and Dietetics : the Official Journal of the British Dietetic Association. 2001 April; 14(2): 83-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11330265&dopt=Abstract

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Single- and multiple-dose-response relationships of beta-carotene in cystic fibrosis. Author(s): Homnick DN, Spillers CR, Cox SR, Cox JH, Yelton LA, DeLoof MJ, Oliver LK, Ringer TV. Source: The Journal of Pediatrics. 1995 September; 127(3): 491-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7658286&dopt=Abstract

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Sputum rheology changes in cystic fibrosis lung disease following two different types of physiotherapy: flutter vs autogenic drainage. Author(s): App EM, Kieselmann R, Reinhardt D, Lindemann H, Dasgupta B, King M, Brand P. Source: Chest. 1998 July; 114(1): 171-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9674466&dopt=Abstract

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Sputum sol-phase proteins and elastase activity in patients with cystic fibrosis. Author(s): Jackson AH, Hill SL, Afford SC, Stockley RA.

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Studies on cystic fibrosis using isoelectric focusing. IV. Distinction between ciliary dyskinesia activity in cystic fibrosis and asthmatic sera and association of cystic fibrosis protein with the activity in cystic fibrosis serum. Author(s): Wilson GB, Fudenberg HH. Source: Pediatric Research. 1977 April; 11(4): 317-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=846785&dopt=Abstract

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Successful treatment of acute lymphoblastic leukemia in a child with cystic fibrosis. Author(s): Gururangan S, Horner M, Rodman JH, Marina NM. Source: Medical and Pediatric Oncology. 1994; 22(6): 414-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8152404&dopt=Abstract

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Supplemental calories improve essential fatty acid deficiency in cystic fibrosis patients. Author(s): Parsons HG, O'Loughlin EV, Forbes D, Cooper D, Gall DG. Source: Pediatric Research. 1988 September; 24(3): 353-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3211621&dopt=Abstract

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Supplementation with carotenoids corrects increased lipid peroxidation in children with cystic fibrosis. Author(s): Lepage G, Champagne J, Ronco N, Lamarre A, Osberg I, Sokol RJ, Roy CC. Source: The American Journal of Clinical Nutrition. 1996 July; 64(1): 87-93. Erratum In: Am J Clin Nutr 1997 February; 65(2): 578. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8669420&dopt=Abstract

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Synergistic activation of guinea-pig cardiac cystic fibrosis transmembrane conductance regulator by the tyrosine kinase inhibitor genistein and cAMP. Author(s): Shuba LM, McDonald TF. Source: The Journal of Physiology. 1997 November 15; 505 ( Pt 1): 23-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9409469&dopt=Abstract

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Systematic reviews in cystic fibrosis. Author(s): Smyth RL, Cheng K, Motley J. Source: Journal of the Royal Society of Medicine. 1998; 91 Suppl 34: 19-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9709384&dopt=Abstract

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Taurine supplementation, fat absorption, and growth in cystic fibrosis. Author(s): Thompson GN, Robb TA, Davidson GP.

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The absorption and effect of dietary supplementation with omega-3 fatty acids on serum leukotriene B4 in patients with cystic fibrosis. Author(s): Kurlandsky LE, Bennink MR, Webb PM, Ulrich PJ, Baer LJ. Source: Pediatric Pulmonology. 1994 October; 18(4): 211-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7838619&dopt=Abstract

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The current physical therapy regimens of 108 consecutive patients attending a regional cystic fibrosis unit. Author(s): Morton S, Gilbert J, Littlewood JM. Source: Scand J Gastroenterol Suppl. 1988; 143: 110-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3164494&dopt=Abstract

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The cystic fibrosis mutation G551D alters the non-Michaelis-Menten behavior of the cystic fibrosis transmembrane conductance regulator (CFTR) channel and abolishes the inhibitory Genistein binding site. Author(s): Derand R, Bulteau-Pignoux L, Becq F. Source: The Journal of Biological Chemistry. 2002 September 27; 277(39): 35999-6004. Epub 2002 July 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12124395&dopt=Abstract

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The effect of 12 months' treatment with eicosapentaenoic acid in five children with cystic fibrosis. Author(s): Thies NH. Source: Journal of Paediatrics and Child Health. 1997 August; 33(4): 349-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9323627&dopt=Abstract

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The effect of oral zinc supplementation on plasma levels of vitamin A and retinolbinding protein in cystic fibrosis. Author(s): Palin D, Underwood BA, Denning CR. Source: The American Journal of Clinical Nutrition. 1979 June; 32(6): 1253-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=571673&dopt=Abstract

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The effect of parental relationships on the management of cystic fibrosis and guidelines for social work intervention. Author(s): Oppenheimer JR, Rucker RW. Source: Soc Work Health Care. 1980 Summer; 5(4): 409-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7434143&dopt=Abstract

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The effects of biofeedback assisted breathing retraining on lung functions in patients with cystic fibrosis. Author(s): Delk KK, Gevirtz R, Hicks DA, Carden F, Rucker R. Source: Chest. 1994 January; 105(1): 23-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8275737&dopt=Abstract

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The effects of inspiratory muscle training in patients with cystic fibrosis. Author(s): Asher MI, Pardy RL, Coates AL, Thomas E, Macklem PT. Source: Am Rev Respir Dis. 1982 November; 126(5): 855-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7149451&dopt=Abstract

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The effects of self-hypnosis for children with cystic fibrosis: a pilot study. Author(s): Belsky J, Khanna P. Source: Am J Clin Hypn. 1994 April; 36(4): 282-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8203356&dopt=Abstract

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The influence of age on aerosol deposition in children with cystic fibrosis. Author(s): J Paediatr Child Health. 1995 Aug;31(4):364 Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1994 December; 7(12): 2185-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7576903

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The influence of long-term cimetidine as an adjuvant to pancreatic enzyme therapy in cystic fibrosis. Author(s): Chalmers DM, Brown RC, Miller MG, Clarke PC, Kelleher J, Littlewood JM, Losowsky MS. Source: Acta Paediatr Scand. 1985 January; 74(1): 114-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3885675&dopt=Abstract

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The role of vitamins in cystic fibrosis. Author(s): Carr SB, McBratney J. Source: Journal of the Royal Society of Medicine. 2000; 93 Suppl 38: 14-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10911814&dopt=Abstract

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The treatment of cystic fibrosis. A statement by the Committee on Therapy. Author(s): Busey JF, Fenger EP, Hepper NG, Kent DC, Kilburn KH, Matthews LW, Simpson DG, Grzybowski S. Source: Am Rev Respir Dis. 1968 April; 97(4): 730-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4868648&dopt=Abstract

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The use of an intravenous fish oil emulsion enriched with omega-3 fatty acids in patients with cystic fibrosis. Author(s): Katz DP, Manner T, Furst P, Askanazi J.

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Therapeutic approach to pancreatic extract-induced hyperuricosuria in cystic fibrosis. Author(s): Nouisa-Arvanitakis S, Stapleton FB, Linshaw MA, Kennedy J. Source: The Journal of Pediatrics. 1977 February; 90(2): 302-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=830926&dopt=Abstract

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Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. Author(s): Li JD, Dohrman AF, Gallup M, Miyata S, Gum JR, Kim YS, Nadel JA, Prince A, Basbaum CB. Source: Proceedings of the National Academy of Sciences of the United States of America. 1997 February 4; 94(3): 967-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9023366&dopt=Abstract

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Trial of amino acid supplements in cystic fibrosis of the pancreas. Author(s): Darby C, Seakins JW. Source: Archives of Disease in Childhood. 1971 December; 46(250): 866-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5129189&dopt=Abstract

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Triglyceride levels after Intralipid infusion in children with cystic fibrosis. Author(s): Allue X, Sanjurjo P. Source: Pediatrics. 1978 June; 61(6): 924-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=97619&dopt=Abstract

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Two mechanisms of genistein inhibition of cystic fibrosis transmembrane conductance regulator Cl- channels expressed in murine cell line. Author(s): Lansdell KA, Cai Z, Kidd JF, Sheppard DN. Source: The Journal of Physiology. 2000 April 15; 524 Pt 2: 317-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10766914&dopt=Abstract

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Unusual clinical course in a child with cystic fibrosis treated with fat emulsion. Author(s): Elliott RB, Robinson PG. Source: Archives of Disease in Childhood. 1975 January; 50(1): 76-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1168448&dopt=Abstract

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Upregulation of cystic fibrosis transmembrane conductance regulator expression by oestrogen and Bak Foong Pill in mouse uteri. Author(s): Rowlands DK, Tsang LL, Cui YG, Chung YW, Chan LN, Liu CQ, James T, Chan HC.

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Source: Cell Biology International. 2001; 25(10): 1033-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11589624&dopt=Abstract •

Use of a membrane potential-sensitive probe to assess biological expression of the cystic fibrosis transmembrane conductance regulator. Author(s): Renier M, Tamanini A, Nicolis E, Rolfini R, Imler JL, Pavirani A, Cabrini G. Source: Human Gene Therapy. 1995 October; 6(10): 1275-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8590731&dopt=Abstract

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Use of famotidine in severe exocrine pancreatic insufficiency with persistent maldigestion on enzymatic replacement therapy. A long-term study in cystic fibrosis. Author(s): Carroccio A, Pardo F, Montalto G, Iapichino L, Soresi M, Averna MR, Iacono G, Notarbartolo A. Source: Digestive Diseases and Sciences. 1992 September; 37(9): 1441-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1505293&dopt=Abstract

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Use of nonmedical treatment by cystic fibrosis patients. Author(s): Stern RC, Canda ER, Doershuk CF. Source: The Journal of Adolescent Health : Official Publication of the Society for Adolescent Medicine. 1992 November; 13(7): 612-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1420216&dopt=Abstract

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Vitamin E supplementation in cystic fibrosis. Author(s): Winklhofer-Roob BM. Source: Journal of Pediatric Gastroenterology and Nutrition. 1997 July; 25(1): 120-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9226544&dopt=Abstract

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Vitamin E supplementation in cystic fibrosis. Author(s): Peters SA, Kelly FJ. Source: Journal of Pediatric Gastroenterology and Nutrition. 1996 May; 22(4): 341-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8732895&dopt=Abstract

Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

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Chinese Medicine: http://www.newcenturynutrition.com/

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drkoop.com®: http://www.drkoop.com/InteractiveMedicine/IndexC.html

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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

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Google: http://directory.google.com/Top/Health/Alternative/

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Healthnotes: http://www.healthnotes.com/

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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

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Open Directory Project: http://dmoz.org/Health/Alternative/

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HealthGate: http://www.tnp.com/

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WebMD®Health: http://my.webmd.com/drugs_and_herbs

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,,00.html

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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

The following is a specific Web list relating to cystic fibrosis; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation (some Web sites are subscription based): •

General Overview Cystic Fibrosis Source: Healthnotes, Inc. www.healthnotes.com Cystic Fibrosis Source: Integrative Medicine Communications; www.drkoop.com Liver Cirrhosis Source: Healthnotes, Inc. www.healthnotes.com Malabsorption Source: Healthnotes, Inc. www.healthnotes.com Pancreatic Insufficiency Source: Healthnotes, Inc. www.healthnotes.com

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Alternative Therapy Hypnotherapy Source: Integrative Medicine Communications; www.drkoop.com Massage Source: Integrative Medicine Communications; www.drkoop.com

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Herbs and Supplements Borago Alternative names: Borage; Borago officinalis Source: Alternative Medicine Foundation, Inc. www.amfoundation.org

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Digestive Enzymes Source: Healthnotes, Inc. www.healthnotes.com Lipase Source: Healthnotes, Inc. www.healthnotes.com Panax Alternative names: Ginseng; Panax ginseng Source: Alternative Medicine Foundation, Inc. www.amfoundation.org

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

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CHAPTER 4. DISSERTATIONS ON CYSTIC FIBROSIS Overview In this chapter, we will give you a bibliography on recent dissertations relating to cystic fibrosis. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “cystic fibrosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cystic fibrosis, we have not necessarily excluded nonmedical dissertations in this bibliography.

Dissertations on Cystic Fibrosis ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to cystic fibrosis. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

A Comparative Study to Assess an Educational Curriculum Designed for Preschool Chronically Ill Children Suffering from Cystic Fibrosis And/or Atopic Diseases. by Tanner, Lillian Catherine, Edd from The University of Mississippi, 1979, 362 pages http://wwwlib.umi.com/dissertations/fullcit/7921525

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Adolescents with Cystic Fibrosis: Effects of Cognitive Problem-solving Skills and Interpersonal Relationships on Adjustment by Guidry, Patrice Louise, Phd from University of Houston, 1988, 157 pages http://wwwlib.umi.com/dissertations/fullcit/8918766

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Adults with Cystic Fibrosis: Negotiating Uncertainty (life Expectancy) by Schweitzer, Eluned, Phd from The Catholic University of America, 1993, 196 pages http://wwwlib.umi.com/dissertations/fullcit/9317272

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Airway Liquid Secretion and Its Inhibition: Possible Relevance to Cystic Fibrosis Lung Disease by Trout, Laura; Phd from University of South Alabama, 2003, 147 pages http://wwwlib.umi.com/dissertations/fullcit/3078583

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An Analysis of the Perceptions of School-age Children with Cystic Fibrosis. by Shannon, Arlene Teresa, Phd from University of Miami, 1979, 143 pages http://wwwlib.umi.com/dissertations/fullcit/7921764

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An Examination of Some Aspects of the Structure, Function and Synthesis of the Extracellular Slime Produced by Cystic Fibrosis Isolates of Pseudomonas Aeruginosa in Relation to the Microcolony Mode of Growth by Chan, Chiu-yeung Raphael; Phd from University of Calgary (canada), 1980 http://wwwlib.umi.com/dissertations/fullcit/NK51240

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An Exploratory Study of the Relationship of Some Psychosocial Factors and Health Beliefs to Compliance with the Therapeutic Regimen among Adolescents with Cystic Fibrosis by Schultz, Susan Kristine, Phd from University of Minnesota, 1981, 245 pages http://wwwlib.umi.com/dissertations/fullcit/8126017

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Beating Cf: Patient Compliance with Chest Physiotherapy in Cystic Fibrosis by Bellisari, Anna W., Phd from The Ohio State University, 1984, 218 pages http://wwwlib.umi.com/dissertations/fullcit/8503985

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Bicarbonate and Proton Transport in Cultured Cystic Fibrosis Jme Human Nasal Surface Cells by Wunderlich, Eric Stephen; Phd from University of California, Berkeley, 2002, 111 pages http://wwwlib.umi.com/dissertations/fullcit/3082466

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Calcium Kinetics and Bone Health in Girls with Cystic Fibrosis by Schulze, Kerry J. Phd from The Johns Hopkins University, 2003, 137 pages http://wwwlib.umi.com/dissertations/fullcit/3080761

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Cell Volume Regulation Is Impaired in Cystic Fibrosis Human Airway Epithelial Cells by Braunstein, Gavin M. Phd from The University of Alabama at Birmingham, 2002, 151 pages http://wwwlib.umi.com/dissertations/fullcit/3066301

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Chronic Childhood Illness/disability and Familial Coping: the Case of Cystic Fibrosis (volumes I and Ii) by Venters, Maurine Henderson, Phd from University of Minnesota, 1980, 389 pages http://wwwlib.umi.com/dissertations/fullcit/8019585

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Conflicting Perspectives: Coping with Cystic Fibrosis in the Age of Molecular Medicine by Stockdale, Alan, Phd from Brandeis University, 1997, 196 pages http://wwwlib.umi.com/dissertations/fullcit/9710899

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Detection and Characterisation of Proteolytic Activity in the Cystic Fibrosis Lung by Coulson, David Thomas Richard; Phd from Queen's University of Belfast (northern Ireland), 2002, 156 pages http://wwwlib.umi.com/dissertations/fullcit/f281009

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Development and Chronic Disease: Functional Adaptation in Cystic Fibrosis (maturation, Growth, Auxology) by Mahaney, Michael Charles, Phd from The Ohio State University, 1984, 227 pages http://wwwlib.umi.com/dissertations/fullcit/8504050

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Effects of a Swimming Program on Cystic Fibrosis Children by Edlund, Larry Lester, Phd from The University of Utah, 1980, 88 pages http://wwwlib.umi.com/dissertations/fullcit/8029201

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Energy Intake in Adult Cystic Fibrosis Patients by Iglesias, Anna; Ms from Texas Woman's University, 2002, 54 pages http://wwwlib.umi.com/dissertations/fullcit/1411696

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Family Adaptation to Chronic Illness: the Case of Cystic Fibrosis by Patterson, Joan Marie Engel, Phd from University of Minnesota, 1983, 218 pages http://wwwlib.umi.com/dissertations/fullcit/8318114

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Fighting for the Breath of Life: a Sociological Study of Patients with Cystic Fibrosis by Narcez, Louis Howard, Phd from City University of New York, 1989, 152 pages http://wwwlib.umi.com/dissertations/fullcit/9000054

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Genetics and the (social) Body: Testing for the Cystic Fibrosis Gene by Hadd, Wendy; Phd from Universite De Montreal (canada), 1999, 307 pages http://wwwlib.umi.com/dissertations/fullcit/NQ47617

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Genomic and Bioinformatic Analysis of Mucoid Pseudomonas Aeruginosa in Cystic Fibrosis by Firoved, Aaron Marshal; Phd from University of Michigan, 2002, 154 pages http://wwwlib.umi.com/dissertations/fullcit/3068862

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High-resolution Linkage Disequilibrium in the Cystic Fibrosis Transmembrane Conductance Regulator Gene: Implications for Association Mapping by Keen Kim, J. Dianne; Phd from Massachusetts Institute of Technology, 2002 http://wwwlib.umi.com/dissertations/fullcit/f201473

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High-resolution Linkage Disequilibrium in the Cystic Fibrosis Transmembrane Conductance Regulator Gene: Implications for Association Mapping by Kim, J. Dianne Keen; Phd from Massachusetts Institute of Technology, 2002 http://wwwlib.umi.com/dissertations/fullcit/f201505

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Inhaled Aminoglycosides for the Treatment of Chronic Respiratory Pseudomonas Aeruginosa Infections in Cystic Fibrosis by Labiris, Nancy Renee; Phd from University of Toronto (canada), 2002, 251 pages http://wwwlib.umi.com/dissertations/fullcit/NQ69218

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Investigating the Role of P-glycoprotein on Drugs Exhibiting Enhanced Renal Clearance in Cystic Fibrosis Patients by Susanto, Miki; Phd from University of California, San Francisco, 2002, 266 pages http://wwwlib.umi.com/dissertations/fullcit/3075311

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Investigation of Modifiers of Intestinal Disease in Cystic Fibrosis Mice by Choi, Caroline May Yuk; Msc from University of Toronto (canada), 2002, 135 pages http://wwwlib.umi.com/dissertations/fullcit/MQ74127

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Mother-child Interaction and Family Functioning: Children with Cystic Fibrosis (chronic Illness) by Sawyer, Elspeth Henry, Phd from The Ohio State University, 1984, 205 pages http://wwwlib.umi.com/dissertations/fullcit/8426470

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Overexpression and Characterization of the Cystic Fibrosis Protein Cftr Using Afm and Maldi-tof-ms by Wooster, David Guire; Phd from Montana State University, 2002, 125 pages http://wwwlib.umi.com/dissertations/fullcit/3042499

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Perceived Efficacy of Symptom-oriented Hypnotherapy in Pediatric Cancer and Cystic Fibrosis Patients (pediatric Patients) by Dorr, Constance Joan, Phd from The University of Toledo, 1991, 134 pages http://wwwlib.umi.com/dissertations/fullcit/9216428

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Percutaneous Endoscopic Gastrostomy Placement Time in People with Cystic Fibrosis by Gunnell, Sarah; Ms from Utah State University, 2002, 54 pages http://wwwlib.umi.com/dissertations/fullcit/1412263

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Pseudomonas Aeruginosa Infection As a Disease Severity Marker in Cystic Fibrosis by Bassil, Katherine Louise; Msc from University of Toronto (canada), 2002, 83 pages http://wwwlib.umi.com/dissertations/fullcit/MQ68670

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Respiratory, Nutritional, and Oral-craniofacial Statuses of Preschool Children with Cystic Fibrosis by Mueller, Donna Helene, Phd from Temple University, 1986, 219 pages http://wwwlib.umi.com/dissertations/fullcit/8627490

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Responses to Physical Exercise of Patients with Cystic Fibrosis in an Adaptive Physical Education Program by Songster, Thomas Bernard, Phd from The University of Utah, 1967, 187 pages http://wwwlib.umi.com/dissertations/fullcit/6717380

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Self-management Behavior in Patients with Cystic Fibrosis by Sockrider, Marianna Martin, Drph from The Univ. of Texas H.s.c. at Houston Sch. of Public Health, 1994, 232 pages http://wwwlib.umi.com/dissertations/fullcit/9513536

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Siblings of Children with Cystic Fibrosis: Perceptions of the Impact of the Disease, Coping Behaviors, and Psychological Adjustment by Harder, Lois Christine, Phd from Purdue University, 1981, 126 pages http://wwwlib.umi.com/dissertations/fullcit/8210199

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Studies on Plasma Membranes and Glycoproteins in Cells Cultured from Patients with Cystic Fibrosis by Maler, Thomas; Phd from University of Toronto (canada), 1982 http://wwwlib.umi.com/dissertations/fullcit/NL07931

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The Caregiver Quality of Life Cystic Fibrosis (cqolcf) Scale: Development and Validation by Boling, Whitney; Phd from University of Alabama and University of Alabama at Birmingham, 2001, 98 pages http://wwwlib.umi.com/dissertations/fullcit/3015854

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The Effects of Family Functioning on Levels of Compliance with Treatment Regimens among Adolescents and Adults with Cystic Fibrosis (cystic Fibrosis) by Venugopal, Geeta, Phd from The University of Akron, 1991, 215 pages http://wwwlib.umi.com/dissertations/fullcit/9208320

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The Impact of Cystic Fibrosis on the Family: the Linkages between Family Functioning and Treatment Adherence by Delambo, Kirsten E. Phd from Pacific Graduate School of Psychology, 2003, 105 pages http://wwwlib.umi.com/dissertations/fullcit/3071918

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The Incidence of Psychological Distress in Adults with Cystic Fibrosis: Are There Differences Based on Lung Transplant List Status, Disease Severity, and Adaptational Factors? by Sedway, Jan Alison; Phd from The University of North Carolina at Chapel Hill, 2002, 175 pages http://wwwlib.umi.com/dissertations/fullcit/3070910

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The Isolation and Characterization of Human Salivary Kallikrein from Normal Subjects and Cystic Fibrosis Patients by Hare, Ester Rose; Phd from Dalhousie University (canada), 1984 http://wwwlib.umi.com/dissertations/fullcit/NK66117

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The Role of Alpha2-macroglobulinin the Pathogenesis of Cystic Fibrosis by Bridges, Michael Anthony; Phd from The University of British Columbia (canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK56579

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Towards Pharmacological Treatment of Cystic Fibrosis by Andersson, Charlotte; Phd from Uppsala Universitet (sweden), 2002, 53 pages http://wwwlib.umi.com/dissertations/fullcit/f580161

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Using Communication to Cope with Serious Illness: a Qualitative Study of Adult Cystic Fibrosis Patients (coping) by Benjamin, Marcia L., Phd from Purdue University, 1993, 173 pages http://wwwlib.umi.com/dissertations/fullcit/9334320

Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

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CHAPTER 5. CLINICAL TRIALS AND CYSTIC FIBROSIS Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning cystic fibrosis.

Recent Trials on Cystic Fibrosis The following is a list of recent trials dedicated to cystic fibrosis.8 Further information on a trial is available at the Web site indicated. •

A Pilot Trial of Phenylbutyrate/Genistein Duotherapy (for Cystic Fibrosis) Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Cystic Fibrosis Foundation Therapeutics Purpose - Excerpt: We are testing a new combination of medicines, to determine if they could be used to treat cystic fibrosis (CF). Subjects with CF who have two copies of the most common mutation (change) found in patients with CF called DF508. CF is caused by a lack of chloride movement in the nose, sinuses, lungs, intestines, pancreas and sweat glands. We are conducting this study to determine the safety of using a combination of two medicines, Phenylbutyrate and Genistein, to improve the ability of the cells lining the nose to regulate movement of salt (chloride) and water in people with CF. Phenylbutyrate has been extensively used to treat patients with rare metabolic diseases (which are very different from CF), Phenylbutyrate is an investigational drug for the purpose of this study. Genistein is a naturally occurring substance that is found in food products such as soy and tofu, but is also an investigational drug for this study. Both drugs may be able to restore normal chloride movements in body organs and glands. We will be studying salt and water in the nose movement by a technique called nasal transepithelial potential difference (NPD). Phase(s): Phase I Study Type: Interventional

8

These are listed at www.ClinicalTrials.gov.

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00016744 •

Bone Health of People with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Cystic Fibrosis Foundation Purpose - Excerpt: People with cystic fibrosis (CF) now frequently live into adulthood and with this extended life expectancy has come new clinical problems. Poor bone health, including osteoporosis and bone fractures, is one of these increasingly important conditions. Preventing the negative outcomes of poor bone health in later life is primarily related to ensuring optimal growth (weight and height) and obtaining maximal amount of bone mass during growth and development. This study will identify factors that influence bone health in a sample of children, adolescents and young adults as measured by dual energy x-ray absorptiometry and new bone densitometry methods (peripheral quantitative computerized tomography [p-QCT] and bone sonometer). We will also identify factors which influence changes in bone status over a 12-month follow-up period in a subsample of people with CF. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00008762

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Efficacy and Safety of 24 Weeks of Oral Treatment with BIIL 284 BS in Adult and Pediatric Patients Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): Boehringer Ingelheim Pharmaceuticals Purpose - Excerpt: The purpose of this study is to determine the effect of 24 weeks of treatment with BIIL 284 BS compared with placebo on pulmonary function and incidence of pulmonary exacerbation in adult and pediatric cystic fibrosis patients. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00060801

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Growth Hormone Use in Cystic Fibrosis - a Multicenter Study Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Genentech Purpose - Excerpt: Cystic Fibrosis (CF) is the most common lethal genetic disorder in America. Previous studies by our group and others have shown that human recombinant growth hormone (GH) improves height velocity, weight velocity, lean body mass (LBM) and pulmonary function. These positive results have prompted us to

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ask further questions regarding GH use in CF including: a) Do patients with better baseline body weight and pulmonary function derive more benefit from treatment than those with worse weight and pulmonary function?, b) Does GH use improve the patient's quality of life?, c) Once GH is discontinued, are the positive effects sustained? We hypothesize that GH treatment in CF patients will improve their clinical status and their quality of life. We further hypothesize that these effects will be present regardless of baseline body weight or pulmonary function, and that positive outcome will be sustained for at least one year after GH treatment is discontinued. To test our hypothesis, we will recruit 40 prepubertal children from five CF centers across the United States (8 per center). Patients will be randomly assigned to receive treatment with GH (0.3mg/kg/wk) during either the first or the second year. All subjects will be seen every three months. We will evaluate the following parameters every three months: 1) height, height velocity and Z-score, 2) body weight and weight velocity. Every six months we will measure: 1) lean body mass utilizing DEXA, 2) pulmonary function, including measurement of respiratory muscle strength (peak inspiratory and peak expiratory pressure), 3) quality of life (QOL), quantitated from QOL forms specific for CF ("The Cystic Fibrosis Questionnaire"). After one year of study, subjects will "crossover" to the other treatment arm. This 24 month study will allow us to statistically compare outcome measures in 20 treated and 20 nontreated subjects from multiple centers, and will allow us to assess sustained effect in the 20 subjects who receive GH during the first year, by comparing their results to results obtained during the year post treatment. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005112 •

Learning and Behavior Problems in Children with Chronic Granulomatous Disease and Related Disorders Condition(s): Chediak Higashi Syndrome; Chronic Granulomatous Disease; Job's Syndrome; Leukocyte Disorder Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: This study will try to determine what causes learning, behavioral and emotional problems in children with chronic granulomatous disease (GCD) and other phagocyte disorders. (Phagocytes are a type of white blood cell.) Children with these disorders have frequent severe infections that require hospitalization, sometimes for long periods of time. Many of them also have problems with school, learning, behavior, anxiety and depression. This study will explore whether these latter problems are a direct result of the illness itself or are a consequence of frequent, long hospitalizations, or are due to other factors. Test findings in these children will be compared with those of children with cystic fibrosis-another disease that causes frequent infections requiring prolonged hospitalization. Patients age 2 or older with GCD or other phagocytic disorders or cystic fibrosis may be eligible for this study. Participants (or a parent or guardian) will complete questionnaires including personal information such as age, gender and marital status, a family medical history, and information on their illness. Patients will be given various psychological and intelligence tests, and they and their parents or guardians will be interviewed by a child psychiatrist. The tests and interviews take a total of about 5 hours and are given in two or three separate sessions.

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The tests may reveal problems such as learning disorders, attention-deficit hyperactivity disorder, anxiety, or depression. If any of these problems are identified, appropriate referrals will be made for specialized services, such as special school placement, tutoring, or counseling. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005933 •

Phase II Study of Growth Hormone in Children With Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): University of Utah Purpose - Excerpt: Objectives: I. Determine the effect of growth hormone on height, height velocity, body weight, and lean body mass in patients with cystic fibrosis. II. Determine the effect of growth hormone on pulmonary function in these patients. III. Determine the impact of this drug on the quality of life in these patients. IV. Determine if the clinical response from this drug is sustained in these patients. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00016445

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Randomized Study of Alendronate in Adult Patients With Cystic Fibrosis Related Osteoporosis Condition(s): Osteoporosis; Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): FDA Office of Orphan Products Development; University of North Carolina Purpose - Excerpt: Objectives: I. Determine the bioavailability and biologic effect of alendronate on bone metabolism in patients with cystic fibrosis. II. Assess the safety and efficacy of this treatment regimen in improving osteoporosis in this patient population. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004489

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Role of Genetic Factors in the Development of Lung Disease Condition(s): Alpha 1 Antitrypsin Deficiency; Cystic Fibrosis; Lung Disease; Obstructive Lung Disease; Sarcoidosis; Asthma Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study is designed to evaluate the genetics involved in the development of lung disease by surveying genes involved in the process of breathing and examining the genes in lung cells of patients with lung disease. The study will focus

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on defining the distribution of abnormal genes responsible for processes directly involved in different diseases affecting the lungs of patients and healthy volunteers. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001532 •

Role of Toxins in Lung Infections Caused by Pseudomonas Aeruginosa Condition(s): Pseudomonas Infection; Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Some bacteria that cause disease can produce toxic substances that may worsen the disease. Pseudomonas aeruginosa is a bacteria that can produce a variety of toxins and is of special interest for patients with cystic fibrosis and repeated long term lung infections. The goal of this study is to determine whether specific toxins produced by Pseudomonas aeruginosa may be important in the disease process of chronic lung infections of patients with cystic fibrosis. This study will attempt to measure bacterial production of toxins in blood and sputum and immune system response to toxins in the blood. Researchers plan to study 4 effector proteins (toxins). 1. exotoxin A 2. Exo S 3. Exo U 4. Pcr V Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00027183

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Study of Hepatic Glucose Production and De novo Lipogenesis in Patients With Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): University of Utah Purpose - Excerpt: Objectives: I. Determine the amount of hepatic glucose production derived from gluconeogenesis and glycogenolysis in the post-absorptive state in patients with cystic fibrosis. II. Determine de novo lipogenesis in relationship to resting energy expenditure in this patient population. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00014781

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Study of INS37217 Inhalation Solution in Mild to Moderate Cystic Fibrosis Lung Disease Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): Inspire Pharmaceuticals; Cystic Fibrosis Foundation Therapeutics Purpose - Excerpt: The purpose of this study is to assess the safety and effectiveness of multiple dosages of INS37217 compared to placebo over 28 days in subjects with mild to

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moderate cystic fibrosis (CF) lung disease. Study drug will be administered through a nebulizer (a device that delivers medication as a mist by breathing it in). Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00056147 •

Study of Mycobacterial Infections Condition(s): Atypical Mycobacterium Infections; Cystic Fibrosis; Job's Syndrome Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: This study will examine the symptoms, course of disease and treatment of non-tuberculous mycobacterial (NTM) infections, as well as the genetics involved in these infections. Patients with NTM have recurrent lung infections and sometimes infections of the skin and other organs as well. They may also have curvature of the spine, barrel chest, and heart valve weakness. The study will compare the features of NTM with those of Job syndrome and cystic fibrosis, other diseases involving recurrent infections of the lungs and possibly other organs. Patients with diagnosed or suspected non-tuberculous mycobacterial infection, cystic fibrosis or Job syndrome may be eligible for this study. All participants will have a medical and family history, blood and urine tests, imaging studies that may include X-rays, computed tomography (CT) or magnetic resonance imaging (MRI) scans, and DNA and other genetic studies. In addition, all patients with Job syndrome and cystic fibrosis, and patients with NTM who have lung disease undergo the following procedures: - Scoliosis survey - X-rays of the spine to look for curvature or other abnormalities of the spinal column Echocardiography - imaging test that uses sound waves to examine the heart chambers and valves - Electrocardiogram - measurement of the electrical activity of the heart Pulmonary function tests - breathing tests to measure how much air the patient can move into and out of the lungs - Body measurements - measurements of height, weight, arm span, finger length, etc. - Joint function - assessment of joint mobility using different maneuvers to test flexibility of joints and ligaments - Examination of physical features that might be associated with NTM, such as high arched palate of the mouth, flat feet, or certain skin features - Dermatology (skin) examination for reactive skin conditions or other skin problems and possibly a skin biopsy (surgical removal of a small skin tissue sample for microscopic examination) - Interview with genetics specialist These tests may require several days to complete. Patients with NTM will also be examined by a cystic fibrosis specialist and may have a sweat test. In addition, NTM patients will be asked to return to NIH every year for 5 years for follow-up tests, if medically indicated, including CT of the chest, scoliosis survey and examination by other specialists. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00018044

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Study of Tauroursodeoxycholic Acid for Hepatobiliary Disease in Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients.

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Sponsor(s): FDA Office of Orphan Products Development; Children's Hospital Medical Center - Cincinnati Purpose - Excerpt: Objectives: I. Determine the optimum dose of tauroursodeoxycholic acid (TUDCA) required to achieve maximal bioavailability for patients with cystic fibrosis-associated liver disease. II. Compare optimized doses of TUDCA with ursodiol (ursodeoxycholic acid; UDCA) for effects on biliary bile acid composition and metabolism, serum biochemistries, fat absorption, and fat-soluble vitamin status in these patients. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004441 •

Study of Total Energy Expenditure in Infants and Children With Moderate to Severe Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Indiana University Purpose - Excerpt: Objectives: I. Compare the resting energy expenditure using respiratory calorimetry in infants and children with moderate to severe cystic fibrosis versus age matched healthy controls. II. Determine the total energy expenditure and energy spent on physical activity using the doubly labeled water method in these patient populations. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006273

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Studying Patients with Cystic Fibrosis and Other Pulmonary and Pancreatic Disorders Condition(s): Bronchiectasis; Cystic Fibrosis; Pancreatic Insufficiency Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: Cystic fibrosis is a disease that affects many parts of the body, particularly the lungs and pancreas. The main purpose of this study is to further understand the natural history, clinical presentation, and genetics of cystic fibrosis. Patients with cystic fibrosis will be asked to participate in this study by undergoing standard medical tests and procedures. Patients will have a history taken and have a physical examination as well as blood tests, and a sweat test (a test for cystic fibrosis of the pancreas in which electrolytes are measured in collected sweat). Patients may also be asked to provide samples of urine, stool, and sputum for additional tests. More complicated procedures such as bronchoscopy or bronchoalveolar lavage may be required for diagnosis, treatment, or research purposes. Patients will receive appropriate treatment with antibiotics, pancreatic enzymes, vitamins, physiotherapy, and other agents. Medications may be given by mouth or injected into a vein. This study will provide patients with information on the prognosis of the disease as well as recommendations for management of cystic fibrosis. In addition this study will provide information to researchers which may be useful in other studies of cystic fibrosis.

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Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001223 •

Tissue Collection from People with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: This study will examine the relationship between bacterial products in lung infections in cystic fibrosis and disease severity. It will examine plasma and lung tissue from cystic fibrosis patients. Patients with cystic fibrosis and having certain genetic characteristics, who are between 9 and 65 years of age and any cystic fibrosis patient undergoing lung transplantation at INOVA Fairfax Hospital in Fairfax, Virginia, may be eligible for this study. Lung specimens of participating transplant patients will be collected at INOVA Fairfax Hospital. Patients who participate in the apheresis portion of the study will be admitted to the NIH Clinical Center for 2 to 3 days. Apheresis is a procedure for collecting large quantities of specific blood components. For this study, plasma-the liquid part of the blood-will be collected. For the procedure, whole blood is collected through a needle in an arm vein, similar to donating blood. The blood is separated into its components by centrifugation (spinning), the plasma and white cells are extracted and collected in a bag, and the red cells are returned to the body, either through the same needle or through another needle in the other arm. During the hospital stay, patients may also be asked to participate in other cystic fibrosis studies involving blood tests, an echocardiogram (ultrasound test of the heart), urine pregnancy test, and pulmonary function (breathing) tests. Patients who cannot undergo apheresis may be asked to provide up to an additional 100 cc (7 tablespoons) of blood for research to look at bacterial products. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00015756

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Benefits and Risks of Newborn Screening for Cystic Fibrosis Condition(s): Cystic Fibrosis; Lung Disease; Pseudomonas Infections Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Center for Research Resources (NCRR) Purpose - Excerpt: Although cystic fibrosis (CF) is the most common, life-threatening autosomal recessive genetic disorder of the white population, there are often delays in diagnosis and hence start of treatment. Advances of the past two decades have made CF screening feasible using routinely collected neonatal blood specimens and measuring an enzyme level followed by CF mutation DNA analysis. Our overall goal of the study is to see if early diagnosis of CF through neonatal screening will be medically beneficial without major risks. ''Medically beneficial'' refers to better nutrition and/or pulmonary status, whereas '' risks'' include laboratory errors, miscommunication or misunderstanding, and adverse psychosocial consequences. Specific aims include assessment of the benefits, risks, costs, quality of life, and cognitive function associated

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with CF neonatal screening and a better understanding of the epidemiology of CF. A comprehensive, randomized clinical trial emphasizing early diagnosis as the key variable has been underway since 1985. Nutritional status has been assessed using height and weight measurements and biochemical methods. The results have demonstrated significant benefits in the screened (early diagnosis) group. We are now focusing on the effect of early diagnosis of CF on pulmonary outcome. Pulmonary status is measured using chest radiographs, chest scans using high resolution computerized tomography, and pulmonary function tests. Other factors that we are looking at include risk factors for the acquisition of respiratory pathogens such as Pseudomonas aeruginosa, quality of life and cognitive function of children with CF who underwent early versus delayed diagnosis, as well as the cost effectiveness of screening and the costs of diagnosis and treatment of CF throughout childhood. If the questions underlying this study are answered favorably, it is likely that neonatal screening using a combination of enzyme level (immunoreactive trypsinogen) and DNA test will become the routine method for identifying new cases of CF not only in the State of Wisconsin, but throughout the country. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00014950 •

Gene Modifiers in Cystic Fibrosis Lung Disease Condition(s): Cystic Fibrosis; Lung Diseases Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To examine genetic modifiers of the severity of cystic fibrosis lung disease. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00037765

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Genetic Modifiers of Cystic Fibrosis: Sibling Study Condition(s): Lung Diseases; Cystic Fibrosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To identify modifier genes in cystic fibrosis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00037778

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Phase I Pilot Study of Gene Therapy for Cystic Fibrosis Using Cationic Liposome Mediated Gene Transfer Condition(s): Cystic Fibrosis Study Status: This study is no longer recruiting patients.

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Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Alabama Purpose - Excerpt: Objectives: Determine whether copies of the cystic fibrosis gene (pGT-1) can be delivered to the cells lining the nose of cystic fibrosis patients using cationic liposome (DMRIE/DOPE) mediated gene transfer. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004471 •

Phase I Randomized Study of Adeno-Associated Virus-CFTR Vector in Patients with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Florida Purpose - Excerpt: Objectives: I. Determine the maximum tolerated dose of recombinant adeno-associated virus-CFTR vector in patients with cystic fibrosis. II. Assess the safety of this gene therapy in these patients. III. Assess the in vivo gene transfer of this vector in these patients. IV. Assess the CFTR gene expression and physiologic activity following gene transfer in these patients. V. Assess the clinical impact of CFTR gene expression following gene transfer in these patients. VI. Monitor patient immune response directed against CFTR or vector components following vector administration. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004533

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Phase II Pilot Study to Compare the Bioavailability of Buffered, Enteric-Coated Ursodiol with Unmodified Ursodiol for Chronic Cholestatic Liver Disease and Cystic Fibrosis-Associated Liver Disease Condition(s): Cystic Fibrosis; Gastrointestinal Diseases; Cholestasis Study Status: This study is no longer recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Children's Hospital Medical Center - Cincinnati Purpose - Excerpt: Objectives: I. Compare the bioavailability of polymer-coated and buffered ursodiol (ursodeoxycholic acid) to unmodified ursodiol in patients with cystic fibrosis-associated liver disease or chronic cholestatic liver disease. II. Compare the differences in pruritus, weight gain, and liver function for both treatments. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004315

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8-Day Safety, Tolerability, and Effects Study of Inhaled INS37217 and Placebo In Adult and Pediatric Cystic Fibrosis Patients Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): Inspire Pharmaceuticals Purpose - Excerpt: The purpose of this ascending dose group study is to assess the safety, tolerability, and effects of multiple dose levels of INS37217 and placebo followed by five days twice daily treatment with maximum tolerated dose administered by inhalation via the Pari LC Star nebulizer in adult and pediatric patients with cystic fibrosis Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00034515

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A multi-centered study of the long-term effect of salmeterol and albuterol in cystic fibrosis Condition(s): Cystic Fibrosis Study Status: This study is suspended. Sponsor(s): National Center for Research Resources (NCRR) Purpose - Excerpt: Long term use of bronchodilators in CF is beneficial to the improvement of pulmonary function and symptoms. This study is investigating the long-term benefit of administration of the drug Salmeterol, a bronchodilator. Salmeterol will be compared to albuterol or placebo. The medication will be inhaled twice a day for 6 months. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005110

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A Study of the Safety and Efficacy of Tobramycin for Inhalation in Young Children with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Center for Research Resources (NCRR) Purpose - Excerpt: This study's primary goals are to test the safety and effectiveness of Tobramycin for Inhalation (TOBIr) in cystic fibrosis (CF) patients who are between 6 months and 6 years of age. This drug is an antibiotic that is inhaled into the lungs by the patient. It has already been studied and approved by the FDA for treatment of CF patients 6 years and older. Lung fluid will be examined for bacteria before and after the 28-day treatment. The amount of bacteria before and after treatment will be compared. This will indicate whether the antibiotic was effective in killing bacteria in the lungs. Once treatment begins, patients will be monitored every 2 weeks throughout the study

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(5 exams in 56 days). Half of the patients will receive TOBIr, half will receive a placebo (a substance that looks like TOBIr but contains no medication). Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006280 •

Interferon gamma-1b by inhalation for the treatment of patients with cystic fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): InterMune Pharmaceuticals Purpose - Excerpt: The purpose of this research study is to evaluate the safety and effectiveness of Interferon gamma-1b (IFN-g 1b) on lung function when given to patients with cystic fibrosis by inhalation (breathed into the lungs) three times a week for 12 weeks. The FDA has not approved Interferon gamma-1b for use with cystic fibrosis patients, which is the condition being examined in this study. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00043316

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Multicenter Study of Nontuberculous Mycobacteria in Cystic Fibrosis Patients Condition(s): Cystic Fibrosis; Atypical Mycobacterium Infection Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); University of North Carolina Purpose - Excerpt: Objectives: I. Determine the prevalence of nontuberculous mycobacteria in sputum cultures from patients with cystic fibrosis. II. Compare the clinical course of patients with negative versus positive cultures. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004296

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Phase I Pilot Study of Ad5-CB-CFTR, an Adenovirus Vector Containing the Cystic Fibrosis Transmembrane Conductance Regulator Gene, in Patients with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); University of North Carolina Purpose - Excerpt: Objectives: I. Assess the safety and efficacy of gene transfer into the nasal epithelium using Ad5-CB-CFTR, an E1-deleted adenovirus vector containing the cystic fibrosis transmembrane conductance regulator gene, in patients with cystic

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fibrosis (CF). II. Determine whether ion transport abnormalities in CF airway cells can be corrected. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004779 •

Phase I Randomized Study of CPX for the Treatment of Adult Patients with Mild Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): FDA Office of Orphan Products Development; SciClone Pharmaceuticals Purpose - Excerpt: Objectives: I. Evaluate the safety of ascending doses of CPX administered to adult patients with mild cystic fibrosis. II. Evaluate the pharmacokinetics of ascending doses of CPX in this patient population. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004428

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Phase I Study of Liposome-Mediated Gene Transfer in Patients with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Alabama Purpose - Excerpt: Objectives: Evaluate the efficacy and safety of lipid-mediated transfer of the cystic fibrosis transmembrane conductance regulator gene to nasal epithelium in patients with cystic fibrosis. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004806

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Phase I Study of the Third Generation Adenovirus H5.001CBCFTR in Patients with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); University of Pennsylvania Purpose - Excerpt: Objectives: I. Assess the safety and feasibility of gene transfer with the third generation adenovirus H5.001CBCFTR in patients with cystic fibrosis. Phase(s): Phase I Study Type: Interventional

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004287 •

Phase II Randomized, Double-Blind, Placebo-Controlled Study of Intravenous Mucoid Exopolysaccharide Pseudomonas Aeruginosa Immune Globulin for Cystic Fibrosis Condition(s): Cystic Fibrosis; Bacterial Infections Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); Vanderbilt University Medical Center Purpose - Excerpt: Objectives: I. Assess the efficacy of monthly intravenous mucoid exopolysaccharide Pseudomonas aeruginosa immune globulin (MEP IGIV) given over 1 year in reducing the frequency of acute pulmonary exacerbation in patients with cystic fibrosis, mild to moderate pulmonary disease, and mucoid P. aeruginosa colonization. II. Assess the effect of MEP IGIV on FEV1, sputum density of mucoid P. aeruginosa, and the quality of life in these patients. III. Assess the safety of monthly MEP IGIV. IV. Assess population-based MEP IGIV pharmacokinetics during chronic therapy. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004747

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Phase III Randomized Study of the Inhalation of Tobramycin in Patients with Cystic Fibrosis Condition(s): Cystic Fibrosis; Bacterial Infection Study Status: This study is completed. Sponsor(s): FDA Office of Orphan Products Development Purpose - Excerpt: Objectives: I. Determine the safety and efficacy of tobramycin in patients with cystic fibrosis who are chronically colonized with Pseudomonas aeruginosa. II. Determine whether this treatment produces tobramycin-resistant bacteria at a frequency different from the placebo group and whether the emergence of resistance is associated with a lack of clinical response. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004829

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Pilot Study of the Process of Prenatal Genetic Counseling Condition(s): Genetic Counseling; MEDLINEplus consumer health information Study Status: This study is completed. Sponsor(s): National Human Genome Research Institute (NHGRI) Purpose - Excerpt: This study will examine the process of prenatal genetic counseling to determine how various client and counselor factors affect the communication process in

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a counseling session. The specific aims of the study are to: -Provide information on prenatal genetic counselors' interactions with clients for the basis of a future larger study of the genetic counseling process. -Determine the average length and the range of length of prenatal genetic counselors' interactions with clients when family history information has already been provided. -Document on videotape the communication content and interaction dynamics of prenatal genetic counselors interacting with clients in order to: Characterize different models of prenatal genetic counseling -Determine the nature of discussions concerning cystic fibrosis carrier testing within the context of prenatal genetic counseling. -Examine the impact of prenatal genetic counselors' characteristics (years of experience, training and background, age, clinical setting, anxiety) on the communication content and interaction dynamics of sessions with clients. -Examine the impact of the presence of a spouse on the communication content and interaction dynamics of prenatal genetic counseling sessions with clients. -Examine the impact of client verbal emotional cues on the communication content and interaction dynamics of prenatal genetic counseling sessions. Counselors will be recruited for this study from among practicing prenatal genetic counselors at regional meetings and a national meeting of the National Society of Genetic Counselors. They will perform prenatal genetic counseling sessions with actors in the roles of client and client's spouse. The sessions will be videotaped, and the counselor and actors will fill out questionnaires regarding the characteristics of the counselor and the session. Counselors may be contacted later to request permission to use segments of their videotaped sessions for creating a video teaching tool for counseling professionals that illustrates different ways to practice the genetic counseling. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00047905 •

Pressure support ventilation during CF exacerbations Condition(s): Cystic Fibrosis Study Status: This study is suspended. Sponsor(s): National Center for Research Resources (NCRR); Cystic Fibrosis Foundation Purpose - Excerpt: Chest physiotherapy is recognized as a mainstay of cystic fibrosis therapy, and is particularly important during treatment of pulmonary exacerbations. For some patients, especially those with moderate to severe compromise of lung function, this therapy may impose a high demand in the work of breathing and energy expenditure. The goal of this study is to evaluate the effectiveness of adding pressure support ventilation (PSV) during chest physiotherapy sessions in patients with cystic fibrosis with moderate to severe lung function compromise being treated for a pulmonary exacerbation. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00008775

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Quantification of pulmonary neutrophil activity in cystic fibrosis using radiolabeled fluorodeoxyglucose and PET imaging Condition(s): Cystic Fibrosis Study Status: This study is not yet open for patient recruitment.

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Sponsor(s): National Center for Research Resources (NCRR) Purpose - Excerpt: It has been shown that neutrophils (a specific type of cell) are involved in inflammation in the lungs of CF patients. Neutrophil levels in CF patients have been measured by bronchoalveolar lavage (BAL), which samples cells in the fluid lining of the lungs. Other studies have measured neutrophil levels and inflammation in other parts of the body using PET scanning. This study aims to show that PET scanning can be used as a non-invasive marker of inflammation in the lungs of patients with CF, which would be a useful tool in treatment. The primary goal of this study is to draw a connection between the level of inflammation shown in the PET scan and the number of neutrophils obtained from the BAL. This study will also look at how the PET images relate to inflammatory molecules in the lungs and to the FEV-1 obtained through spirometry. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023465 •

Randomized Study of Pancrelipase With Bicarbonate (PANCRECARB) Capsules in Reducing Steatorrhea in Patients With Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); Indiana University School of Medicine Purpose - Excerpt: Objectives: I. Compare the efficacy of enteric coated pancrelipase with bicarbonate (PANCRECARB) capsules versus the patient's usual enteric coated pancreatic enzyme without bicarbonate in decreasing fecal fat and nitrogen losses in patients with cystic fibrosis. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006063

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Study of Ibuprofen to Preserve Lung Function in Patients with Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): FDA Office of Orphan Products Development; Case Western Reserve University Purpose - Excerpt: Objectives: I. Determine the effect of different doses of ibuprofen on neutrophil (polymorphonuclear leukocyte; PMN) delivery to a mucosal surface (the oral mucosa) in patients with cystic fibrosis and healthy controls. II. Determine the duration of effect (and possible rebound effect) of ibuprofen on PMN delivery to a mucosal surface in these patients. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004440

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Study of Interferon gamma-1b by injection for the treatment of patients with cystic fibrosis Condition(s): Cystic Fibrosis Study Status: This study is terminated. Sponsor(s): InterMune Pharmaceuticals Purpose - Excerpt: The purpose of this research study is to evaluate the safety, tolerability, and efficacy of Interferon gamma-1b (IFN-gamma 1b) when administered by subcutaneous injection over a period of 4 weeks to patients with mild-to-moderate cystic fibrosis. Additionally, preliminary assessments on the effects of IFN-gamma 1b on lung function and other indicators of health will be made. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00043342

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Study of Metabolic Effects of Pregnancy in Women With Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is terminated. Sponsor(s): National Center for Research Resources (NCRR); University of Utah Purpose - Excerpt: Objectives: I. Compare the clinical status of pregnant vs nonpregnant women with cystic fibrosis. II. Determine glucose tolerance during each trimester of pregnancy in these women. III. Evaluate peripheral insulin sensitivity in these women. IV. Evaluate whole body protein turnover and hepatic glucose production in these women. V. Determine resting energy expenditure in these women. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00014768

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Study of Uridine Triphosphate (UTP) as an Aerosol Spray for Cystic Fibrosis Condition(s): Cystic Fibrosis Study Status: This study is completed. Sponsor(s): FDA Office of Orphan Products Development; University of North Carolina Purpose - Excerpt: Objectives: I. Determine the stability of uridine triphosphate (UTP) and examine the metabolism of exogenous nucleotides on airway epithelial surfaces in patients with cystic fibrosis. II. Determine the acute safety and efficacy of aerosolized UTP in children with cystic fibrosis. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004705

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Weight Gain in CF Condition(s): Cystic Fibrosis

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Study Status: This study is completed. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The current study examines the efficacy of two treatments to help children with cystic fibrosis (CF) meet their dietary calorie requirements of 120% to 150% of the recommended daily allowance of energy and the effect of these treatments on weight gain and maintenance. One treatment provides children with CF and their parents nutrition education about the best foods for meeting their dietary needs. The second treatment gives children with CF and their families similar nutritional information plus behavioral parenting methods for motivating children to eat the recommended foods. Children with CF and their families are seen weekly for 7 treatment sessions across 9 weeks for the active phase of treatment. Families are then followed for 2 years after treatment in order to better understand how long the treatments are effective and to determine the health benefits of better nutrition status and weight gain. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006169

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “cystic fibrosis” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

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For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

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CHAPTER 6. PATENTS ON CYSTIC FIBROSIS Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “cystic fibrosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cystic fibrosis, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Cystic Fibrosis By performing a patent search focusing on cystic fibrosis, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 9Adapted from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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example of the type of information that you can expect to obtain from a patent search on cystic fibrosis: •

Antibodies specific for cystic fibrosis transmembrane conductance regulator and uses therefor Inventor(s): Rafter; Patrick W. (Natick, MA), Gregory; Richard J. (Ayer, MA), Marshall; John (Milford, MA), Cheng; Seng H. (Bosaton, MA) Assignee(s): Genzyme Corporation (Cambridge, MA) Patent Number: 5,981,714 Date filed: August 15, 1996 Abstract: Antibodies for binding epitopes of cystic fibrosis transmembrane conductance regulator (CFTR) and hybridomas which produce such antibodies are described. The antibodies of the present invention can be used in a method for detecting CFTR in a biological sample and/or in a method for purifying CFTR from an impure solution. In addition, the present invention includes a method for detecting CFTR in a biological sample from a nonhuman cystic fibrosis knockout animal wherein the the nonhuman cystic fibrosis knockout animal has been subjected to human CFTR replacement therapy. Another aspect of the present invention is a method for determining the orientation of CFTR in the membrane of a lipid vesicle. Yet another aspect of the invention is a kit for detecting CFTR in a biological sample. Excerpt(s): Cystic Fibrosis (CF) is the most common fatal genetic disease in humans (Boat, T. et al. Cystic fibrosis. In: The Metabolic Basis of Inherited Disease, C. Scriver, A. Beaudet, W. Sly, and D. Valle, eds. (McGraw Hill, New York, 1989), 2649-2860). Based on both genetic and molecular analysis, a gene associated with CF was isolated as part of 21 individual cDNA clones and its protein product predicted (Kerem, B-S. et al. Science 245:1073-1080 (1989); Riordan, J. et al. Science 245:1066-1073 (1989); Rommens, J. H. et al. Science 245:1059-1065 (1989)).... U.S. Ser. No. 07/488,307, filed Mar. 5, 1990, and now abandoned, describes the construction of the gene into a continuous strand, expression of the gene as a functional protein and confirmation that mutations of the gene are responsible for CF. (See also Gregory, R. J. et al. Nature 347:382-386 (1990); Rich, D. P. et al. Nature 347:358-363 (1990)). The copending patent application also discloses experiments which showed that proteins expressed from wild type but not a mutant version of the cDNA complemented the defect in the cAMP regulated chloride channel shown previously to be characteristic of CF.... The protein product of the CF associated gene is called the cystic fibrosis transmembrane conductance regulator (CFTR) (Riordan, J. et al. Science 245:1066-1073 (1989)). CFTR is a protein of approximately 1480 amino acids made up of two repeated elements, each having six transmembrane segments and a nucleotide binding domain. The two repeats are separated by a large, polar, so-called R-domain containing multiple potential phosphorylation sites. Based on its predicted domain structure, CFTR is a member of a class of related proteins which includes the multi-drug resistant (MDR) P-glycoprotein, bovine adenyl cyclase, the yeast STE6 protein as well as several bacterial amino acid transport proteins (Riordan, J. et al. Science 245:1066-1073 (1989); Hyde, S. C. et al. Nature 346:362-365 (1990). Proteins in this group, characteristically, are involved in pumping molecules into or out of cells. Web site: http://www.delphion.com/details?pn=US05981714__

Patents 347

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Chemical modification of chloride channels as a treatment for cystic fibrosis and other diseases Inventor(s): Cuppoletti; John (University of Cincinnati, Intellectual Property Office, 3233 Eden Ave.,, Cincinnati, OH 45267-0829) Assignee(s): none reported Patent Number: 6,015,828 Date filed: May 23, 1997 Abstract: This invention relates generally to medical treatment methods. Specifically, the invention relates to methodology for the correction of defective chloride transport by activation of chloride channels of the lung and other epithelia using genetic or chemical modification. These methods relate to the treatment of epithelia with compounds which cause activation of the channel as measured by increased probability (Po) of opening of the channel at physiologically relevant holding potentials. These methods also relate to the treatment of epithelia with gene therapy to introduce chloride channels genes with site mutations which cause activation of the channel as measured by increased probability (Po) of opening of the channel at physiologically relevant holding potentials. These treatments will reduce life-threatening complications frequently found in diseases such as cystic fibrosis. These methods of activation of chloride channels also comprise treatment of chloride channels with amidation reactions. Excerpt(s): The research underlying this invention has been supported by one or more of the following grants: CFF RDP R457 to Children's Hospital, Cincinnati, Ohio, NIH DK 43816, NIH DK 43377, and NIH 1P01 51832.... This invention relates generally to medical treatment methods. Specifically, the invention relates to methodology for the correction of defective chloride transport by activation of chloride channels of the lung and other epithelia using genetic or chemical modification. These methods relate to the treatment of epithelia with compounds which cause activation of the channel as measured by increased probability (Po) of opening of the channel at physiologically relevant holding potentials. These methods also relate to the treatment of epithelia with gene therapy to introduce chloride channels genes with site mutations which cause activation of the channel as measured by increased probability (Po) of opening of the channel at physiologically relevant holding potentials. These treatments will reduce lifethreatening complications frequently found in diseases such as cystic fibrosis. These methods of activation of chloride channels also comprise treatment of chloride channels with amidation reactions.... Cystic fibrosis is a lethal disease affecting approximately one in 2,500 live Caucasian births and is the most common autosomal recessive disease in Caucasians. Patients with this disease have reduce chloride ion permeability in the secretory and absorptive cells of organs with epithelial cell linings, including the airways, pancreas, intestine, sweat glands and male genital tract. This, in turn, reduces the transport of water across the epithelia. The lungs and the GI tract are the predominant organ systems affected in this disease and the pathology is characterized by blocking of the respiratory and GI tracts with viscous mucus. The chloride impermeability in affected tissues is due to mutations in a specific chloride channel, the cystic fibrosis transmembrane conductance regulator protein (CFTR), which prevents normal passage of chloride ions through the cell membrane (Welsh et al., Neuron, 8:821829 (1992)). There is no effective treatment for the disease, and therapeutic research is focused on gene therapy and/or activating the defective or other chloride channels in the cell membrane to normalize chloride permeability (Tizzano et al., J. Pediat., 120:337349 (1992)). Damage to the lungs due to mucus blockage, frequent bacterial infections and inflammation is the primary cause of morbidity and mortality in CF patients and,

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although maintenance therapy has improved the quality of patients' lives, the median age at death is still only around 30 years. Web site: http://www.delphion.com/details?pn=US06015828__ •

Composition and methods for alleviating cystic fibrosis Inventor(s): Roy; Claude C. (Quebec, CA) Assignee(s): Universite de Montreal (Montreal, CA) Patent Number: 4,826,679 Date filed: May 23, 1986 Abstract: The invention relates to an oral composition for alleviating digestive manifestations in patients afflicted with cystic fibrosis, which comprises a therapeutic amount of taurine in association with a pharmaceutically acceptable carrier, and to a method of alleviating digestive manifestations in patients afflicted with cystic fibrosis by the administration of said oral composition. Excerpt(s): Cystic fibrosis is an inherited disease of the exocrine glands and exocrine sweat glands which primarily affects the digestive and respiratory systems. This disease usually characterized by chronic respiratory infections, pancreatic insufficiency, abnormally viscid mucuous secretions and premature death.... The main clinical effects of cystic fibrosis are observed in evidence of respiratory tract involvement and pancreatic insufficiency characterized by failure to grow despite an excellent appetite, frequent foul stools and abnormal pancreatic function tests.... As far as the respiratory tract is concerned life expectancy can be improved by preventing pulmonary complications or by treating them early. Treatment includes preventing airway obstruction, as well as controlling infection. Many ways of treating pulmonary complications in patients having cystic fibrosis are known to the medical profession specializing in the treatment of this disease. Web site: http://www.delphion.com/details?pn=US04826679__

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Compositions and methods for cystic fibrosis therapy Inventor(s): Illek; Beate (Albany, CA), Fischer; Horst (Albany, CA) Assignee(s): Children's Hospital Oakland Research Institute (Oakland, CA) Patent Number: 6,329,422 Date filed: October 16, 1998 Abstract: Compositions and methods for therapy of cystic fibrosis and other conditions are provided. The compositions comprise one or more compounds such as flavones and/or isoflavones capable of stimulating chloride transport in epithelial tissues. Therapeutic methods involve the administration (e.g., orally or via inhalation) of such compositions to a patient afflicted with cystic fibrosis and/or another condition responsive to stimulation of chloride transport. Excerpt(s): The present invention relates generally to the treatment of cystic fibrosis. The invention is more particularly related to compositions comprising one or more compounds such as flavones and/or isoflavones, which may be used to activate chloride transport (i.e., absorption and/or secretion) in epithelial tissues of the airways, the

Patents 349

intestine, the pancreas and other exocrine glands, and for cystic fibrosis therapy.... Cystic fibrosis is a lethal genetic disease afflicting approximately 30,000 individuals in the United States. Approximately 1 in 2500 Caucasians is born with the disease, making it the most common lethal, recessively inherited disease in that population.... Cystic fibrosis affects the secretory epithelia of a variety of tissues, altering the transport of water, salt and other solutes into and out of the blood stream. In particular, the ability of epithelial cells in the airways, pancreas and other tissues to transport chloride ions, and accompanying sodium and water, is severely reduced in cystic fibrosis patients, resulting in respiratory, pancreatic and intestinal ailments. The principle clinical manifestation of cystic fibrosis is the resulting respiratory disease, characterized by airway obstruction due to the presence of a thick mucus that is difficult to clear from airway surfaces. This thickened airway liquid contributes to recurrent bacterial infections and progressively impaired respiration, eventually resulting in death. Web site: http://www.delphion.com/details?pn=US06329422__ •

Cystic fibrosis detection method Inventor(s): Shapiro; Burton L. (St. Paul, MN) Assignee(s): The Regents of the University of Minnesota (Minneapolis, MN) Patent Number: 4,273,869 Date filed: April 16, 1979 Abstract: A method of diagnosing cystic fibrosis, identifying carriers for cystic fibrosis, and non-carriers or "normal" persons. Heretofore, no carrier or prenatal detection procedure for cystic fibrosis existed. The detection method is based on the discovery of the genetic abnormality or biochemical defect in cystic fibrosis, which occurs in mitochondria, minute bodies found in the cytoplasma of most cells which are the principal energy source of the cell and contain the cytochrome enzymes of terminal electron transport. The method comprises an assay carried out on preparations derived from human cells possessing mitochondria. The assay may be a kinetic assay of the enzyme complex of the energy conserving site of the mitochondrial electron transport system of the cells or an assay of mitochondrial activity governed by the enzyme complex. The assay is then evaluated by comparison with standards established as the result of similar assays of cells of other subjects of known condition. The assays provide determination of characteristics which differ in the three types of individuals (normal, carrier and affected) and provide a basis for their distinction. Excerpt(s): This invention is directed to an unequivocal method of diagnosing cystic fibrosis, identifying carriers for cystic fibrosis, and non-carriers or "normal" persons.... Cystic fibrosis (CF) is an inherited disease of the exocrine glands, affecting most characteristically the pancreas, respiratory system, and sweat glands. It is transmitted within families as an autosomal recessive trait, affected individuals possessing a double dose of the mutant gene. Biological parents of subjects with CF each possess a single dose of the mutant gene and by definition are obligatory carriers for the condition. Carriers are, however, clinically normal and their detection prior to the birth of an affected child has been precluded by the absence of detectable effects of the gene in single dose. The disease has a 1:4 chance of occurring in a child of either sex if both parents are carriers. It primarily involves Caucasians and usually begins in infancy.... The disease is typified by chronic respiratory infection, pancreatic insufficiency, and susceptibility to heat prostrations. It is a major cause of death in children. It is estimated that there are between ten and twelve million carriers for cystic fibrosis in the United

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States. Eacy year between two and three thousand children are born in the United States who are affected by cystic fibrosis. The cost of therapy for cystic fibrosis patients is estimated at between about $15,000 to $20,000 per year per patient. Of patients diagnosed in early childhood, fewer than fifty percent reach adulthood. Web site: http://www.delphion.com/details?pn=US04273869__ •

Cystic fibrosis gene Inventor(s): Buchwald; Manuel (Toronto, CA), Riordan; John R. (Toronto, CA), Kerem; Bat-Sheva (Toronto, CA), Iannuzzi; Michael C. (Ann Arbor, MI), Collins; Francis S. (Ann Arbor, MI), Lap-Chee; Tsui (Toronto, CA), Rommens; Johanna M. (Willowdale, CA), Drumm; Mitchell L. (Ann Arbor, MI) Assignee(s): The Board of Regents, Acting for and on Behalf of the University of (Ann Arbor, MI), HSC Research Development Corporation (Toronto, CA) Patent Number: 6,201,107 Date filed: June 6, 1995 Abstract: The cystic fibrosis gene and its gene product are described for both the normal and mutant forms. The genetic and protein information is used in developing DNA diagnosis, protein diagnosis, carrier and patient screening, drug and gene therapy, cloning of the gene and manufacture of the protein, and development of cystic fibrosis affected animals. Excerpt(s): The present invention relates generally to the cystic fibrosis (CF) gene, and, more particularly to the identification, isolation and cloning of the DNA sequence corresponding to the normal and mutant CF genes, as well as their transcripts and gene products. The present invention also relates to methods of screening for and detection of CF carriers, CF diagnosis, prenatal CF screening and diagnosis, and gene therapy utilizing recombinant technologies and drug therapy using the information derived from the DNA, protein, and the metabolic function of the cystic fibrosis transmembrane inductance regulator protein (CFTR).... Cystic fibrosis (CF) is the most common severe autosomal recessive genetic disorder in the Caucasian population. It affects approximately 1 in 2000 live births in North America (Boat et al, The Metabolic Basis of Inherited Disease, 6th ed, pp 2649-2680, McGraw Hill, N.Y. (1989)). Approximately 1 in 20 persons are carriers of the disease.... Although the disease was first described in the late 1930's, the basic defect remains unknown. The major symptoms of cystic fibrosis include chronic pulmonary disease, pancreatic exocrine insufficiency, and elevated sweat electrolyte levels. The symptoms are consistent with cystic fibrosis being an exocrine disorder. Although recent advances have been made in the analysis of ion transport across the apical membrane of the epithelium of CF patient cells, it is not clear that the abnormal regulation of chloride channels represents the primary defect in the disease. Given the lack of understanding of the molecular mechanism of the disease, an alternative approach has therefore been taken in an attempt to understand the nature of the molecular defect through direct cloning of the responsible gene on the basis of its chromosomal location. Web site: http://www.delphion.com/details?pn=US06201107__

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Cystic fibrosis tester Inventor(s): Peranich; Larry S. (San Diego, CA) Assignee(s): Borrego Analytical, Inc. (San Diego, CA) Patent Number: 5,525,521 Date filed: June 15, 1995 Abstract: A device and method for testing for Cystic Fibrosis includes a sample cell having a capillary tube with a lumen that will hold approximately five microliters of sweat. The capillary tube has metallic rings around each end of the tube with an RF oscillator attached to one ring and a microprocessor attached to the other. An RF signal, which is transmitted from the RF oscillator through the sweat in the sample cell, is subsequently analyzed at the microprocessor by comparing the transmitted signal to a reference. In accordance with the comparison made by the microprocessor, the presence of Cystic Fibrosis may be detected. Excerpt(s): This invention is in the field of devices which are used to test biological fluids for salinity content. The present invention is particularly, but not exclusively, useful as a test apparatus for determining the salinity content of sweat as an indicator of the presence of cystic fibrosis.... Cystic fibrosis is a genetically transmitted disorder that affects infants, children, and young adults. Specifically, cystic fibrosis involves a dysfunction of the exocrine glands and is characterized by symptoms of chronic pulmonary disease, pancreatic deficiency, and high levels of electrolytes in the sweat of the patient. It is generally fatal, and the majority of deaths occur in victims under the age of twenty-five. One out of approximately every two thousand live births in the United States is afflicted with the disorder.... The pulmonary problems associated with cystic fibrosis result from excessive production of mucous in the respiratory tract. These problems can be treated through long term care or lung transplant and thus, early diagnosis can be beneficial in such cases. The pancreatic damage associated with the disorder can be avoided through the use of recently developed therapies, if diagnosis occurs at an early stage. It is obvious, then, that early diagnosis is crucial. Web site: http://www.delphion.com/details?pn=US05525521__

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Cystic fibrosis therapy Inventor(s): Widdicombe; Jonathan H. (Lafayette, CA), Shen; Ben-Quan (San Francisco, CA), Mrsny; Randall J. (Redwood City, CA) Assignee(s): Children's Hospital Medical Center of Northern California (Oakland, CA), The Regents of the University of California (Oakland, CA), Genentech, Inc. (South San Francisco, CA) Patent Number: 6,033,688 Date filed: September 2, 1997 Abstract: The invention provides methods for treating cystic fibrosis and other pathological conditions in mammals using hepatocyte growth factor ("HGF"). The invention also provides articles of manufacture and kits containing HGF. Excerpt(s): The invention relates generally to methods and compositions which can be employed in treating mammals having pulmonary or respiratory disease, including cystic fibrosis. The invention also relates generally to methods and compositions which can be employed in treating mammals having pathological conditions associated with

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increased Na.sup.+ and fluid absorption by cells.... Various pulmonary and respiratory diseases, such as pneumonia, bronchitis, and cystic fibrosis, are often accompanied by viscous secretions in respiratory airways of the patient. Obstruction of the airways by such secretions can cause respiratory distress, and in some cases, can lead to respiratory failure and death.... Investigators have compared the Na.sup.+ and Cl.sup.- permeability of normal epithelia and epithelia in patients suffering from such diseases described above. [See, e.g., Welsh et al., J. Clin. Invest., 80:1523-1526 (1987)]. Measurements of short-circuit current ("I.sub.sc ") have shown that normal human airway epithelia are predominantly Na.sup.+ absorbing under baseline conditions while Cl.sup.- secretion is relatively small or absent [Smith et al., J. Clin. Invest., 91:1590-1597 (1993)]. Baseline Na.sup.+ absorption, however, is elevated approximately two-fold in cystic fibrosis ("CF") patients [Boucher et al., J. Clin. Invest., 78:1245-1252 (1986)]. Web site: http://www.delphion.com/details?pn=US06033688__ •

Cystic fibrosis transmembrane conductance regulator (CFTR) protein Inventor(s): Li; Canhui (Toronto, CA), Ramjeesingh; Mohabir (Mississauga, CA), Bear; Christine E. (North York, CA), Riordan; John R. (Toronto, CA) Assignee(s): HSC Research & Development Limited Partnership (CA) Patent Number: 5,543,399 Date filed: October 13, 1994 Abstract: A substantially homogeneous protein having cystic fibrosis transmembrane conductance regulator activity is provided. Also provided is a therapeutically effective composition for treating a subject having cystic fibrosis. Excerpt(s): This invention relates to purified and functionally reconstituted preparations of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and to pharmaceutical compositions and methods of use employing these preparations.... The discovery of the gene which is mutated in patients with cystic fibrosis (CF) and the principal disease-causing mutation (Rommens et al., 1989; Riordan et al., 1989; Kerem et al., 1989) has given rise to the possibility of the development of molecular therapies. These can be considered in at least three broad categories: A.) The creation or identification of drugs to appropriately modify CFTR function or biosynthesis; B.) gene therapy by the delivery of the CFTR DNA sequence in an appropriate vector to affected epithelial cells; C.) protein replacement therapy in which the CFTR protein in an appropriate vehicle is delivered to the same cells.... The steps to be accomplished for the effective application of the third strategy 1) the production of large quantities of functional CFTR protein; 2) the solubilization and purification of the CFTR protein; 3) the reconstitution of the homogeneous purified protein into a lipid environment in which it can function; 4) demonstration that the purified and reconstituted CFTR molecule has the same functional properties as it had in the epithelial cells to which it is native; 5) fusion of proteoliposomes containing functional purified CFTR with the apical surfaces of CF epithelial cells expressing nonfunctional mutant CFTR or no CFTR at all in order to restore regulated chloride channel activity. Web site: http://www.delphion.com/details?pn=US05543399__

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Cystic fibrosis treatment Inventor(s): Bedwell; David M. (Birmingham, AL) Assignee(s): UAB Research Foundation (Birmingham, AL) Patent Number: 5,840,702 Date filed: March 22, 1996 Abstract: The present invention provides a method of stimulating expression of a functional full-length cystic fibrosis transmembrane conductance regulator protein in an individual in need of such treatment, comprising the step of administering to said individual a pharmacologically effective dose of an aminoglycoside. Also provided is a method of treating cystic fibrosis in an individual in need of such treatment, comprising the step of administering to said individual a therapeutically effective dose of an aminoglycoside. Further provided is a method of screening for a drug useful in the treatment of an individual having cystic fibrosis, comprising the step of determining said drug's ability to suppress premature stop mutations in a model of cystic fibrosis and a method of pharmacologically suppressing premature stop mutations in an individual having such mutations, comprising the step of administering to said individual a pharmacologically effective dose of an aminoglycoside. Excerpt(s): The present invention relates generally to the fields of molecular genetics and pharmacotherapy of genetic diseases. More specifically, the present invention relates to a novel treatment for cystic fibrosis using aminoglycoside antibiotics.... The process of translation termination has been studied most extensively in E. coli. One of the major factors found to effect the efficiency of translation termination (or conversely, the rate of termination suppression) in E. coli is the local sequence context surrounding the termination codon. The upstream sequence context has been shown to affect the efficiency of translation termination in only a limited number of cases (Feinstein and Altman, 1977; Buckingham et al., 1990; Moffat et al., 1994; Mottagui-Tabar et al., 1994), and a generally accepted model for the role of upstream sequences in this process has not yet emerged. In contrast, the importance of nucleotides distal to the termination codon has been more clearly established. Results from a large number of studies indicate that the nucleotide sequence immediately distal to the termination codon plays an important role in determining the efficiency of translation termination in this prokaryotic organism (Feinstein and Altman, 1977; Bossi and Roth, 1980; EngelbergKulka, 1981; Bossi, 1983; Miller and Albertini, 1983; Ayer and Yarus, 1986; Pedersen and Curran, 1991; Kopelowitz et al., 1992). Consistent with these results, the nucleotide context immediately following known termination codons in both prokaryotic and eukaryotic species is clearly non-random (Brown et al, 1990; Brown et al., 1993). This observation led to the proposal that polypeptide chain release factors may recognize a tetranucleotide (rather than a triplet) termination signal to facilitate polypeptide chain release. A recent analysis of the role of the first nucleotide distal to the termination codon supports the existence of an extended termination sequence in E. coli (Poole et al., 1995).... The importance of the local sequence context in determining the efficiency of translation termination in eukaryotic organisms is much less well characterized, and is derived largely from the study of naturally occurring examples of termination suppression in viral systems. For example, translation of the gag-pol reading frame in Maloney murine leukemia virus depends on the suppression of an in-frame amber termination codon, which normally occurs at a frequency of 5-10% (Yoshinaka et al., 1985). Suppression of translation termination in this system has been shown to be mediated by a distal sequence that includes an RNA pseudoknot (Wills et al., 1991; Feng et al., 1992). Furthermore, this mechanism of suppression does not appear to be codon

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specific, since ochre and opal codons are also suppressed by this sequence context (Feng et al., 1989; Feng et al., 1990). Because readthrough in this system requires a downstream pseudoknot structure, expression of the complete gag-pol reading frame appears to be an example of reprogrammed genetic decoding, or recoding (Gesteland et al., 1992). Recoding occurs when specific sequence elements (such as a pseudoknot) cause normally rare events such as readthrough or frameshifting to occur at a physiologically significant level. In another natural example of the suppression of translation termination, the expression of the RNA replicase of tobacco mosaic virus also depends on the readthrough of an in-frame amber codon (Pelham, 1978). A systematic study of this process in tobacco protoplasts concluded that upstream sequences did not play a significant role in mediating readthrough. However, a nucleotide sequence motif immediately distal to the termination codon having the consensus CARYYA was capable of reducing the efficiency of readthrough (Skuzeski et al., 1991). This distal sequence also reduced the termination efficiency at ochre and opal termination codons. More recently, Tate and co-workers found that the sequence context distal to the stop codon also plays a role in the efficiency of translation termination in human cells, particularly the first nucleotide following the stop codon (McCaughan et al, 1995). Web site: http://www.delphion.com/details?pn=US05840702__ •

Detection of conversion to mucoidy in Pseudomonas aeruginosa infecting cystic fibrosis patients Inventor(s): Martin; Daniel W. (Palo Alto, CA), Deretic; Vojo (San Antonio, TX) Assignee(s): Board of Regents, The University of Texas System (Austin, TX) Patent Number: 6,426,187 Date filed: June 30, 2000 Abstract: Compositions and methods for detecting the conversion to mucoidy in Pseudomonas aeruginosa are disclosed. Chronic respiratory infections with mucoid Pseudomonas aeruginosa are the leading cause of high mortality and morbidity in cystic fibrosis. The initially colonizing strains are nonmucoid but in the cystic fibrosis lung they invariably convert into the mucoid form causing further disease deterioration and poor prognosis. Mucoidy is a critical P. aeruginosa virulence factor in cystic fibrosis that has been associated with biofilm develoment and resistance to phagocytosis. The molecular basis of this conversion to mucoidy is also disclosed. The present invention provides for detecting the switch from nonmucoid to mucoid state as caused by either frameshift deletions and duplications or nonsense changes in the second gene of the cluster, mucA. Inactivation of mucA results in constitutive expression of genes, such as algD, dependent on algU for transcription. Also disclosed is a novel alginate biosynthesis heterologous expression system for use in screening candidate substances that inhibit conversion to mucoidy. Excerpt(s): Cystic Fibrosis (CF) is the most common inheritable lethal disease among Caucasians. There are approximately 25,000 CF patients in the U.S.A. The frequency of CF in several other countries (e.g., Canada, United Kingdom, Denmark) is high (ranging from 1 in 400 to 1 in 1,600 live births). There are numerous CF centers in the U.S.A. and Europe--specialized clinical facilities for diagnosing and treating children and adolescents with CF.... Chronic respiratory infections caused by mucoid Pseudomonas aeruginosa are the leading cause of high morbidity and mortality in CF. The initially colonizing P. aeruginosa strains are nonmucoid but in the CF lung they inevitably convert into the mucoid form. The mucoid coating composed of the exopolysaccharide

Patents 355

alginate leads to the inability of patients to clear the infection, even under aggressive antibiotic therapies. The emergence of the mucoid form of P. aeruginosa is associated with further disease deterioration and poor prognosis.... The microcolony mode of growth of P. aeruginosa, embedded in exopolysaccharide biofilms in the lungs of CF patients (Costerton et al., 1983), among other functions, plays a role in hindering effective opsonization and phagocytosis of P. aeruginosa cells (Pier et al., 1987; Pier 1992). Although CF patients can produce opsonic antibodies against P. aeruginosa antigens, in most cases phagocytic cells cannot effectively interact with such opsonins (Pressler et al., 1992; Pier et al., 1990; Pier 1992). Physical hindrance caused by the exopolysaccharide alginate and a functionally important receptor-opsonin mismatch caused by chronic inflammation and proteolysis are contributing factors to these processes (Pedersen et al., 1990; Tosi et al., 1990; Pier, 1992). Under such circumstances, the ability of P. aeruginosa to produce alginate becomes a critical persistence factor in CF; consequently, selection for alginate overproducing (mucoid) strains predominates in the CF lung. Web site: http://www.delphion.com/details?pn=US06426187__ •

Detection of pancreatitis-associated protein for screening for cystic fibrosis Inventor(s): Sarles; Jacques (Gemenos, FR), Keim; Volker (Heddesheim, DE), Dagorn; Jean-Charles (Marseilles, FR), Iovanna; Juan-Lucio (Marseilles, FR) Assignee(s): Institut National de la Sante et de la Recherche Medicale (Paris, FR) Patent Number: 5,834,214 Date filed: August 30, 1995 Abstract: The invention relates to in vitro detection of human pancreatitis-associated protein (hPAP) for the purpose of screening for cystic fibrosis. hPAP is quantitated in a biological sample, preferably blood, and a high value is indicative of pancreatic dysfunction. Immunoassays as rapid, reliable methods for hPAP quantitation are provided as are antibodies for use in the assays and hybridomas for production of monoclonal antibodies preferred for use in the assays. Excerpt(s): The human pancreatitis-associated protein (PAP) was isolated, purified and characterized in man and described in the PCT patent application published on 31 Oct. 1991 under the No 91/16428. In the earlier application the PAP was suggested as a means for the detection of a specific disease, acute pancreatitis.... Mucoviscidosis, also called "cystic fibrosis" in English is a very frequent genetic disease in certain populations, which is characterized by a global insufficiency of exocrine secretions of the pancreas and the lung and the exocrine glands in general. Clinically, the disease is associated with abnormally viscous secretions, the mucus formed being capable of obstructing the bronchi and causing serious or mortal disorders.... The mucoviscidosis gene has been localized on human chromosome 7. This gene, called the CFTR gene ("cystic fibrosis transmembrane conductance regulator") shows mutations in different regions in the subjects suffering from mucoviscidosis. Mutations of the same type may be detected on only one of the two chromosomes 7 in subjects called "carriers" but not showing clinical signs of the disease. These persons are heterozygous for the mutation in the CFTR gene. Web site: http://www.delphion.com/details?pn=US05834214__

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Diagnostic means for the rapid detection of mucoviscidosis Inventor(s): Emrich; Hinderk M. (Lortzingsstrasse 16, D-8011 Vaterstetten, DE) Assignee(s): none reported Patent Number: 4,163,039 Date filed: January 11, 1978 Abstract: Mucoviscidosis is rapidly detected by determining the sodium or chlorine concentration in the sweat secretions of the subject by diagnostic means comprising an absorbent support impregnated with an indicator substance for indicating sodium or chlorine ions by way of a color change and capable of producing a plainly visible color when the sodium or chlorine ion concentration is at least 50 mval/l of absorption volume, and a transparent envelope which seals in the color indicating substance on all sides of said absorbent support, and which is perforated on one flat side to permit absorption of sweat directly from the skin surface of the subject. Excerpt(s): The invention relates to a diagnostic means which permits the rapid and simple detection of mucoviscidosis (cystic fibrosis of the pancreas).... Mucoviscidosis is a disease whose symptoms are caused by a dysfunction of exocrine glands, in which there is an increase in the viscosity of the mucoid secretions, affecting mainly the excretory cells of the pancreas in addition to the bronchial mucous glands. The secretory disturbances caused by the greatly increased viscosity of the secretion lead to severe disease symptoms. In children suffering from this disease, failure to diagnose it early leads to great danger. Consequently, there is a great need for a means which will permit the rapid diagnosis of mucoviscidosis, and especially which will make possible the routine testing of newborn infants.... A variety of methods for the diagnosis of mucoviscidosis are already known. These methods determine abnormal protein digestion, for example, by what is known as the film digestion test, or the abnormal digestion of fats by means of oily complex compounds. These test methods, however, are expensive and unspecific. Web site: http://www.delphion.com/details?pn=US04163039__

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Epithelial cell line expressing a cystic fibrosis phenotype Inventor(s): Jetten; Anton M. (Durham, NC) Assignee(s): The United States of America as represented by the Secretary of the (Washington, DC) Patent Number: 5,420,033 Date filed: June 21, 1989 Abstract: An airway epithelial cell line (CF/T43) was developed by infecting cultured cystic fibrosis (CF) airway epithelial cells with the pZIPneoSV(X)1/SV40T retrovirus and selecting for Genetian (G418) resistance and ion transport properties. The distinctive chloride secretory phenotype of CF/T43 [an apical membrane chloride permeability (P.sub.cl -) activated by calcium-mediated, but not by adenosine 3',5'-monophosphate (cAMP)-dependent agonists] was not perturbed by SV40T-induced cell transformation. Epithelial cell lines generated from CF cells with the SV40T gene can be used to test candidate CF genes, to evaluate the molecular mechanisms responsible for the CF phenotype and to test putative therapeutic CF drugs.

Patents 357

Excerpt(s): The present invention relates to a transformed epithelial cell line that maintains the abnormal ion transport characteristics of cystic fibrosis while extending the proliferation capability beyond that of a primary epithelial cell culture. Moreover it relates to the testing of putative therapeutic compounds on such transformed cells as well as to applying genetic complementation analysis of candidate cystic fibrosis genes on such transformed cells.... Cystic fibrosis (CF) is an autosomal recessive disease that affects epithelia of the airways, sweat glands, pancreas, and other organs. Abnormal regulation of transport proteins in the apical cell membrane, including the conductive Cl.sup.- channel, is the direct effect of the abnormal gene.... There is a pressing need to develop treatments for CF. Based on what is presently known of the biochemical effects resulting from the genetic defect it may be possible to find compounds that are able to ameliorate the effects of the disease. In the case of many physiological defects therapeutic drugs have been identified using isolated cells for rapid mass screening of candidate drugs. Therefore it would be ideal to have such a screening system for CF. Web site: http://www.delphion.com/details?pn=US05420033__ •

Gene therapy for cystic fibrosis Inventor(s): Smith; Alan E. (Dover, MA), Couture; Larry A. (Louisville, CO), Armentano; Donna (Belmont, MA), Gregory; Richard J. (Westford, MA) Assignee(s): Genzyme Corporation (Cambridge, MA) Patent Number: 6,093,567 Date filed: February 10, 1999 Abstract: Gene Therapy vectors, which are especially useful for cystic fibrosis, and methods for using the vectors are disclosed. Excerpt(s): Cystic Fibrosis (CF) is the most common fatal genetic disease in humans (Boat, T. F. et al. in The Metabolic Basis of Inherited Diseases (Scriver, C. R. et al. eds., McGraw-Hill, New York (1989)). Approximately one in every 2,500 infants in the United States is born with the disease. At the present time, there are approximately 30,000 CF patients in the United States. Despite current standard therapy, the median age of survival is only 26 years. Disease of the pulmonary airways is the major cause of morbidity and is responsible for 95% of the mortality. The first manifestation of lung disease is often a cough, followed by progressive dyspnea. Tenacious sputum becomes purulent because of colonization of Staphylococcus and then with Pseudomonas. Chronic bronchitis and bronchiectasis can be partially treated with current therapy, but the course is punctuated by increasingly frequent exacerbations of the pulmonary disease. As the disease progresses, the patient's activity is progressively limited. Endstage lung disease is heralded by increasing hypoxemia, pulmonary hypertension, and cor pulmonale.... The upper airways of the nose and sinuses are also involved by CF. Most patients with CF develop chronic sinusitis. Nasal polyps occur in 15-20% of patients and are common by the second decade of life. Gastrointestinal problems are also frequent in CF; infants may suffer meconium ileus. Exocrine pancreatic insufficiency, which produces symptoms of malabsorption, is present in the large majority of patients with CF. Males are almost uniformly infertile and fertility is decreased in females.... Based on both genetic and molecular analyses, a gene associated with CF was isolated as part of 21 individual cDNA clones and its protein product predicted (Kerem, B. S. et al. (1989) Science 245:1073-1080; Riordan, J. R. et al. (1989) Science 245:1066-1073; Rommens, J. M. et al. (1989) Science 245:1059-1065)). U.S. Ser. No. 07/488,307 describes the construction of the gene into a continuous strand, expression of

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the gene as a functional protein and confirmation that mutations of the gene are responsible for CF. (See also Gregory, R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362). The co-pending patent application also discloses experiments which show that proteins expressed from wild type but not a mutant version of the cDNA complemented the defect in the cAMP regulated chloride channel shown previously to be characteristic of CF. Web site: http://www.delphion.com/details?pn=US06093567__ •

Genistein for the treatment of cystic fibrosis Inventor(s): Clarke; Lane L. (Columbia, MO), Cohn; Leah A. (Columbia, MO), Konig; Peter (Columbia, MO), Smith; Arnold L. (Columbia, MO), Hwang; Tzyh-Chang (Columbia, MO), Price; Elmer M. (Hartsburg, MO) Assignee(s): The Curators of the University of Missouri (Columbia, MO) Patent Number: 5,948,814 Date filed: February 20, 1998 Abstract: A method of treating cystic fibrosis by generating cystic fibrosis transmembrane conductance regulator (CFTR) function in cells containing mutant CFTR and the therapeutic composition for treatment are described. The method of treatment comprising administering an effective amount of genistein, or genistein analogues and derivatives, to a person afflicted with cystic fibrosis. Excerpt(s): The present invention relates to a therapeutic treatment for cystic fibrosis, particularly to the restoration of chloride channel function caused by mutations in the protein designated Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).... Cystic fibrosis (CF) is the most common fatal genetic disease among persons of Caucasian origin. The frequency of the disease in this population is approximately 1 in 2500 live births ›Boat et al., 1989!, which translates into a carrier frequency of approximately 1 in 25. CF is associated with a wide-spread defect in the secretory processes of all secretory epithelia. Patients with CF, who rarely live for more than 30 years, exhibit abnormalities in a variety of respiratory, gastrointestinal and genitourinary tract systems, as well as elevated sweat electrolyte concentrations. Patients with CF exhibit abnormally viscid mucous secretions that block the airways and the pancreatic ducts. The blockage of the airways and pancreatic ducts are responsible for the two most clinically important manifestations of CF, that being chronic pulmonary infection and pancreatic insufficiency. The damage to the pancreas resulting in over 80% pancreatic insufficiency occurs in utero.... The above manifestations appear related to abnormal ion transport in the secretory epithelia of the affected organ ›Quinton, 1983; Knowles et al., 1983; Frizzell et al., 1986; Boucher et al., 1986; Quinton, 1990!. This was shown in the identification of reduced chloride permeability in isolated sweat ducts and nasal epithelia of patients with CF. This observation led to the conclusion that a fundamental defect in the transport of chloride (Cl) ions, and possibly other ions, across epithelial cells must exist. Web site: http://www.delphion.com/details?pn=US05948814__

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Introns and exons of the cystic fibrosis gene and mutations thereof Inventor(s): Tsui; Lap-Chee (Toronto, CA), Rommens; Johanna M. (Willowdale, CA), Kerem; Bat-sheva (Jerusalem, IL) Assignee(s): HSC Research Development Corporation (Toronto, CA) Patent Number: 6,001,588 Date filed: July 13, 1992 Abstract: The identification, isolation and cloning of DNA sequences coding for mutant forms of the cystic fibrosis gene and their gene product are described. DNA sequence information and information relating to the genomic structure of the cystic fibrosis gene are provided. The mutant forms of the CF gene include specific sequence alterations in coding portions or of other genetic information at exon/intron boundaries and altered RNA transcripts and mutant protein products. Such DNA and protein information is useful in developing DNA or protein diagnosis for CF mutations, carrier and patient screening, as well as cloning of mutant genes and manufacturing of their proteins for investigation into therapies for cystic fibrosis. Excerpt(s): The present invention relates generally to the cystic fibrosis (CF) gene, and, more particularly to the identification, isolation and cloning of the DNA sequence corresponding to mutants of the CF gene, as well as their transcripts, gene products and genetic information at exon/intron boundaries. The present invention also relates to methods of screening for and detection of CF carriers, CF diagnosis, prenatal CF screening and diagnosis, and gene therapy utilizing recombinant technologies and drug therapy using the information derived from the DNA, protein, and the metabolic function of the protein.... Cystic fibrosis (CF) is the most common severe autosomal recessive genetic disorder in the Caucasian population. It affects approximately 1 in 2000 live births in North America [Boat et al, The Metabolic Basis of Inherited Disease, 6th ed, pp 2649-2680, McGraw Hill, NY (1989)]. Approximately 1 in 20 persons are carriers of the disease.... Although the disease was first described in the late 1930's, the basic defect remains unknown. The major symptoms of cystic fibrosis include chronic pulmonary disease, pancreatic exocrine insufficiency, and elevated sweat electrolyte levels. The symptoms are consistent with cystic fibrosis being an exocrine disorder. Although recent advances have been made in the analysis of ion transport across the apical membrane of the epithelium of CF patient cells, it is not clear that the abnormal regulation of chloride channels represents the primary defect in the disease. Given the lack of understanding of the molecular mechanism of the disease, an alternative approach has therefore been taken in an attempt to understand the nature of the molecular defect through direct cloning of the responsible gene on the basis of its chromosomal location. Web site: http://www.delphion.com/details?pn=US06001588__

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Macroscopic sweat test for cystic fibrosis Inventor(s): Zeitlin; Pamela Leslie (Baltimore, MD), Rubenstein; Ronald Craig (Ardmore, PA) Assignee(s): Johns Hopkins University (Baltimore, MD) Patent Number: 5,976,499 Date filed: September 4, 1998

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Abstract: The present invention relates to methods of diagnosing CF comprising: stimulating sweat production via.beta.-adrenergic pathway, by increasing cAMP production; collecting sweat into a sweat collection device; determining the sweat rate as a function of the weight of the sweat collected; correlating the sweat rate with the functional state of CFTR and/or presence or absence of CF. The invention also relates to methods of screening compounds for treatment of cystic fibrosis. Excerpt(s): This invention relates to methods for discriminating between fully functional, partially functional and non-functional forms of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). More particularly, this invention relates to a macroscopic cyclic-AMP (cAMP)-stimulated "sweat rate" test that will discriminate between fully functional, partially functional, and non-functional forms of CFTR.... Cystic fibrosis (CF) is one of the most common genetic diseases among Caucasians and is a contributing factor in causing suffering among children and adults. CF affects the mucus-producing glands and other exocrine glands in the body. The gene encoding CFTR, the absence of function of which is responsible for causing CF, is located on chromosome 7q. Lack of CFTR function causes abnormal mucus production in the respiratory and gastrointestinal tracts and abnormal sweat gland function. Clinically, CF is characterized by chronic respiratory infections and obstructive lung disease, pancreatic gland insufficiency leading to an inability to digest fats, male infertility and abnormally high levels of electrolytes in the sweat.... Sweat production is stimulated through two pathways: the cholinergic pathway and by the adrenergic/sympathetic pathway (i.e., fight or flight response). Thus, sweat production can be stimulated by both cholinergic and adrenergic agonists. Collection of cholinergic stimulated sweat, using the cholinergic agonist pilocarpine, and the subsequent measurement of sweat chloride concentration is the basis of a standard diagnostic test for cystic fibrosis (CF), the pilocarpine iontophoresis sweat test. Stimulation of sweat production with pilocarpine leads to initial production of an isotonic secretion in the sweat gland. In non-CF patients, as the secretion traverses the sweat duct, chloride is reabsorbed. This leads to low concentration of chloride in sweat as it appears on the skin. This chloride resorption is dependent on the presence of functional CFTR. In CF patients, who lack functional CFTR, the sweat chloride concentration remains high, and distinguishes most, but not all, CF from non-CF patients. However, this technique does not distinguish heterozygote carriers of CFTR mutations from non-carriers, nor does the sweat chloride concentration correlate with disease severity. Furthermore, the pilocarpine iontophoresis sweat test involves the use of a sweat test apparatus consisting of electrodes and a voltage source and the use of specially trained personnel. These methods require the elution of the sweat electrolytes collected on the pads and determination of chloride content of the sweat. While this method remains the "gold standard", it occasionally yields ambiguous results. Therefore, it would be useful to have an alternative method of diagnosing CF. Web site: http://www.delphion.com/details?pn=US05976499__ •

Method and composition for treating cystic fibrosis Inventor(s): McCracken; John D. (Redlands, CA), Wechter; William J. (Redlands, CA) Assignee(s): Loma Linda University Medical Center (Loma Linda, CA) Patent Number: 5,981,592 Date filed: April 9, 1998

Patents 361

Abstract: A composition for use in preventing colorectal cancer and other neoplastic diseases, such as breast cancer, includes an enantiomerically stable R-NSAID or a pharmaceutically acceptable salt thereof in an amount effective to elicit a chemoprotective effect. The composition is substantially free of the S-enantiomer of the R-NSAID. Therapeutic use of the composition is accompanied by reduced adverse side effects. A method of treating cystic fibrosis likewise includes the step of administering to a patient in need of such treatment a composition having an effective cystic fibrosis therapeutic amount of an enantiomerically stable R-NSAID or a pharmaceutically acceptable salt thereof, the composition being substantially free of the S-enantiomer of the selected R-NSAID. Excerpt(s): The present invention relates to compositions and methods useful in the treatment and prevention of neoplastic diseases, such as colorectal and other gastrointestinal epithelial cancers as well as breast cancer and other cancers, and also useful in the treatment of cystic fibrosis.... Cancer of the colon is common in the western world and is an important cause of morbidity and mortality, having an incidence of about 5% in the U.S. population. As with other types of cancers, cancers of the gastrointestinal tract, including colon cancer, are characterized by abnormal development in cell proliferation and differentiation in the gastrointestinal tract.... The gastrointestinal tract, including the rectum and colon, is lined with epithelial cells which have a high proliferation rate. The lining of the colon, in particular, made up of columnar rows of epithelial cells, is characterized by a series of indentations or crypts. Epithelial cells in the bottom regions of the crypts proliferate and move upward toward the tops of the crypts. In the normal colon, the proliferation region of the large intestine normally occupies the basal or deeper three-quarters of the crypts. A relationship has been observed between the expansion of cell proliferation zones to the upper regions of the crypts and colon cancer. See M. Lipkin, "Biomarkers of Increased Susceptibility to Gastrointestinal Cancer: New Application to Studies of Cancer Prevention in Human Subjects," Cancer Research, Vol. 48, pp. 235-245 (Jan. 15, 1988). Web site: http://www.delphion.com/details?pn=US05981592__ •

Method and formulations for the therapy of cystic fibrosis, Bartter's syndrome and secretory diarrheas, and for diuretic treatment Inventor(s): Kelepouris; Ellie (Merion, PA), Agus; Zalman S. (Cherry Hill, NJ), Morad; Martin (Philadelphia, PA) Assignee(s): The Trustees of the University of Pennsylvania (Philadelphia, PA) Patent Number: 5,100,647 Date filed: October 2, 1990 Abstract: Methods for the therapy of cystic fibrosis, Bartter's syndrome, and secretory diarrheas, and for diuretic treatment, by administering to a patient dodecahydro-7,14methano-2H,6H-di-pyrido[1,2-a:1',2'-e][1,5]diazocine or a pharmaceutically acceptable derivative thereof are disclosed. The formulations include an aerosol formulation comprising the active ingredient in association with an aerosol propellant. Excerpt(s): The present invention relates to methods and formulations for the therapy of cystic fibrosis, Bartter's syndrome and secretory diarrheas such as cholera, and for diuretic treatment.... Cystic fibrosis: This is a congenital disease for which an accurate diagnosis has long been available. Historically, a midwife would lick the forehead of a newborn. If the sweat tasted abnormally salty, the infant was destined to die of

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pulmonary congestion and its side effects. Today, cystic fibrosis remains the most common lethal congenital disease among caucasians where it has a prevalence of about of about 1 in 2,000 live births.... Cystic fibrosis is a disease of secretory epithelia, tissues that mediate the transport of water, salt, and other solutes between the blood and the outside world. Epithelial cells exhibit anatomical and functional polarity. The basolateral membrane, which faces the blood, and the apical membrane, which faces the lumen (the outside world) mediate different transport events. Together they give rise to net chloride transport across the epithelium from blood to lumen. Web site: http://www.delphion.com/details?pn=US05100647__ •

Method for the treatment of cystic fibrosis Inventor(s): Macias; William Louis (Indianapolis, IN) Assignee(s): Eli Lilly and Company (Indianapolis, IN) Patent Number: 6,576,654 Date filed: March 8, 2000 Abstract: A method is disclosed for the treatment of cystic fibrosis by administering to a human in need thereof a therapeutically effective amount of an sPLA.sub.2 inhibitor, such as a 1H-indole-3-glyoxylamide. Excerpt(s): The present invention is directed to a method for treating cystic fibrosis. More specifically, the present invention is directed to a method for treating the symptoms of cystic fibrosis by administering a therapeutically effective amount of an sPLA.sub.2 inhibitor.... Cystic fibrosis is a hereditary disorder of the lungs, digestive, and reproductive systems. One in 2500 people in the general population in America are born with cystic fibrosis. It typically appears in early childhood and is a lifelong illness that generally gets more severe with age. Average life expectancy and quality of life are significantly reduced. There is no cure for cystic fibrosis at this time.... In cystic fibrosis the glands which produce mucus, saliva, and intestinal fluids do not work properly. Thick mucus in the lungs interferes with removal of pollutants and can cause breathing problems, infections, and lung damage. Thick secretions also may clog the pancreatic duct and block transfer of enzymes from the pancreas to the intestine. These enzymes help break down food so the body has proper growth and weight gain. Web site: http://www.delphion.com/details?pn=US06576654__

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Method for treating cystic fibrosis Inventor(s): Rothstein; David M. (Lexington, MA), Spacciapoli; Peter (Newbury, MA), Friden; Phillip M. (Bedford, MA) Assignee(s): Demegen, Inc. (Pittsburgh, PA) Patent Number: 6,528,488 Date filed: January 8, 1999 Abstract: Methods for treating cystic fibrosis in a mammal that include administering to the mammal an effective amount of a histatin, a histatin fragment, or a histatin-related peptide are disclosed.

Patents 363

Excerpt(s): The invention relates to methods for treating cystic fibrosis.... Cystic fibrosis is a hereditary disease that affects a number of organs, particularly the lungs and pancreas. The exocrine glands of a cystic fibrosis patient secrete abnormally thick mucous, which blocks the patient's bronchi. As a result, many cystic fibrosis patients have chronic bronchitis; they are also susceptible to pneumonia and other pulmonary infections. In particular, cystic fibrosis patients are susceptible to Pseudomonas infections.... As there is currently no cure for cystic fibrosis, treatments for this disabling disease focus on alleviating the symptoms of the disease. Unfortunately, the infections of many cystic fibrosis patients do not respond to the antibiotics traditionally used to treat pulmonary infections. Web site: http://www.delphion.com/details?pn=US06528488__ •

Method for treating mucoviscidosis and chronic pain syndromes deriving from degenerative locomotor diseases Inventor(s): Beres, Jr. Jozsef (Budapest, HU), Beres; Jozsef (Kisvarda, HU) Assignee(s): Beres Export-Import Rt. (Budapest, HU) Patent Number: 5,312,629 Date filed: July 26, 1991 Abstract: The pharmaceutical composition according to the invention consists essentially of:i) one or more, pharmaceutically acceptable, water soluble compounds of boron, fluorine, magnesium, vanadium, manganese, iron, cobalt, nickel, copper, zinc and molybdenum, which compounds do not precipitate with each other or with the other components of the composition and exhibit a neutral or acidic pH in an aqueous medium;ii) glycine;iii) glycerol;iv) L-(+)-ascorbic acid;v) succinic acid;vi) a neutral or acidic and water-soluble, pharmaceutically acceptable salt of ethylenediamine tetraacetic acid;vii) potassium sodium tartrate; andviii) L-(+)-tartaric acid. The composition can be used for the treatment of mucoviscidosis and chronic pain syndromes deriving from locomotor diseases or accompanying diseases of tumorous origin. Excerpt(s): The present invention relates to a pharmaceutical composition suitable for influencing the reticuloendothelic system and for treating mucoviscidosis an& chronic pain syndromes deriving from degenerative locomotor diseases or accompanying diseases of tumorous origin, and a process for preparing the same.... vii) potassium sodium tartrate; and the weight ratio of the boron compound : fluorine compound : magnesium compound : vanadium compound : manganese compound : iron compound : cobalt compound : nickel compound : copper compound zinc compound : molybdenum compound : glycine : glycerol: L-(+)-ascorbic acid: 2,4,5,7tetrahalofluorescein salt: ethylenediaminetetraacetic acid salt: potassium sodium tartrate is 0.01-1:0.02-1:0.4-3:0.02-0.6:0.1-2:1-6:0.1-1:0.02-2:0.05-1:1:0.1-3:0.01-0. 8:0.1-2:2-8:0.012:0.003-0.5:0.1-3:0.7-10.... The said composition is prepared by dissolving the components in aqueous medium, mixing the same with pharmaceutically acceptable carriers, diluents and/or excipients, then transforming the mixture thus obtained into a pharmaceutical composition in a manner known per se. Web site: http://www.delphion.com/details?pn=US05312629__

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Method of determining cystic fibrosis ciliostatic factor Inventor(s): Nix; Paul T. (Jackson, NJ), Kelleher; Thomas J. (Springlake Heights, NJ) Assignee(s): CooperBiomedical, Inc. (Malvern, PA) Patent Number: 4,673,633 Date filed: June 28, 1984 Abstract: A method for detecting the presence of cystic fibrosis ciliostatic factor in mammalian body fluid comprisescontacting an enzyme whose activity is inhibited by the factor with a substrate for the enzyme in the presence of the body fluid, the substrate being substantially resistant to reactions catalyzed by enzymes in the body fluid, whereby the substrate is converted by the enzyme at a measurable rate, andcomparing the rate of substrate conversion with the rate of substrate conversion by the enzyme in the absence of cystic fibrosis ciliostatic factor. Excerpt(s): Cystic fibrosis (CF) is a debilitating genetic disease characterized by abnormalities of secretory organs in the body The disease is the most common lethal genetic disease of Caucasian children, and those individuals who are diagnosed as having CF usually die before the age of twenty-five. The basic genetic defect and its mode of operation are unknown, but the defective gene is relatively common in the Causasian population, about 5% of the populace being heterozygous carriers. Since the inheritance follows the typical autosomal recessive pattern, CF homozygotes express the gene and exhibit symptoms of the disease, while CF heterozygotes are carriers of the gene but do not have symptoms of the disease.... Because the disease is life-threatening, therapy is essential. Accordingly, an accurate and reliable method of diagnosis is very important. However, the clinical picture of the disease is highly variable and clinical findings alone cannot be relied on for diagnosis. A summary of various biochemical tests for CF is found in Heeley, A. F., et al, Clin. Chem. 29, 2011-2018 (1983). The most frequently used method for CF diagnosis at present is the "sweat test", in which CF homozygotes show increased concentration of NaCl in their sweat caused by malreabsorption of salt. At present, there is no test for CF heterozygotes.... Other biochemical tests for CF have been based on the finding that the body fluids (blood, urine, saliva, etc.) of CF positive individuals have been found to contain abnormal substances. One of such substances which has been found to be a useful marker for cystic fibrosis is ciliostatic factor. Web site: http://www.delphion.com/details?pn=US04673633__

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Method of diagnosing cystic fibrosis patients and asymptomatic carrier of the cystic fibrosis gene Inventor(s): Wilson; Gregory B. (2706 Cameron Blvd., Isle of Palms, SC 29451), Fudenberg; H. Hugh (9 Second Ave., Isle of Palms, SC 29451) Assignee(s): none reported Patent Number: 4,322,274 Date filed: August 28, 1980 Abstract: An immunologic method has been devised enabling diagnosis of patients with cystic fibrosis, as well as asymptomatic carriers of the cystic fibrosis gene. Mono-specific antibody to Cystic Fibrosis Protein (CFP) is inserted into a first position on an electrophoresis plate. A body fluid from the subject to be tested is placed into a second

Patents 365

position on the plate. An electrical potential is imposed across the positions with the anode being adjacent to the section containing the serum and the cathode being adjacent to the section containing the antibody. The presence of Cystic Fibrosis Protein is indicated by one or more precipitation zones forming where the body fluid proteins meet the antibody due to movement induced by an applied electrical potential. The relative position of the precipitation zone between the first and second positions, or the area of the precipitation zone, indicates a concentration of the Cystic Fibrosis Protein. Methods for producing the purified Cystic Fibrosis Protein antibody and for purifying the Cystic Fibrosis Protein itself are also disclosed. Excerpt(s): In our article in Pediatric Research, Volume 12, pages 801-804 (1978), we discussed the possibility that individuals who possess two defective genes causing them to be victims of cystic fibrosis, or asymptomatic genetic carriers having one abnormal gene produce a unique protein termed "Cystic Fibrosis Protein" (CEP). This CFP can be isolated using isoelectric focusing in thin layer polyacrylamide gels as described in the publication by Wilson, Jahn and Fonesca, Clin. Chim. Acta, Volume 49, page 79 (1973); G. B. Wilson et al. Pediatric Research, 9:635 (1975); and G. B. Wilson et al. Pediatric Research, 11:986 (1977). The Cystic Fibrosis Protein is characterized as a protein with an isoelectric point (pI) of 8.46.+-.0.05, and is found in more than 90 percent of individuals tested who are homozygous and heterozygous for the cystic fibrosis gene. However, the Cystic Fibrosis Protein is absent from 92 percent of normal control subjects tested under standardized and controlled conditions.... In accordance with this invention, a method is provided for diagnosing cystic fibrosis in patients and also diagnosing asymptomatic carriers of the cystic fibrosis gene, based upon the detection of Cystic Fibrosis Protein in the blood plasma or serum of patients. Frequently it has been found that the test of this invention can distinguish between those actively suffering from cystic fibrosis and asymptomatic carriers by the concentration of Cystic Fibrosis Protein present in the serum, as determined by the method of this invention.... Furthermore, it is preferred in the method of this invention to utilize a monospecific antibody to Cystic Fibrosis Protein. Methods are described herein for obtaining antibody to Cystic Fibrosis Protein and particularly highly purified, monospecific antibody formulations. Web site: http://www.delphion.com/details?pn=US04322274__ •

Method of mucociliary clearance in cystic fibrosis patients using alkylaryl polyether alcohol polymers Inventor(s): Kennedy; Thomas P. (Richmond, VA), Piantadcsi; Claude A. (Durham, NC), Ghio; Andrew J. (Durham, NC) Assignee(s): Duke University (Durham, NC) Patent Number: 5,830,436 Date filed: March 30, 1995 Abstract: A method and medicament for the inhibition of oxidants comprising administering a treatment effective amount of alkylaryl polyether alcohol polymers to a chemical or biologic system in need thereof. Also, a method and medicament for mucociliary clearance, inhibition of cytokine production, and inhibition of interleukin-8 production in cystic fibrosis patients. The method involves administering a treatment effective amount of alkylaryl polyether alcohol polymers to a chemical or biologic system in need thereof. The medicament is preferably administered by aerosolization into the mammalian respiratory system. The medicament may also be applied to the mammalian skin. Preferably, the medicament includes a physiologically acceptable

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carrier which may be selected from the group consisting of physiologically buffered saline, isotonic saline, normal saline, petrolatum based ointments and U.S.P. cold cream. Excerpt(s): The invention in the present Continuation-in-Part relates, in general, to cystic fibrosis, the most common lethal recessive genetic disease in the United States. Cystic fibrosis is characterized by abundant production in a cystic fibrosis patient of thick, tenacious, purulent airway secretions. These secretions are difficult to clear, even with physiotherapy, and hence, obstruct airways and contribute greatly to the progression of obstructive lung disease by stagnating the inflammatory process within airways.... More particularly, the invention in the present Continuation-in-Part relates to use of alkylaryl polyether alcohol polymers, particularly tyloxapol, as mucolytic agents for breaking up cystic fibrosis sputum or mucous in patients with cystic fibrosis, as inhibitors of monocyte tumor necrosis factor secretion in patients with cystic fibrosis, and as inhibitors of production of interleukin-8 by patients with cystic fibrosis.... The parent applications of the present Continuation-in-Part, namely, U.S. Ser. No. 08/219,770 now U.S. Pat. No. 5,474,760 issued Dec. 12, 1995 and U.S. Ser. No. 08/039,732, now abandoned relate to use of alkylaryl polyether alcohol polymers as antioxidants to suppress certain oxidant chemical reactions that cause tissue injury and disease in mammals and plants. Web site: http://www.delphion.com/details?pn=US05830436__ •

Method of testing potential cystic fibrosis treating compounds using cells in culture Inventor(s): Dawson; David C. (Ann Arbor, MI), Collins; Francis S. (Ann Arbor, MI), Wilkinson; Daniel J. (Ypsilanti, MI), Drumm; Mitchell L. (Ann Arbor, MI) Assignee(s): The Regents of the University of Michigan (Ann Arbor, MI) Patent Number: 5,434,086 Date filed: December 9, 1993 Abstract: Cystic fibrosis (CF), a lethal genetic disease associated with a defect in Cl transport, is caused by mutations in the gene coding for cystic fibrosis transmembrane conductance regulator (CFTR). Surprisingly, not only wild type CFTR, but several naturally-occurring CFTR mutants carrying a defect in the first nucleotide binding fold (NFB1) all expressed cAMP-activatable Cl currents. Treatment of the CFTR mutants with appropriate concentrations of methylxanthine phosphodiesterase inhibitor (which increases cAMP levels) activated Cl conductance to near wild type levels. The present invention thus provides a new avenue for treating cystic fibrosis by the administration of therapeutically effective amounts of compounds which elevate cAMP levels. Dosage and patient responsiveness to treatment, as well as relative efficacies of the compounds being or to be administered can also be determined in accordance with the methods of present invention. Excerpt(s): The present invention relates generally to the treatment of chloride secretion insufficiencies caused by defects in cystic fibrosis transmembrane conductance regulator (CFTR) with compounds which increase or supplement cyclic AMP (cAMP)levels and, more specifically, to the treatment of cystic fibrosis (CF) with therapeutically effective amounts of phosphodiesterase inhibitors such as methylxanthines.... Cystic fibrosis (CF) is the most common lethal autosomal recessive disease among Caucasians, affecting nearly 1 in 2500 newborns. Boat et al., Metabolic Basis of Inherited Disease. (McGrawHill, N.Y. 1989) 2649-2680. CF is caused by mutations in the gene coding for cystic fibrosis transmembrane conductance regulator (CFTR), a 1480 amino acid protein which

Patents 367

has been associated with the expression of chloride conductance in a variety of eukaryotic cell types. See Rommens et al., Science 245:1059 (1989); Riorden et al., Science 245:1066 (1989); Kerem et al., Science 245:1073 (1989); Drumm et al., Cell 64:681 (1991); Kartner et al., Cell 64:681 (1991); Gregory et al., Nature 347:382 (1990); Rich et al., Nature 347:358 (1990); Rommens et al., PNAS (USA) 88:7500 (1991). Defects in CFTR destroy or reduce the ability of epithelial cells in the airways, sweat glands, pancreas and other tissues to secret CI in response to cAMP-mediated agonists and impair activation of apical membrane channels by cAMP-dependent protein kinase A (PKA). See Frizell et al., Trends Neurosci 10:190 (1987); Welsh, FASEB J. 4:2718 (1990).... Although over 100 different mutations have been identified in the CFTR gene, a single NBF1 mutation, the deletion of phenylalanine 508 (.DELTA.F508), accounts for almost 70% of the CF alleles in the population. Kerem et al., Science 245:1073 (1989); The Cystic Fibrosis Genetic Analysis Consortium, Am. J. Hum. Genet. (1990). Patients homozygous for the.DELTA.F508 mutation present a similar clinical picture, including elevated sweat chloride levels, chronic pulmonary disease, and pancreatic insufficiency and are generally classified as severely affected. Kerem et al., N. Engl. J. Med. 323:1 51 7 (1990). The clinical profiles of patients carrying other mutations, however, show a broad spectrum of severity. Kerem et al., N. Engl. J. Med. 323:1517 (1990); Cutting et al., Nature 346:366 (1990); Osborne et al., Am. J. Hum. Genet. 48:608 (1990); White et al., Nature 344:665 (1990); Iannuzi et al., Am. J. Hum. Genet. 48:226 (1991). Web site: http://www.delphion.com/details?pn=US05434086__ •

Method of treating cystic fibrosis Inventor(s): Jacobson; Kenneth A. (11606 Fulham St., Silver Spring, MD 20903), Pollard; Harvey B. (11008 Lamplighter La., Potomac, MD 20854) Assignee(s): none reported Patent Number: 6,083,954 Date filed: July 13, 1998 Abstract: The present invention provides a method of identifying CFTR-binding compounds for treating cells having a reduced apical Cl.sup.- conductance, such as cystic fibrosis cells. This identification method involves the use of polypeptide I.alpha., which constitutes a portion of the CFTR protein. The present invention also provides a method of treating CF cells by contacting cells having a reduced apical Cl.sup.conductance with a therapeutically effective quantity of a compound selected by the present inventive identification method. Preferred compounds for such treatment have little or no affinity for adenosine cell receptors. The present invention provides novel compounds useful in practicing the present inventive method, as well as pharmaceutical compositions containing such compounds. Excerpt(s): The present invention relates to a method of identifying CFTR-binding compounds for treating cells having a reduced apical Cl.sup.- conductance, such as cystic fibrosis cells. The present invention further relates to compounds and pharmaceutical compositions thereof useful in treating such cells.... Healthy animal cells require, among other conditions and materials, the movement of various inorganic ions across the cell membrane to be maintained such that a proper balance of the ions provide the requisite electrical potential across the cellular membrane as well as a lifepromoting internal ionic strength. For example, Na.sup.+, Cl.sup.-, K.sup.+, and Ca.sup.++ are known to cross cell membranes in animals such that K.sup.+ and Ca.sup.++ are accumulated intracellularly to a varying extent in different cells at

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different times of development, whereas Na.sup.+, in large measure, is excluded from the interior of a cell. The cross-cellular movement of these ions is mediated by Na.sup.+ /K.sup.+ - and Ca.sup.++ -dependent ATPases that are membrane bound at the sites of appropriate ion channels. Chloride ion was believed to permeate animal cells by passive means to equilibrate in concentration between the external and internal fluid, resulting in an underrepresentation of Cl.sup.- intracellularly in consequence of the overall negative intracellular change. Conductance of chloride, however, has been shown to be mediated actively as well, by means of a Cl.sup.- channel (see Edwards, Neuroscience, 7, 1335-1366 (1982)).... Results from research directed to the pathology of cystic fibrosis ("CF") has provided information on the ill-effects that an ion conductance impairment at the cellular level can have on a person's health, at many levels. CF was known to have a genetic basis because of its differential incidence among white Americans (between 1/1600 and 1/2000 live births) as compared to African Americans (about 1/17,000 live births). Indeed, research over the past decade has revealed that a heritable discrete gene mutation is associated with the clinical symptoms of CF, including abnormal exocrine gland and lung functions. Web site: http://www.delphion.com/details?pn=US06083954__ •

Method of treating cystic fibrosis using 8-cyclopentyl-1,3-dipropylxanthine or xanthine amino congeners Inventor(s): Jacobson; Kenneth A. (Silver Spring, MD), Pollard; Harvey B. (Potomac, MD), van Galen; Philip J. M. (Rockville, MD) Assignee(s): The United States of America, as represented by the Department of Health (Washington, DC) Patent Number: 5,366,977 Date filed: September 29, 1992 Abstract: A method of treating cells having a reduced apical Cl.sup.- conductance, such as that characteristic of cystic fibrosis cells, by contacting cells having a reduced apical Cl.sup.- conductance with a therapeutically effective quantity of a compound that antagonizes the A.sub.1 -adenosine cell receptor and does not antagonize the A.sub.2 adenosine cell receptor. Suitable compounds include 8-cyclopentyl-1,3-dipropylxanthine (CPX), xanthine amino congener (XAC), and therapeutically effective derivatives thereof. Excerpt(s): The present invention relates to a method of treating cells having a reduced apical Cl.sup.- conductance, such as cystic fibrosis cells. Specifically, the present inventive method involves contacting cells having a reduced apical Cl.sup.conductance with a therapeutically effective quantity of a compound that antagonizes the A.sub.1 -adenosine cell receptor and does not antagonize the A.sub.2 -adenosine cell receptor.... Cystic fibrosis (CF) is an inherited multi-system disorder that is characterized by an abnormality in exocrine gland function. More specifically, CF is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. The mutations in the CFTR gene result in an abnormal potential difference across CF epithelia. The abnormality is due to a reduced cellular apical Cl.sup.- conductance. Consequently, chloride and sodium transport across mucous membranes is abnormal. This abnormality is apparently responsible for pathophysiological changes in the respiratory system. Nearly all patients suffering from the disease develop chronic progressive disease of the respiratory system. Also, in the majority of cases, pancreatic dysfunction occurs, and hepatobiliary and genitourinary diseases are also frequent. The incidence of

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the disease among white Americans is between 1/1600 and 1/2000 live births. Among Afro-Americans, the incidence is much reduced--about 1/17,000 live births. Although survival of cystic fibrosis patients has improved in recent years, the median survival is still only about 20 years despite intensive supportive and prophylactic treatment.... Present efforts to combat the disease have focused on drugs that are capable of either activating the mutant CFTR gene product or causing additional secretion of Cl.sup.from affected cells, as well as gene therapy, wherein the anion conductance deficit is repaired by the introduction of a recombinant wild-type CFTR gene, i.e., a CFTR gene that lacks a mutation that results in the abnormality. Web site: http://www.delphion.com/details?pn=US05366977__ •

Methods and therapeutic compositions for treating cystic fibrosis Inventor(s): Hoppe, IV; Henry (Acton, MA), Fang; Shaona Lee (Sudbury, MA), Cheng; Seng Hing (Wellesley, MA), Smith; Alan Edward (Dover, MA) Assignee(s): Genzyme Corporation (Cambridge, MA) Patent Number: 5,750,571 Date filed: December 23, 1996 Abstract: Methods for treating cystic fibrosis are described. The methods involve the administration of a protein enhancing agent, differentiating agent and/or carboxycompound to a subject afflicted with cystic fibrosis such that mutant cystic fibrosis transmembrane regulator protein present within cystic fibrosis-associated cells becomes functional. Other aspects described include therapeutic compositions and packaged drugs. Excerpt(s): Cystic Fibrosis (CF) is the most common fatal genetic disease in humans (Boat et al., 1989). Based on both genetic and molecular analysis, a gene associated with CF was isolated as part of 21 individual cDNA clones and its protein product predicted (Kerem et al., 1989; Riordan et al., 1989; Rommens et al., 1989).... U.S. patent application Ser. No. 488,307 describes the construction of the gene into a continuous strand, expression of the gene as a functional protein and confirmation that mutations of the gene are responsible for CF. (See also Gregory et al., 1990; Rich et al., 1990). The copending patent application also discloses experiments which showed that proteins expressed from wild type but not a mutant version of the cDNA complemented the defect in the cAMP regulated chloride channel shown previously to be characteristic of CF.... The protein product of the CF associated gene is called the cystic fibrosis transmembrane conductance regulator (CFTR) (Riordan et al., 1989). CFTR is a protein of approximately 1480 amino acids made up of two repeated elements, each having six transmembrane segments and a nucleotide binding domain. The two repeats are separated by a large, polar, so-called R-domain containing multiple potential phosphorylation sites. Based on its predicted domain structure, CFTR is a member of a class of related proteins which includes the multi-drug resistance (MDR) or Pglycoprotein, bovine adenyl cyclase, the yeast STE6 protein as well as several bacterial amino acid transport proteins (Riordan et al., 1989; Hyde et al., 1990). Proteins in this group, characteristically, are involved in pumping molecules into or out of cells. Web site: http://www.delphion.com/details?pn=US05750571__

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Methods for purifying cystic fibrosis transmembrane conductance regulation Inventor(s): O'Riordan; Catherine R. (Boston, MA), Helgerson (Erickson); Amy L. (Charlton, MA) Assignee(s): Genzyme Corporation (Framingham, MA) Patent Number: 5,939,536 Date filed: January 21, 1997 Abstract: The present invention provides a method for purifying a membrane associated protein, e.g., cystic fibrosis transmembrane conductance regulator (hereinafter CFTR) in a functional form. The method involves contacting a membrane-associated proteinmembrane fraction complex with a detergent forming a solubilized complex and chromatographically isolating the membrane-associated protein from the solubilized complex in a functional form. The functional form of the purified membrane-associated protein of the present invention preferably is sufficiently pure to allow its introduction into humans for therapeutic purposes. Excerpt(s): Cystic Fibrosis (CF) is the most common fatal genetic disease in humans (Boat, T. et al. Cystic fibrosis. In: The Metabolic Basis of Inherited Disease, C. Scriver, A. Beaudet, W. Sly, and D. Valle, eds. (McGraw Hill, New York, 1989), 2649-2860). Based on both genetic and molecular analysis, a gene associated with CF was isolated as part of 21 individual cDNA clones and its protein product predicted (Kerem, B-S. et al. Science 245:1073-1080 (1989); Riordan, J. et al. Science 245:1066-1073 (1989); Rommens, J. H. et al. Science 245:1059-1065 (1989)).... U.S. Ser. No. 07/488,307 describes the construction of the gene into a continuous strand, expression of the gene as a functional protein and confirmation that mutations of the gene are responsible for CF. (See also Gregory, R. J. et al. Nature 347:382-386 (1990); Rich, D. P. et al. Nature 347:358-363 (1990)). The co-pending patent application also discloses experiments which showed that proteins expressed from wild type but not a mutant version of the cDNA complemented the defect in the cAMP regulated chloride channel shown previously to be characteristic of CF.... The protein product of the CF associated gene is called the cystic fibrosis transmembrane conductance regulator (CFTR) (Riordan, J. et al. Science 245:1066-1073 (1989)). CFTR is a protein of approximately 1480 amino acids made up of two repeated elements, each having six transmembrane segments and a nucleotide binding domain. The two repeats are separated by a large, polar, so-called R-domain containing multiple potential phosphorylation sites. Based on its predicted domain structure, CFTR is a member of a class of related proteins which includes the multi-drug resistant (MDR) P-glycoprotein, bovine adenyl cyclase, the yeast STE6 protein as well as several bacterial amino acid transport proteins (Riordan, J. et al. Science 245:1066-1073 (1989); Hyde, S. C. et al. Nature 346:362-365 (1990). Proteins in this group, characteristically, are involved in pumping molecules into or out of cells. Web site: http://www.delphion.com/details?pn=US05939536__

Patents 371

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Methods for screening for mutations at various positions in the introns and exons of the cystic fibrosis gene Inventor(s): Kerem; Bat-sheva (Jerusalem, IL), Tsui; Lap-Chee (Toronto, CA), Rommens; Johanna M. (Willowdale, CA) Assignee(s): HSC Research Development Corporation (Toronto, CA) Patent Number: 5,981,178 Date filed: June 6, 1995 Abstract: The cystic fibrosis gene and its gene product are described for mutant forms. The genetic and protein information is used in developing DNA diagnosis, protein diagnosis, carrier and patient screening, cloning of the gene and manufacture of the protein, and development of cystic fibrosis affected animals. Excerpt(s): The present invention relates generally to the cystic fibrosis (CF) gene, and, more particularly to the identification, isolation and cloning of the DNA sequence corresponding to mutants of the CF gene, as well as their transcripts, gene products and genetic information at exon/intron boundaries. The present invention also relates to methods of screening for and detection of CF carriers, CF diagnosis, prenatal CF screening and diagnosis, and gene therapy utilizing recombinant technologies and drug therapy using the information derived from the DNA, protein, and the metabolic function of the protein.... Cystic fibrosis (CF) is the most common severe autosomal recessive genetic disorder in the Caucasian population. It affects approximately 1 in 2000 live births in North America [Boat et al, The Metabolic Basis of Inherited Disease, 6th ed, pp 2649-2680, McGraw Hill, NY (1989)]. Approximately 1 in 20 persons are carriers of the disease.... Although the disease was first described in the late 1930's, the basic defect remains unknown. The major symptoms of cystic fibrosis include chronic pulmonary disease, pancreatic exocrine insufficiency, and elevated sweat electrolyte levels. The symptoms are consistent with cystic fibrosis being an exocrine disorder. Although recent advances have been made in the analysis of ion transport across the apical membrane of the epithelium of CF patient cells, it is not clear that the abnormal regulation of chloride channels represents the primary defect in the disease. Given the lack of understanding of the molecular mechanism of the disease, an alternative approach has therefore been taken in an attempt to understand the nature of the molecular defect through direct cloning of the responsible gene on the basis of its chromosomal location. Web site: http://www.delphion.com/details?pn=US05981178__

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Methods for treatment of cystic fibrosis Inventor(s): Whitehead; Clark M. (Warminster, PA), Alila; Hector W. (North Wales, PA), Earle; Keith A. (North Wales, PA), Thompson; W. Joseph (Doylestown, PA) Assignee(s): Cell Pathways, Inc. (Horsham, PA) Patent Number: 6,465,494 Date filed: August 24, 2001 Abstract: Substituted condensation products of N-benzyl-3-indenylacetamides with heterocyclic aldehydes and other such inhibitors are useful for the treatment of cystic fibrosis.

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Excerpt(s): This invention relates to the treatment of cystic fibrosis.... Patients with cystic fibrosis suffer from chronic lung problems and digestive disorders. The lungs of cystic fibrosis patients become covered with a sticky mucus which is hard to remove and promotes infection by bacteria. Many CF patients require frequent hospitalizations and continuous use of antibiotics, enzyme supplements, and other medications. The life expectancy of these patients used to be is just under 30 years but appears to be increasing to an extent. There are approximately 40,000 people in the United States with cystic fibrosis.... For many years the causes of cystic fibrosis were a mystery. Today, recent advances in biology have made the cause more clear: cystic fibrosis is caused by an inherited genetic defect. Humans have a gene encoded in their DNA that manufactures a special protein called CFTR. This protein controls the transport of chloride ions across the cell membrane. Each gene is made up of two alleles, a single correctly encoded allele is adequate for normal CFTR production. Thus it is only when a person has two defective CFTR alleles that they actually have cystic fibrosis. Those with a single defective allele are called carriers, and those with two defective alleles have cystic fibrosis. About one in every 23 people in the United States carry at least one defective CFTR gene, which makes it the most common genetic defect of its severity in the United States. Web site: http://www.delphion.com/details?pn=US06465494__ •

Methods of detecting cystic fibrosis gene by nucleic acid hybridization Inventor(s): Buchwald; Manuel (Toronto, CA), Drumm; Mitchell L. (Ann Arbor, MI), Iannuzzi; Michael C. (Ann Arbor, MI), Rommens; Johanna M. (Willowdale, CA), Collins; Francis S. (Ann Arbor, MI), Riordan; John R. (Toronto, CA), Tsui; Lap-Chee (Toronto, CA), Kerem; Bat-Sheva (Toronto, CA) Assignee(s): HSC Research Development Corporation (Toronto, CA), The Board of Regents, Acting for and on Behalf of The University of (Ann Arbor, MI) Patent Number: 5,776,677 Date filed: June 6, 1995 Abstract: The cystic fibrosis gene and its gene product are described for both the normal and mutant forms. The genetic and protein information is used in developing DNA diagnosis, protein diagnosis, carrier and patient screening, drug and gene therapy, cloning of the gene and manufacture of the protein, and development of cystic fibrosis affected animals. Excerpt(s): The present invention relates generally to the cystic fibrosis (CF) gene, and, more particularly to the identification, isolation and cloning of the DNA sequence corresponding to the normal and mutant CF genes, as well as their transcripts and gene products. The present invention also relates to methods of screening for and detection of CF carriers, CF diagnosis, prenatal CF screening and diagnosis, and gene therapy utilizing recombinant technologies and drug therapy using the information derived from the DNA, protein, and the metabolic function of the cystic fibrosis transmembrane inductance regulator protein (CFTR).... Although the disease was first described in the late 1930's, the basic defect remains unknown. The major symptoms of cystic fibrosis include chronic pulmonary disease, pancreatic exocrine insufficiency, and elevated sweat electrolyte levels. The symptoms are consistent with cystic fibrosis being an exocrine disorder. Although recent advances have been made in the analysis of ion transport across the apical membrane of the epithelium of CF patient cells, it is not clear that the abnormal regulation of chloride channels represents the primary defect in the

Patents 373

disease. Given the lack of understanding of the molecular mechanism of the disease, an alternative approach has therefore been taken in an attempt to understand the nature of the molecular defect through direct cloning of the responsible gene an the basis of its chromosomal location.... However, there is no clear phenotype that directs an approach to the exact nature of the genetic basis of the disease, or that allows for an identification of the cystic fibrosis gene. The nature of the CF defect in relation to the population genetics data has not been readily apparent. Both the prevalence of the disease and the clinical heterogeneity have been explained by several different mechanisms: high mutation rate, heterozygote advantage, genetic drift, multiple loci, and reproductive compensation. Web site: http://www.delphion.com/details?pn=US05776677__ •

Pharmaceutical composition for treating mucoviscidosis and chronic pain syndromes deriving from degenerative locomotor diseases or tumorous origin Inventor(s): Beres, Jr. Jozsef (Budapest, HU), Beres; Jozsef (Kisvarda, HU) Assignee(s): Beres Export-Import Rt. (Budapest, HU) Patent Number: 5,405,620 Date filed: November 12, 1993 Abstract: The pharmaceutical composition according to the invention consists essentially of:i) one or more, pharmaceutically acceptable, water soluble compounds of boron, fluorine, magnesium, vanadium, manganese, iron, cobalt, nickel, copper, zinc and molybdenum, which compounds do not precipitate with each other or with the other components of the composition and exhibit a neutral or acidic pH in an aqueous medium;ii) glycine;iii) glycerol;iv) L-(+)-ascorbic acid;v) succinic acid;vi) a neutral or acidic and water-soluble, pharmaceutically acceptable salt of ethylenediamine tetraacetic acid;vii) potassium sodium tartrate; andviii) L-(+)-tartaric acid. The composition can be used for the treatment of mucoviscidosis and chronic pain syndromes deriving from locomotor diseases or accompanying diseases of tumorous origin. Excerpt(s): The present invention relates to a pharmaceutical composition suitable for influencing the reticuloendothelic system and for treating mucoviscidosis and chronic pain syndromes deriving from degenerative locomotor diseases or accompanying diseases of tumorous origin, and a process for preparing the same.... vii) potassium sodium tartrate; and the weight ratio of the boron compound:fluorine compound:magnesium compound:vanadium compound:manganese compound:iron compound:cobalt compound:nickel compound:copper compound:zinc compound:molybdenum compound:glycine:glycerol:L-(+)-ascorbic acid:2,4,5,7tetrahalofluorescein salt:ethylenediaminetetraacetic acid salt:potassium, sodium tartrate is 0.01-1:0.02-1:0.4-3:0.02-0.6:0.1-2:1-6:0.1-1:0.02-2:0.05-1:0.1 -3:0.01 -0.8:0.1-2:2-8:0.01 2:0.003-0.5:0.1-3:0.7-10.... The said composition is prepared by dissolving the components in aqueous medium, mixing the same with pharmaceutically acceptable carriers, diluents and/or excipients, then transforming the mixture thus obtained into a pharmaceutical composition in a manner known per se. Web site: http://www.delphion.com/details?pn=US05405620__

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Therapeutic medicine for cystic fibrosis Inventor(s): Yamashita; Tetsuo (Kagawa, JP), Nishimura; Minoru (Ayabe, JP), Sakaguchi; Kenji (11-18, Daizawa 1-chome, Setagaya-ku, Tokyo 155, JP), Hisano; Tomohiro (Ayabe, JP), Abe; Shiro (Ayabe, JP), Murata; Kosaku (Kyoto, JP), Kimura; Akira (Kyoto, JP), Yonemoto; Yoshimasa (Tokushima, JP), Yamaguchi; Hisako (Suita, JP), Okayama; Kenichi (Toyonaka, JP) Assignee(s): Sakaguchi; Kenji (Tokyo, JP), Otsuka Kagaku Kabushiki Kaisha (Osaka, JP), Gunze Limited (Kyoto, JP) Patent Number: 5,582,825 Date filed: October 20, 1994 Abstract: The object of this invention is to provide a therapeutic medicine for cystic fibrosis. The therapeutic medicine for cystic fibrosis according to this invention contains an alginate lyase capable of lysing the alginate produced by strains of microorganisms of the genus Pseudomonas as the active ingredient. Excerpt(s): This invention relates to a therapeutic medicine for cystic fibrosis.... In the white population, an inherited gene-defective disease known as cystic fibrosis is encountered with a frequency of 1/1000-2000. This disease is caused by the defect of a gene coding for cystic fibrosis transmembrane conductance regulator (CFTR) protein and in the event of bacterial infection to the respiratory organ with mucoid forms of Pseudomonas aeruginosa,. Mucous substances collect in the lungs to cause an obstruction of airways leading to premature death. Though antibiotics and digestive enzymes are currently in use for the treatment of this disease, adequate therapeutic responses remain to be achieved as yet.... Recently (Richard C. Hubbard, et al.) have reported that symptomatic improvements in cystic fibrosis may be expected if the DNA contained in said mucus is lysed with a DNase [The New England Journal of Medicine 326, 812-815, 1992]. However, the DNase is little capable of lysing the mucus produced by bacteria of the genus Pseudomonas so that no sufficient efficacy can be expected. Web site: http://www.delphion.com/details?pn=US05582825__

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Therapy aid for treating cystic fibrosis Inventor(s): Metzger; Dorothy (4412 Cathey Cir., Peoria, IL 61615) Assignee(s): none reported Patent Number: 4,530,349 Date filed: December 6, 1983 Abstract: A vest, made from quilted material, has a plurality of individually numbered positions formed thereon to establish a prescription sequence of therapy steps to aid victims of cystic fibrosis. Graphic material may be associated with each position to identify a body posture for the patient. Excerpt(s): This invention relates to medical aid devices, and more particularly, to therapy aids for treating cystic fibrosis.... Cystic fibrosis is a disease which attacks the lungs and bronchial tubes. A characteristic of this disease is that some portion of the respiratory tract collects mucus or phlegm to a degree that breathing becomes impaired. Therefore, when a patient finds it difficult to breathe, it is necessary to undertake a physical therapy program to produce bronchial drainage by loosening and eliminating the mucus or phlegm.... The therapy program for bronchial drainage uses vibration plus

Patents 375

a sequence of physical maneuvers of the patient's body to stimulate movement of secretions and to relieve respiratory airway obstructions due to accumulated mucus or phlegm. A careful positioning of the patient during a vibration treatment helps secretions to move under gravity from small airways into the bronchi and larger airways. There, the secretions can be either coughed up or swallowed. Web site: http://www.delphion.com/details?pn=US04530349__ •

Treatment of cystic fibrosis Inventor(s): Glass; Mitchell (Wilmington, DE) Assignee(s): Imperial Chemical Industries PLC (London, GB2) Patent Number: 5,162,348 Date filed: May 24, 1990 Abstract: There is provided a novel therapeutic product for use in the symptomatic treatment of cystic fibrosis and for use in the manufacture of a medicament for the treatment of cystic fibrosis, as well as a method for treatment of cystic fibrosis with the therapeutic product and a method of treatment of cystic fibrosis with the therapeutic product in combination with one or more other agents indicated for the treatment of cystic fibrosis. Excerpt(s): Cystic fibrosis is an inherited form of chronic bronchitis with mucus hypersecretion, generally accompanied by poor clearance of the airway secretions, obstruction of airflow and chronic bacterial infection of the airways, commonly by Pseudomonas aeruginosa. It is known that the sputum and bronchoalveolar lavage fluid from cystic fibrosis patients reduce the ability of neutrophils to take up and kill P. aeruginosa.... Accordingly, the present invention provides a novel therapeutic product for use in the treatment of cystic fibrosis in a mammal, especially a human, in need thereof which product comprises 4-(4-chlorophenylsulphonylcarbamoyl)benzoyl-Lvalyl-L-proline 1(RS)-(1-trifluoroacetyl-2-methylpropyl)amide, or a pharmaceutically acceptable salt thereof.... As a further aspect of the invention, there is provided the use of 4-(4-chlorophenylsulphonylcarbamoyl)benzoyl-L-valyl-L-proline 1(RS)-(1trifluoroacetyl-2-methylpropyl)amide, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cystic fibrosis. Web site: http://www.delphion.com/details?pn=US05162348__

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Yeast artificial chromosomes containing DNA encoding the cystic fibrosis (CFTR) gene Inventor(s): Elvin; Paul (Barnton, GB), Ogilvie; Donald James (Sale, GB), Anwar; Rashida (Northwich, GB), Smith; John Craig (Nr Knutsford, GB), Markham; Alexander Fred (Crewe, GB), Anand; Rakesh (Sandbach, GB), Riley; John Hamilton (Nr Northwich, GB) Assignee(s): Zeneca Limited (London, GB) Patent Number: 5,939,255 Date filed: May 27, 1994 Abstract: Yeast Artificial Chromosomes (YACS) containing DNA encoding the cystic fibrosis (CFTR) gene are described. The YACs allow detailed analysis of the coding and

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non-coding regions of the gene and the determination of cystic fibrosis alleles in sample DNA from an individual or individuals. Excerpt(s): The present invention relates to nucleotide sequences and their use in methods for the detection, diagnosis and therapy of genetically inherited disorders. In particular the nucleotide sequences of the invention may be used for the detection of cystic fibrosis alleles. The invention also relates to nucleotide sequences coding for inherited disease associated genes such as cystic fibrosis and to RNA, such as mRNA, and polypeptides such as proteins, derived therefrom. Diagnostic kits are also provided for use in the diagnostic methods of the present invention.... Available methods for the detection of cystic fibrosis are based on linkage studies. In general these comprise the use of labelled probes to detect restriction fragment length polymorphisms in sample genomic DNA. The distinguishing power of the genetic loci detected by the probes mentioned above is limited by the observed degree of polymorphism at such loci. Such probes may therefore identify the same restriction fragment for many individuals and the ability to distinguish between normal and cystic fibrosis alleles in such individuals is no longer possible. A need therefore exists for further and more informative methods of detection and diagnosis.... Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in the Western world with a carrier frequency of.sup..about. 1/20 and an incidence of 1/1600 live births. The disease is extremely rare in African and Asian populations, although cases have been reported in Japan. Affected patients exhibit elevated sodium chloride secretion in sweat and suffer from a variety of symptoms including bronchiectasis, respiratory failure and pancreatic insufficiency. The nature of the defect causing CF is unknown although it has been shown that sweat gland cells and respiratory epithelial cells from affected patients show a diminished permeability to chloride ions and a defective response to beta adrenergic agents (M J Stutts et al, 1985, PNAS, 82, 6677-6681). More recently, it has been demonstrated that the chloride channel can be activated in CF cells and that in CF patients it is the regulation of the chloride channel that is defective (R. A. Frizzell et al, 1986, Science, 233, 558-560, M. J. Welsh and C. M. Liedtke, 1986, Nature, 322, 467-470). Web site: http://www.delphion.com/details?pn=US05939255__

Patent Applications on Cystic Fibrosis As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to cystic fibrosis: •

Compositions and methods for cystic fibrosis therapy Inventor(s): Fischer, Horst; (Albany, CA), Illek, Beate; (Albany, CA) Correspondence: SEED INTELLECTUAL PROPERTY LAW GROUP PLLC; 701 FIFTH AVE; SUITE 6300; SEATTLE; WA; 98104-7092; US Patent Application Number: 20030096762 Date filed: October 17, 2001

10

This has been a common practice outside the United States prior to December 2000.

Patents 377

Abstract: Compositions and methods for therapy of cystic fibrosis and other conditions are provided. The compositions comprise one or more compounds such as flavones and/or isoflavones capable of stimulating chloride transport in epithelial tissues. Therapeutic methods involve the administration (e.g., orally or via inhalation) of such compositions to a patient afflicted with cystic fibrosis and/or another condition responsive to stimulation of chloride transport. Excerpt(s): This application is a continuation-in-part of U.S. Ser. No. 08/951,912, filed Oct. 16, 1998.... The present invention relates generally to the treatment of cystic fibrosis. The invention is more particularly related to compositions comprising one or more compounds such as flavones and/or isoflavones, which may be used to activate chloride transport (i.e., absorption and/or secretion) in epithelial tissues of the airways, the intestine, the pancreas and other exocrine glands, and for cystic fibrosis therapy.... Cystic fibrosis is a lethal genetic disease afflicting approximately 30,000 individuals in the United States. Approximately 1 in 2500 Caucasians is born with the disease, making it the most common lethal, recessively inherited disease in that population. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compositions and methods for the treatment of cystic fibrosis Inventor(s): Perrine, Susan P. (Weston, MA), Faller, Douglas V. (Weston, MA), Stamatoyannopoulos, George; (Seattle, WA) Correspondence: HELLER EHRMAN WHITE & MCAULIFFE LLP; SUITE 300; 101 ORCHARD RIDGE DR. GAITHERSBURG; MD; 20878-1917; US Patent Application Number: 20030018069 Date filed: July 1, 2002 Abstract: The invention is directed to novel pharmaceutical compositions comprising chemicals agents that are useful in the treatment and prevention of cystic fibrosis and the prevention of signs and symptoms of this disease. These pharmaceutical compositions are surprisingly successful in the treatment disorders related to cystic fibrosis including disorders of blood production. Many of these compositions of the invention are even more effective when administered to a patient in pulses. Pulse therapy is not a form of discontinuous administration of the same amount of a composition over time, but comprises administration of the same dose of the composition at a reduced frequency or administration of reduced doses. Excerpt(s): The invention relates to pharmaceutically acceptable compositions for administration to humans to treat cystic fibrosis and also to methods for effectively utilizing these compositions.... Cystic fibrosis (CF) is a systemic disorder that results when mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an apical membrane glycoprotein, lead to a reduction in apical membrane chloride transport. CFTR is a cAMP-dependent chloride channel that regulates fluid composition in the respiratory and gastrointestinal tracts. CF is a heritable disease that follows an autosomal recessive pattern of transmission. It is the most common invariably lethal genetic disease in the United States, with frequency among Caucasians being one in two thousand. One in twenty are carriers of the defective gene. CF is characterized by abnormal endocrine and exocrine gland function. In CF, unusually thick mucus leads chronic pulmonary disease and respiratory infections, insufficient pancreatic and digestive function, and abnormally concentrated sweat. Seventy percent of the mutant CFTR alleles in the Caucasian population result from deletion of phenylalanine at

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position 508 (.DELTA.F508-CFTR), the result of a three base pair deletion in the genetic code. Other mutations have also been described and many may exist. The.DELTA.F508CFTR mutation results in a CFTR protein capable of conducting chloride, but absent from the plasma membrane because of aberrant intracellular processing. Under usual conditions (37.degree. C.), the.DELTA.F508-CFTR protein is retained in the endoplasmic reticulum (ER), by prolonged association with the ER chaperones, including calnexin and hsp70. The retained CFTR protein is then targeted for degradation by the ubiquitin proteasome pathway. Over expression of.DELTA.F508-CFTR can result in.DELTA.F508CFTR protein appearing at the cell surface, and this protein is functional once it reaches the cell surface. The.DELTA.F508 "trafficking" block is also reversible by incubation of cultured CF epithelial cells at reduced temperatures (25-27.degree. C.). Lowered temperature results in the appearance of CFTR protein and channel activity at the cell surface, suggesting an intrinsic thermodynamic instability in.DELTA.F508-CFTR at 37.degree. C. that leads to recognition of the mutant protein by the ER quality control mechanism, prevents further trafficking, and results in protein degradation. High concentrations of glycerol (1 M or 10%), a protein stabilizing agent or chemical chaperone, also appears to facilitate movement of.DELTA.F508-CFTR from the ER to the plasma membrane.... Some of the palliative treatments involve the administration of biologically active proteins or chemical compounds to decrease the viscosity of secretions, or to suppress chronic infections of the airways. These treatments have a number of limitations, and do not address the illness directly, but rather attempt to treat the symptoms. Some require continuous use at fairly high doses while others have short effective half-lives. Tolerance to the active ingredient often develops rendering the composition functionally useless. In addition to problems associated with tolerance, the substances themselves or their metabolic by-products or carriers can quickly reach toxic levels in the patient's system which impair kidney or liver function. Further, the chemical compounds themselves can be rapidly destroyed by catabolic enzymes, found in the cells and serum such as aminases, oxidases and hydrolases. Many of these enzymes are also found in hepatic cells, the principal sites for cleansing of the blood. Those able to survive cellular and hepatic catabolic processes are quickly eliminated from the patient's system by the kidneys. Consequently, in vivo retention times for active compounds are extremely short and the ability to achieve any sort of sustained biological effect becomes nearly impossible or, at least, impractical. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compositions and methods for treatment of cystic fibrosis Inventor(s): Reenstra, William; (Radnor, PA), Rubenstein, Ronald C. (Ardmore, PA) Correspondence: DANN DORFMAN HERRELL & SKILLMAN; SUITE 720; 1601 MARKET STREET; PHILADELPHIA; PA; 19103-2307; US Patent Application Number: 20020115619 Date filed: October 4, 2001 Abstract: The invention includes a method of enhancing the chloride ion transport function of a mutant CFTR polypeptide in epithelial cells in a mammal. In a preferred embodiment, the mammal is a human patient afflicted with cystic fibrosis (CF). Specifically, the method comprises administering to a patient a therapeutically effective amount of a first compound to enhance trafficking of a mutant CFTR polypeptide to the surface of epithelial cells in the patient, and a therapeutically effective amount of a second compound to increase the chloride ion transport activity of a mutant CFTR

Patents 379

polypeptide at the surface of epithelial cells, whereby, the chloride ion transport function of the mutant CFTR polypeptide is enhanced. The invention also includes a method of treating CF in a patient, wherein a mutant CFTR polypeptide is present in an epithelial cell in a patient with CF. Compositions for treating CF in a patient are also included, as well as kits for practicing the method of the invention. Excerpt(s): Cystic Fibrosis (CF) is an autosomal recessive systemic disorder of exocrine glands and secretory epithelia. The disease is a consequence of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which cause a variety of abnormalities in CFTR protein expression and/or regulation. CFTR functions as a cAMP-regulated chloride channel in the apical membranes of epithelial cells, including: nasal, pulmonary, sweat gland, hepatic, and intestinal cells. Most of the defects in CF result from reduced chloride ion transport. Recent improvements in CF diagnosis and the treatment of lung disease have improved the median survival for patients with this disorder to greater than 30 years, but respiratory failure from chronic infections remains the most common cause of death in CF.... More than one thousand unique disease causing mutations have been identified in the CFTR gene. These mutations can be classified in five general categories with respect to the CFTR protein (Table 1). These classes of CFTR dysfunction include limitations in CFTR production (Class I), aberrant folding and/or trafficking (Class II), abnormal regulation of conduction (Class III), decreases in chloride conduction (Class IV), and reductions in synthesis (Class V). Due to the lack of functional CFTR, Class I, II, and III mutations are typically associated with a more severe phenotype in CF (i.e. pancreatic insufficiency) than the Class IV or V mutations, which may have very low levels of functional CFTR expression.... The most common mutation,.DELTA.F508, is present on over 60% of CF chromosomes and greater than 85% of all CF patients have at least one.DELTA.F508-CFTR gene..DELTA.F508 is considered the prototype Class II trafficking mutation..DELTA.F508 encodes a cAMP-activated chloride channel with reduced activity in cells (Dalemans et al., 1991, Nature 354:526-528; Drum et al., 1991, Science 254:1797-9; Hwang et al., 1997, Am. J. Physiol. 273 (Cell Physiol. 42):C988-C998) which is also misprocessed in the endoplasmic reticulum (Cheng et al., 1990, Cell 63: 827-834; Ward et al., 1994, J. Biol. Chem. 269:25710-25718). The absence of cell surface CFTR caused by this trafficking defect is typically associated with a severe phenotype of CF, including pancreatic insufficiency. When expressed in systems which facilitate protein trafficking studies such as Xenopus oocytes (Drumm et al., 1991, Science 254: 1797-1799), or in high level expression systems that allow some.DELTA.F508-CFTR to reach the cell surface (Cheng et al., 1995, Am. J. Physiol. 268: L615-L624),.DELTA.F508-CFTR is found to be less active than wild type CFTR. Several experimental conditions, however, have been shown to increase the activity of.DELTA.F508-CFTR to levels that approach or exceed those of wild type CFTR (Drumm et al., 1991, Science 254:1797-9; Hwang et al., 1997, Am. J. Physiol. 273 {Cell Physiol. 42}:C988-C998). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Compositions for treating cystic fibrosis Inventor(s): Budny, Matthew J. (Westlake Village, CA), Budny, John A. (Westlake Village, CA) Correspondence: COLIN P ABRAHAMS; 5850 CANOGA AVENUE; SUITE 400; WOODLAND HILLS; CA; 91367 Patent Application Number: 20020022005 Date filed: June 6, 2001 Abstract: A composition for degrading biofilm structure associated with cystic fibrosis and the debris associated therewith comprises an enzyme selected for its ability to dismantle the biofilm structure, and an anchor molecule coupled to an enzyme to form an enzyme-anchor complex. The anchor molecule is selected for its ability to attach to a surface on or proximal the biofilm structure. The attachment to the surface permits prolonged retention time of the enzyme-anchor complex where the biofilm structure and associated debris are present. Excerpt(s): This application is a continuation-in-part of U.S. application Ser. No. 09/587,818 filed Jun. 06, 2000, which is a continuation-in-part of U.S. application Ser. No. 09/249,674 filed Feb. 12, 1999 (issued as U.S. Pat. No. 6,159,447 on Dec. 12, 2000), which is a continuation-in-part of U.S. application Ser. No. 08/951,393 filed Oct. 16, 1997 (issued as U.S. Pat. No. 5,871,714 on Feb. 16, 1999), both of which are incorporated herein by reference.... Cystic fibrosis, a genetically inherited disease, is caused by the mutation of a gene that produces an electrolyte transfer protein. The consequence of the mutation affects a multitude of organ systems. However, the tissues that are most directly affected are those that secrete mucus or have mucus membranes. Serious adverse consequences occur with tissues that are associated with the respiratory system i.e. lungs and airway passage tissues. In response to the genetic defect, the host produces secretions to counteract the ionic imbalance. These secretions in response to the disease allow opportunistic infections to develop which causes additional fluid and mucus to infiltrate the respiratory system from the host. The additional fluid from the host in response to the infection is under the influence of the immune system. Finally, the infectious bacteria and the associated bacterial biofilm add additional mucus and fluid at the site. Furthermore, the principal bacterial pathogen associated with the opportunistic infection is Pseudomonas aeruginosa, which often mutates to a mucoid form that is a prolific producer of alginate biofilm, which further exacerbates the disease condition. The result is an accumulation of copious amount of mucus, fluid and biofilm material which affects not only the respiratory system, but the entire host.... The current treatment of cystic fibrosis involves a dual approach to: 1) promote and facilitate the removal of mucus and secretions from the respiratory tract and; 2) control the infection that is associated with the disease. The infection, with the bacteria's production of a biofilm, obstructs the host's defenses, shields the bacteria from the killing action of antibiotics and increases the viscosity of the mucus, making it increasingly difficult for the patient to expectorate the interfering mucus. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 381

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Method for treating cystic fibrosis Inventor(s): Jacobson, Kenneth A. (Silver Spring, MD), Pollard, Harvey B. (Potomac, MD) Correspondence: LEYDIG VOIT & MAYER, LTD; 700 THIRTEENTH ST. NW; SUITE 300; WASHINGTON; DC; 20005-3960; US Patent Application Number: 20030114375 Date filed: July 3, 2002 Abstract: The present invention provides a method of identifying CFTR-binding compounds for treating cells having a reduced apical Cl.sup.- conductance, such as cystic fibrosis cells. This identification method involves the use of polypeptide I.alpha., which constitutes a portion of the CFTR protein. The present invention also provides a method of treating CF cells by contacting cells having a reduced apical Cl.sup.conductance with a therapeutically effective quantity of a compound selected by the present inventive identification method. Preferred compounds for such treatment have little or no affinity for adenosine cell receptors. The present invention provides novel compounds useful in practicing the present inventive method, as well as pharmaceutical compositions containing such compounds. Excerpt(s): This is a continuation-in-part of copending application Ser. No. 07/952,965, filed Sep. 29, 1992, now U.S. Pat. No. 5,366,977.... The present invention relates to a method of identifying CFTR-binding compounds for treating cells having a reduced apical Cl.sup.- conductance, such as cystic fibrosis cells. The present invention further relates to compounds and pharmaceutical compositions thereof useful in treating such cells.... Healthy animal cells require, among other conditions and materials, the movement of various inorganic ions across the cell membrane to be maintained such that a proper balance of the ions provide the requisite electrical potential across the cellular membrane as well as a life-promoting internal ionic strength. For example, Na.sup.+, Cl.sup.-, K.sup.+, and Ca.sup.++ are known to cross cell membranes in animals such that K.sup.+ and Ca.sup.++ are accumulated intracellularly to a varying extent in different cells at different times of development, whereas Na.sup.+, in large measure, is excluded from the interior of a cell. The cross-cellular movement of these ions is mediated by Na.sup.+/K.sup.+- and Ca.sup.++-dependent ATPases that are membrane bound at the sites of appropriate ion channels. Chloride ion was believed to permeate animal cells by passive means to equilibrate in concentration between the external and internal fluid, resulting in an underrepresentation of Cl.sup.- intracellularly in consequence of the overall negative intracellular change. Conductance of chloride, however, has been shown to be mediated actively as well, by means of a Cl.sup.channel (see Edwards, Neuroscience, 7, 1335-1366 (1982)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Methods of determining altered NDPK functions and the diagnosis of cystic fibrosis Inventor(s): Mehta, Anil; (Angus, GB), Muimo, Richmond; (Leeds, GB) Correspondence: Braman & Rogalskjy, LLP; PO Box 352; Canandaigua; NY; 14424-0352; US Patent Application Number: 20020065225 Date filed: August 31, 2001

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Abstract: A peptide of relative molecular mass less than 6500 comprising at least ten consecutive amino acid residues surrounding the phenylalanine (508), or at least ten consecutive residues including a portion of the region between residues (508 and 551), in the polypeptide sequence of human cystic fibrosis transmembrane regulator (CFTR), or a variant or precursor thereof. A peptide as defined above having between 12 and 50 amino acid residues. Methods of treating cystic fibrosis are also disclosed. A method of classifying a disease state associated with epithelial cell dysfunction in a patient is disclosed. The method includes obtaining a suitable epithelial cell sample from the patient and determining for one or more of the following whether the measured parameter is altered compared to a control epithelial cell, the measured parameters being: (i) nucleoside diphosphate kinase (NDPK) function, (ii) phosphorylation of annexin, (iii) phosphorylation of other membrane proteins, and (iv) ATPase activity. Excerpt(s): The present invention relates to compounds which are believed to be useful in the treatment of cystic fibrosis (CF) and it also relates to various methods of screening patients in order to determine whether they have CF, and to methods of screening for drugs which may be useful in the treatment of CF.... CF is the most important autosomal recessive inherited cause of early death of young adults in the UK.... CF results from mutations in the cystic fibrosis transmembrane-conductance regulator protein (CFTR) which controls epithelial transport. The defects in this gene are many (over 500 described to date). In about 70% of cases the defect is very simple, being the loss of the phenylalanine residue at position 508 in the protein (.DELTA.AF508 in CFTR). Having lost this amino acid, epithelial cells fail to function properly. Specifically, they fail to regulate the movement of ions across their membranes. This results in a very sticky lung mucus and failure to digest food properly. The mechanism is unknown. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of secretin-receptor ligands in treatment of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) Inventor(s): Page, Keith J. (Hertfordshire, GB), Davis, Richard J. (Hertfordshire, GB) Correspondence: NIXON & VANDERHYE P.C. 8th Floor; 1100 North Glebe Road; Arlington; VA; 22201; US Patent Application Number: 20020142956 Date filed: July 3, 2001 Abstract: The invention is based on the finding that the secretin receptor is expressed in tissues present in the distal lung of humans. In patient with CF, levels of the receptor are elevated compared to normal tissue. Treatment of tissue by secretin stimulates the movement of negative ions in the tissue. The invention provides methods of treatment of cystic fibrosis or COPD in a patient by administering to said patient an effective amount of an agent which triggers anion efflux in respiratory tissue via the activation of a secretin receptor. Excerpt(s): The present invention relates to the treatment of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) with or by activation of the hormone secretin or other secretin receptor ligands.... Cystic Fibrosis.... Cystic fibrosis (CF) is the most common, fatal, autosomal recessive inherited disease, with over 7000 people currently diagnosed in the UK alone and approximately 30,000 in the United States. The incidence of CF is strongly dependent on ethnic background. Caucasian individuals

Patents 383

with Northern European ancestry are most at risk exhibiting a probability of approximately 1 in 2500, based on a heterozygous carrier rate of about 1 in 25. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with cystic fibrosis, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “cystic fibrosis” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on cystic fibrosis. You can also use this procedure to view pending patent applications concerning cystic fibrosis. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 7. BOOKS ON CYSTIC FIBROSIS Overview This chapter provides bibliographic book references relating to cystic fibrosis. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on cystic fibrosis include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “cystic fibrosis” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on cystic fibrosis: •

Gallbladder and Biliary Tract Diseases Source: New York, NY: Marcel Dekker, Inc. 2000. 928 p. Contact: Available from Marcel Dekker, Inc. Cimarron Road, P.O. Box 5005, Monticello, NY 12701. (800) 228-1160 or (845) 796-1919. Fax (845) 796-1772. E-mail: [email protected]. International E-mail: [email protected]. Website: www.dekker.com. PRICE: $250.00 plus shipping and handling. ISBN: 0824703111. Summary: The gallbladder and biliary tract are the 'orphan' organs of the digestive system, falling between the realms of the solid organ liver specialist and the hollow organ intestinal expert. This comprehensive text covers the gallbladder and biliary tract disease, noting that the management of gallbladder and biliary disease is truly multidisciplinary, involving gastroenterologists, surgeons, endoscopists, and radiologists. The text attempts to translate advances in basic science into clinically relevant treatment and to bridge the gap between clinical disciplines. Parts I and II focus

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on important physiological and pathophysiological principles, with a special emphasis on gallstones. In Parts III to V, the authors focus on clinical disorders of the gallbladder and biliary tree, with input on management from surgeons, endoscopists, and radiologists. New imaging techniques, such as magnetic resonance cholangiography and endoscopic ultrasound, are discussed from both the radiologist's and endoscopist's perspective, and their role in disease management is defined. The 37 chapters cover the neurobiology of the gallbladder, gallbladder mucosal function, gallbladder smooth muscle function and dysfunction, canalicular lipid secretion, bile ductal secretion and its regulation, the pathogenesis of gallstones, pigment gallstones, cholesterol crystallization in bile, normal gallbladder motor functions, gallbladder motility and gallstones, the role of intestinal transit, prevention of gallstones, the gallbladder and biliary tree in cystic fibrosis, the silent gallstone, biliary crystals and sludge, biliary colic and acute cholecystitis (gallbladder infection), laparoscopic cholecystectomy (removal of the gallbladder), nonsurgical therapy of gallstones, biliary lithotripsy, topical contact dissolution of gallbladder stones, common bile duct stones, acalculous cholecystitis, gallbladder cancer, primary sclerosing cholangitis, vanishing bile duct syndrome, cholangiocarcinoma (bile duct cancer), ampullary tumors, infections of the bile ducts, and bile duct injuries. Each chapter includes extensive references and the text concludes with a detailed subject index. •

Pediatric Gastrointestinal Disease. 2nd ed Source: Philadelphia, PA: W.B. Saunders Company. 1999. 823 p. Contact: Available from W.B. Saunders Company. Book Order Fulfillment Department, 11830 Westline Industrial Drive, Saint Louis, MO 63146-9988. (800) 545-2522 or (314) 4537010. Fax (800) 568-5136 or (314) 453-7095. E-mail: [email protected]. Website: customerservice.wbsaunders.com. PRICE: $155.00 plus shipping and handling. ISBN: 0721674615. Summary: This medical textbook covers all facets of clinical pediatric gastrointestinal disease. The text emphasizes a clinical focus and incorporates anatomy and physiology considerations into each chapter rather than a separate section. The book is organized into distinct sections, starting with the common clinical problems and followed by organ specific diseases. General chapters on clinical problems cover chronic abdominal pain of childhood and adolescence, vomiting, diarrhea, constipation and encopresis (fecal soiling), failure to thrive, gastrointestinal hemorrhage, eating disorders and obesity, jaundice, ascites, caustic ingestion and foreign bodies, abdominal masses in pediatric patients, and abdominal surgical emergencies. Sections on diseases of the esophagus, stomach, and the small and large bowel (intestine) are followed by chapters reviewing the clinical facets of pediatric liver disease. Specific chapters include gastrointestinal reflux, achalasia and other motor disorders, congenital anomalies, gastric motility disorders, bezoars (a mass of food, hair or other components found in the stomach or intestine), maldigestion and malabsorption, celiac disease, short bowel syndrome, enteric parasites, Crohn's disease, ulcerative colitis, polyps, appendicitis, hernia, Hirschsprung's disease, neoplasms (cancerous and noncancerous), hepatitis, gallbladder diseases, and liver transplantation. The last two sections review diseases of the pancreas and basic nutrition in children, including pancreatitis, cystic fibrosis, nutritional assessment, parenteral (outside the digestive system, for example, intravenous nutrition) and enteral nutrition, and the management of diarrhea. Each chapter offers black and white photographs and figures and concludes with extensive references. A detailed subject index concludes the text.

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Clinical Practice of Gastroenterology. Volume Two Source: Philadelphia, PA: Current Medicine. 1999. 861 p. Contact: Available from W.B. Saunders Company. Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 545-2522. Fax (800) 874-6418 or (407) 352-3445. Website: www.wbsaunders.com. PRICE: $235.00 plus shipping and handling. ISBN: 0443065209 (two volume set); 0443065217 (volume 1); 0443065225 (volume 2). Summary: This lengthy textbook brings practitioners up to date on the complexities of gastroenterology practice, focusing on the essentials of patient care. This second volume includes 113 chapters in five sections: liver, gallbladder and biliary tract, pancreas, pediatric gastroenterology, and special topics. Specific topics include hepatic (liver) structure and function, jaundice, viral hepatitis, alcoholic liver injury, liver tumors, parasitic diseases of the liver, Wilson's disease, hemochromatosis, the pregnancy patient with liver disease, portal hypertension, hepatic encephalopathy, fulminant hepatic failure, liver transplantation, the anatomy of the gallbladder and biliary tract, gallstones, laparoscopic cholecystectomy (gallbladder removal), cholecystitis (gallbladder infection), primary sclerosing cholangitis, biliary obstruction, pancreatic anatomy and physiology, acute pancreatitis, pancreatic fistulas and ascites (fluid accumulation), chronic pancreatitis, cancer of the pancreas, endoscopic retrograde cholangiopancreatography, esophageal atresia, gastroesophageal reflux in infants and children, achalasia and esophageal motility disorders, caustic and foreign body ingestion, vomiting, chronic abdominal pain, gastritis and peptic ulcer disease in children, malabsorption syndromes in children, inflammatory bowel disease in children and adolescents, acute appendicitis, cystic fibrosis, constipation and fecal soiling (incontinence), hepatitis in children, liver transplantation in children, failure to thrive, pediatric AIDS, the gastrointestinal manifestations of AIDS, the evaluation and management of acute upper gastrointestinal bleeding, principles of endoscopy, eating disorders, nutritional assessment, enteral and parenteral nutrition, gastrointestinal diseases in the elderly and in pregnancy, nosocomial infections, and the psychosocial aspects of gastroenterology (doctor patient interactions). The chapters include figures, algorithms, charts, graphs, radiographs, endoscopic pictures, intraoperative photographs, photomicrographs, tables, and extensive references. The volume concludes with a detailed subject index and a section of color plates.

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Gastroenterology and Hepatology: The Comprehensive Visual Reference. Volume 8: Pancreas Source: Philadelphia, PA: Current Medicine. 1998. [200 p.]. Contact: Available from Current Medicine. 400 Market Street, Suite 700, Philadelphia, PA 19106. (800) 427-1796 or (215) 574-2266. Fax (215) 574-2270. E-mail: [email protected]. Website: current-medicine.com. PRICE: $125.00 plus shipping and handling. ISBN: 0443078629. Summary: This atlas is one in an 8-volume collection of images that pictorially displays the gastrointestinal tract, liver, biliary tree, and pancreas in health and disease, both in children and adults. This volume includes 10 chapters on the pancreas. Topics covered include neurohormonal control of the pancreas, pathogenesis of pancreatic diseases, acute pancreatitis, chronic pancreatitis, surgery for chronic pancreatitis, developmental anomalies of the pancreas, pancreatic cancer, the rationale and application of radioligand imaging in gastroenterology, cystic fibrosis, and hereditary pancreatitis. The format of the atlas is visual images supported by relatively brief text. Tables, charts,

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diagrams, and photomicrographs are used extensively. A subject index concludes the volume. •

Gastroenterology and Hepatology: The Comprehensive Visual Reference. Volume 4: Pediatric GI Problems Source: Philadelphia, PA: Current Medicine. 1997. [200 p.]. Contact: Available from Current Medicine. 400 Market Street, Suite 700, Philadelphia, PA 19106. (800) 427-1796 or (215) 574-2266. Fax (215) 574-2270. E-mail: [email protected]. Website: current-medicine.com. PRICE: $125.00 plus shipping and handling. ISBN: 0443078521. Summary: This atlas is one in an 8-volume collection of images that pictorially displays the gastrointestinal tract, liver, biliary tree, and pancreas in health and disease, both in children and adults. This volume includes 11 chapters on pediatric gastrointestinal (GI) problems, each written by experts in their respective fields. Topics include the newborn, nutrition, neonatal surgery and the acute abdomen, gastroesophageal reflux, peptic ulcer disease and Helicobacter pylori related gastroduodenal disease, diarrheal disease in infants and children, pediatric inflammatory bowel disease (IBD) and functional bowel disorders, cystic fibrosis, anorectal malformations, and pediatric liver disease. The editor emphasizes that, in pediatric gastroenterology, there is an emphasis on assuring optimal nutritional support for every child because a child's potential for growth and development must be maximized, even in the presence of digestive disease. The chapters emphasize the medical, surgical, and nutritional management care of infants and children with gastrointestinal and liver disease. The format of the atlas is visual images supported by relatively brief text. Tables, charts, diagrams, and photomicrographs are used extensively.

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Pediatric Clinical Gastroenterology. 4th ed Source: St. Louis, MO: Mosby-Year Book, Inc. 1995. 1065 p. Contact: Available from Mosby-Year Book, Inc. 11830 Westline Industrial Drive. St. Louis, MO 63146. (800) 426-4545 or (800) 325-4177 or (314) 872-8370. Fax (314) 432-1380. PRICE: $100 (as of 1995). ISBN: 0815174063. Summary: This textbook of pediatric clinical gastroenterology presents 37 chapters in 5 sections: symptoms and signs; diseases of the gastrointestinal tract; diseases of the liver; diseases of the pancreas; and nutritional support. Specific topics include gastrointestinal (GI) emergencies of the neonate; intestinal obstruction; sucking and swallowing disorders; diseases of the esophagus; disorders of the stomach and duodenum; diarrheal disorders; carbohydrate intolerance; malabsorption syndrome; protein losing gastroenteropathy; immune homeostasis and the gut; inflammatory bowel diseases; constipation, fecal incontinence, and proctologic conditions; functional recurrent abdominal pain; parasitic and fungal disease of the GI tract; neonatal unconjugated hyperbilirubinemias; neonatal hepatitis; prolonged obstructive jaundice; acute and chronic viral hepatitis; bacterial, rickettsial, and parasitic infections and infestations; fulminant hepatic failure and hepatic coma; cirrhosis; portal hypertension; inborn errors of metabolism; hepatic tumors; liver transplantation; congenital anomalies and heredity disorders; cystic fibrosis; pancreatitis and pancreatic tumors; energy and nutrient requirements; infant feeding; and enteral and parenteral alimentation. Each chapter includes numerous references and a subject index concludes the volume.

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Health Effects of Exposure to Environmental Tobacco Smoke: The Report of the California Environmental Protection Agency Source: Bethesda, MD, National Cancer Institute, Smoking and Tobacco Control Monograph No. 10, NIH Publication No. 99-4645, 430 p., 1999. Contact: U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Bethesda, MD. Summary: Health Effects of Exposure to Environmental Tobacco Smoke: Report of the California Environmental Protection Agency is the tenth volume in the Smoking and Tobacco Control series of the National Cancer Institute. It presents an assessment of the health risks of environmental tobacco smoke (ETS) performed by the California Environmental Protection Agency (Cal/EPA). Cal/EPA spent 5 years preparing this document, and solicited input from all interested parties, including the tobacco industry and its consultants. The final draft was peer-reviewed by California's Scientific Review Panel, a body created under California law to provide independent peer review of many scientific aspects of the state's toxic air contaminants and air pollution programs. The monograph is divided into eight chapters that (1) present the methodology used by Cal/EPA in preparing the report, define ETS, and summarize its impact on the health of Californians; (2) describe the properties of ETS and its constituents, and discuss methods for preventing exposure to ETS and the prevalence of ETS exposure; (3) discuss perinatal manifestations of ETS-induced developmental toxicity; (4) discuss the postnatal manifestations of ETS-induced developmental toxicity; (5) discuss the reproductive effects of ETS exposure; (6) discuss the effects of ETS on respiratory health; (7) discuss the carcinogenic effects of ETS; and (8) discuss the cardiovascular effects of ETS. In the report, Cal/EPA, using the most up-to-date evidence available, concluded that ETS causes not only lung cancer in adults, but also (1) low birthweight, (2) sudden infant death syndrome, (3) middle ear infections, (4) nasal sinus cancer, and (5) heart disease morbidity and mortality. ETS was estimated to account for up to 62,000 heart disease deaths annually, 20 times the number of ETS-related lung cancer deaths. Cal/EPA also found evidence suggestive of links between ETS exposure and (1) spontaneous abortion, (2) adverse effects on cognition and behavior, (3) exacerbation of cystic fibrosis, (4) decreased pulmonary function in adults and children, and (5) cervical cancer.

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Exercise and Children's Health Source: Champaign, IL, Human Kinetics Books, 356 p., 1990. Contact: Human Kinetics Books, P.O. Box 5076, Champaign, IL 61825-5076. (800) DIALHKP. (800) 334-3665 (in Illinois). Summary: Exercise and Children's Health provides pediatric cardiologists, pediatricians, family practitioners, and other primary care providers with a guide on improving and maintaining children's health through exercise. The text offers practical guidelines for exercise prescription and physical fitness for healthy children and for children with special health concerns such as obesity, heart disease, asthma, cystic fibrosis, diabetes, and seizure disorders. The book contains three parts: (1) Developmental Exercise Physiology: The Physiological basis of Physical Fitness in Children; (2) Influence of Exercise on Health; and (3) Strategies for Improving Exercise Habits on Children. Part one provides basic information regarding children's physiological responses to exercise, emphasizing developmental changes that occur during the growing years. Part two reviews the scientific grounds for promoting exercise as a beneficial health measure. Part three provides specific strategies for

390 Cystic Fibrosis

increasing physical activity in children through both structured and unsupervised programs; practical guidelines give physicians and other professionals useful materials for prescribing exercise programs for young patients. 38 figures, 12 tables, 775 references. •

Chronic and disabling disorders Source: Philadelphia, PA: Hanley and Belfus. 1994. 169 pp. Contact: Available from Hanley and Belfus, 210 South 13th Street, Philadelphia, PA 19107. Telephone: (215) 546-4995. $66.00 for yearly subscription to three issues in the series; single issues available. Summary: This edition addresses both general issues of importance in health care for adolescents with special health needs and specific chronic conditions. The first set of articles focuses on the epidemiology of chronic illness in adolescence and developmental, educational, and health care delivery issues. The second set discusses specific chronic conditions that are prevalent in the adolescent population (i.e., deafness, cancer, traumatic brain injury, and sickle cell disease) or that have had recent advances in management (i.e., cystic fibrosis, organ transplants, and spinal cord injuries).

•

Listen, my child has a lot of living to do Source: New York, NY: Oxford University Press. 1990. 192 pp. Contact: Available from Oxford University Press, 2001 Evans Road, Cary, NC 27513. Telephone: (800) 451-7556 or (919) 677-0977 / fax: (919) 677- 1303. $15.95 paper, $45.00 hardbound. Summary: This book discusses the partnership between parents and professionals in caring for children with life-threatening conditions. It describes initiatives taken in England to redress deficiencies in providing care to terminally ill children and their families so as to provide a comprehensive, flexible, and compassionate national network of care. It covers domiciliary and respite hospice care, specialist organ/system failure and parent self-help groups (congenital heart disease, infant deaths, children with AIDS, cystic fibrosis, and mucopolysaccharide disease), education of children and of professionals, and bereavement.

Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print®). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “cystic fibrosis” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “cystic fibrosis” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “cystic fibrosis” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

A Parent's Guide to Cystic Fibrosis (University of Minnesota Guides to Birth and Childhood Disorder) by Burton L. Shapiro, Ralph C. Heussner (1991); ISBN:

Books 391

0816614881; http://www.amazon.com/exec/obidos/ASIN/0816614881/icongroupinterna •

A Parents's Guide to Newborn Screening for Phenylketonuria, Congenital Hypothryroidism and Cystic Fibrosis (2002); ISBN: 1902030729; http://www.amazon.com/exec/obidos/ASIN/1902030729/icongroupinterna

•

A Perspective of sodium and chloride ion-sensitive electrode sweat tests for screening in cystic fibrosis; ISBN: 0903155095; http://www.amazon.com/exec/obidos/ASIN/0903155095/icongroupinterna

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Alive at 25: How I'm Beating Cystic Fibrosis by Andy Lipman (2002); ISBN: 1563526816; http://www.amazon.com/exec/obidos/ASIN/1563526816/icongroupinterna

•

Animal Models for Cystic Fibrosis: The Reserpine-Treated Rat by J. R. Martinez (Editor), B. J. Barbero (Editor) (1985); ISBN: 0911302549; http://www.amazon.com/exec/obidos/ASIN/0911302549/icongroupinterna

•

Cellular and Molecular Basis of Cystic Fibrosis by G. Mastella (Editor), P. M. Quinton (Editor) (1988); ISBN: 0911302638; http://www.amazon.com/exec/obidos/ASIN/0911302638/icongroupinterna

•

Cftr and the Molecular Basis of Cystic Fibrosis (Medical Intelligence Unit Series) by Jeffrey Wine (1998); ISBN: 0412134810; http://www.amazon.com/exec/obidos/ASIN/0412134810/icongroupinterna

•

Clinical Ecology of Cystic Fibrosis: Proceedings of the 18th European Cystic Fibrosis Conference, Madrid, 21-26 May 1993 (International Congress, No) by H. Escobar, et al; ISBN: 0444816704; http://www.amazon.com/exec/obidos/ASIN/0444816704/icongroupinterna

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Consensus Conference on the Management of Cystic Fibrosis with Enzymes by a.G. Knoll (Editor); ISBN: 3540587667; http://www.amazon.com/exec/obidos/ASIN/3540587667/icongroupinterna

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Current Problems and New Trends in Cystic Fibrosis by M. Schoeni (Editor), R. Kraemer (Editor) (1981); ISBN: 3805534175; http://www.amazon.com/exec/obidos/ASIN/3805534175/icongroupinterna

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Cystic Fibrosis by Ann Harris, Maurice Super (Contributor); ISBN: 019262024X; http://www.amazon.com/exec/obidos/ASIN/019262024X/icongroupinterna

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Cystic Fibrosis by Lynn M. Taussig (Editor); ISBN: 0865771146; http://www.amazon.com/exec/obidos/ASIN/0865771146/icongroupinterna

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Cystic Fibrosis by Percy Bray; ISBN: 0285650777; http://www.amazon.com/exec/obidos/ASIN/0285650777/icongroupinterna

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Cystic Fibrosis by Margaret E., Md, Msc, Frcp, Dmed Ed Hodson (Editor), et al; ISBN: 0340742089; http://www.amazon.com/exec/obidos/ASIN/0340742089/icongroupinterna

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Cystic Fibrosis by Pamela B. Davis (Editor); ISBN: 082478815X; http://www.amazon.com/exec/obidos/ASIN/082478815X/icongroupinterna

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Cystic Fibrosis by Michael E. Fritz (1973); ISBN: 0842271333; http://www.amazon.com/exec/obidos/ASIN/0842271333/icongroupinterna

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Cystic Fibrosis by J. C. Warner (Editor) (1992); ISBN: 0443047162; http://www.amazon.com/exec/obidos/ASIN/0443047162/icongroupinterna

392 Cystic Fibrosis

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Cystic Fibrosis by Dennis J. Shale (Editor) (2002); ISBN: 072790826X; http://www.amazon.com/exec/obidos/ASIN/072790826X/icongroupinterna

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Cystic Fibrosis (Diseases & Disorders) by Melissa Abramovitz (2003); ISBN: 1590182995; http://www.amazon.com/exec/obidos/ASIN/1590182995/icongroupinterna

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Cystic Fibrosis (Experience of Illness) by Evan Willis, Rosemary Miller; ISBN: 0415125928; http://www.amazon.com/exec/obidos/ASIN/0415125928/icongroupinterna

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Cystic Fibrosis (Health Watch) by Susan Dudley Gold, et al; ISBN: 0766016552; http://www.amazon.com/exec/obidos/ASIN/0766016552/icongroupinterna

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Cystic Fibrosis (Molecular Medicine) by Peter Goodfellow (Editor); ISBN: 0192618350; http://www.amazon.com/exec/obidos/ASIN/0192618350/icongroupinterna

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Cystic Fibrosis (Perspectives on Disease and Illness) by Judy Monroe; ISBN: 0736810269; http://www.amazon.com/exec/obidos/ASIN/0736810269/icongroupinterna

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Cystic Fibrosis (Venture Book) by Alvin Silverstein, et al; ISBN: 0531125521; http://www.amazon.com/exec/obidos/ASIN/0531125521/icongroupinterna

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Cystic fibrosis : manual of diagnosis and management by Charlotte M. Anderson; ISBN: 0632004789; http://www.amazon.com/exec/obidos/ASIN/0632004789/icongroupinterna

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Cystic fibrosis : projections into the future : an international conference held at the Israel National Academy of Sciences, Jerusalem, Israel, May 25-27, 1976; ISBN: 0883720426; http://www.amazon.com/exec/obidos/ASIN/0883720426/icongroupinterna

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Cystic Fibrosis [DOWNLOAD: PDF] by Datamonitor (Author); ISBN: B00008R3NA; http://www.amazon.com/exec/obidos/ASIN/B00008R3NA/icongroupinterna

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Cystic Fibrosis a Guide for Patient and Family by David M., MD Orenstein (2003); ISBN: 0781741521; http://www.amazon.com/exec/obidos/ASIN/0781741521/icongroupinterna

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Cystic Fibrosis and DNA Tests: Implications of Carrier Screening by United States (1992); ISBN: 0160379865; http://www.amazon.com/exec/obidos/ASIN/0160379865/icongroupinterna

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Cystic Fibrosis in Adults by James R., Md. Yankaskas (Editor), Michael R., Md. Knowles (Editor); ISBN: 0781710111; http://www.amazon.com/exec/obidos/ASIN/0781710111/icongroupinterna

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Cystic Fibrosis in the 20th Century: People, Events, and Progress by Carl F. Doershuk (Editor); ISBN: 0971706409; http://www.amazon.com/exec/obidos/ASIN/0971706409/icongroupinterna

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Cystic Fibrosis of the Pancreas by Anderson; ISBN: 0397603894; http://www.amazon.com/exec/obidos/ASIN/0397603894/icongroupinterna

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Cystic Fibrosis Pulmonary Infections: Lessions from Around the World by A. Bauernfeind, Adolf Baurnfeind (1996); ISBN: 376435027X; http://www.amazon.com/exec/obidos/ASIN/376435027X/icongroupinterna

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Cystic Fibrosis, Basic and Clinical Research: Proceedings of the 17th Annual Meeting of the European Working Group for Cystic Fibrosis, Copenhagen, by Niels Hoiby,

Books 393

Svend Stenvang Pedersen (Editor); ISBN: 0444813780; http://www.amazon.com/exec/obidos/ASIN/0444813780/icongroupinterna •

Cystic Fibrosis: A Family Affair by Jane Chumbley (1999); ISBN: 0859697711; http://www.amazon.com/exec/obidos/ASIN/0859697711/icongroupinterna

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Cystic Fibrosis: A Guide for Parents and Sufferers (A Condor Book) by Percy Bray; ISBN: 0285650769; http://www.amazon.com/exec/obidos/ASIN/0285650769/icongroupinterna

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Cystic Fibrosis: A State-Of-The-Art Series (Thematic Review Series' (2000): 'Respiration) (2001); ISBN: 3805572247; http://www.amazon.com/exec/obidos/ASIN/3805572247/icongroupinterna

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Cystic Fibrosis: Access to and Availability of Specialist Services by Nuala Sterling; ISBN: 0113216009; http://www.amazon.com/exec/obidos/ASIN/0113216009/icongroupinterna

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Cystic Fibrosis: Directory of Authors of New Medical and Scientific Reviews With Subject Index by Science & Life Consultants Association S (1996); ISBN: 0788310437; http://www.amazon.com/exec/obidos/ASIN/0788310437/icongroupinterna

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Cystic Fibrosis: Everything You Need to Know (Your Personal Health) by Wayne Kepron (2003); ISBN: 1552977404; http://www.amazon.com/exec/obidos/ASIN/1552977404/icongroupinterna

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Cystic Fibrosis: Horizons: Proceedings of the Ninth International Cystic Fibrosis Congress, Brighton, England. June 9Th-15th 1984 by David Lawson (Editor), Cystic Fibrosis Research Trust; ISBN: 0471904392; http://www.amazon.com/exec/obidos/ASIN/0471904392/icongroupinterna

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Cystic Fibrosis: Infection, Immunopathology, and Host Response (Allergy and Immunology: Clinical and Experimental Progress) by Richard B. Moss (Editor) (1990); ISBN: 0896031926; http://www.amazon.com/exec/obidos/ASIN/0896031926/icongroupinterna

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Cystic Fibrosis: Manual of Diagnosis and Management by Goodchild, Dodge; ISBN: 0702011290; http://www.amazon.com/exec/obidos/ASIN/0702011290/icongroupinterna

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Cystic Fibrosis: Medical Care by David M. Orenstein (Editor), et al (2000); ISBN: 0781717981; http://www.amazon.com/exec/obidos/ASIN/0781717981/icongroupinterna

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Cystic Fibrosis: Methods and Protocols by William R., Md. Skach (Editor) (2002); ISBN: 0896038971; http://www.amazon.com/exec/obidos/ASIN/0896038971/icongroupinterna

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Cystic Fibrosis: Nutri-tional and Intestinal Disorders by Ross W. Shepherd, et al; ISBN: 0849369541; http://www.amazon.com/exec/obidos/ASIN/0849369541/icongroupinterna

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Cystic Fibrosis: the Facts by Ann Harris, Maurice Super; ISBN: 0192625438; http://www.amazon.com/exec/obidos/ASIN/0192625438/icongroupinterna

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Cystic fibrosis; [papers and discussion of the] Ciba Foundation Study Group No. 32; ISBN: 0700013733; http://www.amazon.com/exec/obidos/ASIN/0700013733/icongroupinterna

394 Cystic Fibrosis

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Cystic Fibrosis; Index to Modern Information by Jonathon Greer (1988); ISBN: 0881649236; http://www.amazon.com/exec/obidos/ASIN/0881649236/icongroupinterna

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Everything You Need to Know About Cystic Fibrosis (Need to Know Library) by Justin Lee; ISBN: 0823933210; http://www.amazon.com/exec/obidos/ASIN/0823933210/icongroupinterna

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Family Nursing: The Case of Cystic Fibrosis by Dorothy A. Whyte (1994); ISBN: 1856285243; http://www.amazon.com/exec/obidos/ASIN/1856285243/icongroupinterna

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Fluid and Electrolyte Abnormalities in Exocrine Glands in Cystic Fibrosis by P. M. Quinton (Editor), et al (1982); ISBN: 091130245X; http://www.amazon.com/exec/obidos/ASIN/091130245X/icongroupinterna

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Fundamental problems of cystic fibrosis and related diseases; selected papers; ISBN: 0883720191; http://www.amazon.com/exec/obidos/ASIN/0883720191/icongroupinterna

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Genetic Counseling and Cystic Fibrosis Carrier Screening: Results of a Survey by United States (1992); ISBN: 0160380936; http://www.amazon.com/exec/obidos/ASIN/0160380936/icongroupinterna

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Genetic Disorders Sourcebook: Basic Consumer Health Information About Hereditary Diseases and Disorders, Including Cystic Fibrosis, Down Syndrome, Hemophilia, Huntington's Disease (Health Reference Series) by Kathy Massimini (Editor) (2000); ISBN: 0780802411; http://www.amazon.com/exec/obidos/ASIN/0780802411/icongroupinterna

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Genetic Studies of the Cystic Fibrosis Transmembrane Conductance Regulator Gene in Belgian Cf Patients (Acta Biomedica Lovaniensia , No 110) by Harry Cuppens (1995); ISBN: 9061866820; http://www.amazon.com/exec/obidos/ASIN/9061866820/icongroupinterna

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Genetics and Epithelial Cell Dysfunction in Cystic Fibrosis (1988); ISBN: 0845151045; http://www.amazon.com/exec/obidos/ASIN/0845151045/icongroupinterna

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Genetics and Epithelial Cell Dysfunction in Cystic Fibrosis: Proceedings (Progress in Clinical and Biological Research, Vol 254) by John R. Riordan (Editor); ISBN: 0471610429; http://www.amazon.com/exec/obidos/ASIN/0471610429/icongroupinterna

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I Have Cystic Fibrosis (One World) by Brenda Pettenuzzo, Victoria Haines; ISBN: 0863137466; http://www.amazon.com/exec/obidos/ASIN/0863137466/icongroupinterna

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Immunological Aspects of Cystic Fibrosis (CRC Series in Immunology and Lymphoid Cell Biology) by Emmanuel Shapira, Gregory B. Wilson (Editor) (1985); ISBN: 084936373X; http://www.amazon.com/exec/obidos/ASIN/084936373X/icongroupinterna

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Inhalation Therapy: Roche and Genentech Symposium European Cystic Fibrosis Conference, Paris, June 1994 (Respiration, Vol 62, Suppl 1) by Ch. Koch, et al (1995); ISBN: 3805561644; http://www.amazon.com/exec/obidos/ASIN/3805561644/icongroupinterna

Books 395

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Ion Transport in Exocrine Glands With Reference to Cystic Fibrosis (Comprehensive Summaries of Uppsala Dissertations, 818) by Ailing Zhang (1999); ISBN: 9155443737; http://www.amazon.com/exec/obidos/ASIN/9155443737/icongroupinterna

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Living With Cystic Fibrosis (Living Well Chronic Conditions) by Susan Heinrichs Gray (2002); ISBN: 156766105X; http://www.amazon.com/exec/obidos/ASIN/156766105X/icongroupinterna

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Miguel and Sarah: Close Friends and Cystic Fibrosis [LARGE PRINT] by Andrea C. Dowell, et al (1999); ISBN: 0964497212; http://www.amazon.com/exec/obidos/ASIN/0964497212/icongroupinterna

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Molecular Analysis of Cftr Mutations in Cystic Fibrosis Patients With Atypical Cf and in Patients With Congenital Bilateral Absence of the Vas (Acta Biomedica Lovaniensia , No 146) by Molecular Teng, Hui Teng (1997); ISBN: 906186805X; http://www.amazon.com/exec/obidos/ASIN/906186805X/icongroupinterna

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Mucus Secretions and Cystic Fibrosis: Conference on Mucus Secretions and Cystic Fibrosis, Southern Ontario, October 24-27, 1976 by G. G. Forstner (Editor) (1977); ISBN: 3805526784; http://www.amazon.com/exec/obidos/ASIN/3805526784/icongroupinterna

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My Life in My Hands: Living on With Cystic Fibrosis by Doug Lab, et al (1990); ISBN: 0962921602; http://www.amazon.com/exec/obidos/ASIN/0962921602/icongroupinterna

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Practical Guidelines for Cystic Fibrosis Care by Catherine M. Hill (Editor); ISBN: 044306234X; http://www.amazon.com/exec/obidos/ASIN/044306234X/icongroupinterna

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Preconception and Prenatal Carrier Screening for Cystic Fibrosis: Clinical and Laboratory Guidelines (2001); ISBN: 0915473747; http://www.amazon.com/exec/obidos/ASIN/0915473747/icongroupinterna

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Psychosocial Aspects of Cystic Fibrosis by Myra Bluebond-Langner (Editor), et al; ISBN: 0340758910; http://www.amazon.com/exec/obidos/ASIN/0340758910/icongroupinterna

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Psychosocial Aspects of Cystic Fibrosis: A Model for Chronic Lung Disease by Paul Patterson (1973); ISBN: 0930194330; http://www.amazon.com/exec/obidos/ASIN/0930194330/icongroupinterna

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Psychosocial Aspects of Cystic Fibrosis; A Model for Chronic Lung Disease.; ISBN: 0882387022; http://www.amazon.com/exec/obidos/ASIN/0882387022/icongroupinterna

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Readings in Cystic Fibrosis by Special Learning Corporation Staff (1984); ISBN: 089568411X; http://www.amazon.com/exec/obidos/ASIN/089568411X/icongroupinterna

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Recent advances in cystic fibrosis research : 8th annual meeting of the European Working Group for Cystic Fibrosis, Bad Gastein, June 2-3, 1978; ISBN: 3805529848; http://www.amazon.com/exec/obidos/ASIN/3805529848/icongroupinterna

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Study of the Cystic Fibrosis Transmembrane Conductance Regulator (Cftr) Protein in Human and Mouse Vas Deferens (Acta Biomedica Lovaniensia, 189) by Ingrid Reynaert (1998); ISBN: 9061869404; http://www.amazon.com/exec/obidos/ASIN/9061869404/icongroupinterna

396 Cystic Fibrosis

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Taking Cystic Fibrosis to School by Cynthia S. Henry, et al (2000); ISBN: 1891383094; http://www.amazon.com/exec/obidos/ASIN/1891383094/icongroupinterna

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Textbook of Cystic Fibrosis by John D. Lloyd-Still; ISBN: 0723670269; http://www.amazon.com/exec/obidos/ASIN/0723670269/icongroupinterna

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The 2002 Official Patient's Sourcebook on Cystic Fibrosis by Icon Health Publications, et al (2002); ISBN: 0597831467; http://www.amazon.com/exec/obidos/ASIN/0597831467/icongroupinterna

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The Cystic Fibrosis Transmembrane Conductance Regulator by Kevin L. Kirk, David C. Dawson (2003); ISBN: 0306478374; http://www.amazon.com/exec/obidos/ASIN/0306478374/icongroupinterna

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Treatment of the Hospitalized Cystic Fibrosis Patient by David M. Orenstein (Editor), et al; ISBN: 0824795008; http://www.amazon.com/exec/obidos/ASIN/0824795008/icongroupinterna

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Understanding Cystic Fibrosis (Understanding Health and Sickness Series) by Karen Hopkin, Karen Hopkins (1998); ISBN: 0878059679; http://www.amazon.com/exec/obidos/ASIN/0878059679/icongroupinterna

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Volume 1, Cystic Fibrosis--Current Topics by J. A. Dodge (Editor), et al; ISBN: 0471931012; http://www.amazon.com/exec/obidos/ASIN/0471931012/icongroupinterna

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Volume 2, Cystic Fibrosis--Current Topics by J. A. Dodge (Editor), et al; ISBN: 0471951668; http://www.amazon.com/exec/obidos/ASIN/0471951668/icongroupinterna

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “cystic fibrosis” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:11 •

[Collection of miscellaneous publications on cystic fibrosis].; Year: 1968

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A Perspective of sodium and chloride ion-sensitive electrode sweat tests for screening in cystic fibrosis Author: Bray, P. T.; Year: 1972; Cardiff, Wales: Chemistry Dept., Univ. of Wales Institute of Science and Technology, 1975

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Chest physical therapy in cystic fibrosis and chronic obstructive pulmonary diseases Author: Baran, D.; Year: 1969; Ghent: European Press, 1977; ISBN: 9062951716

11

In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a "Books" button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

Books 397

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Chronic bronchitis and cystic fibrosis: two chronic obstructive lung diseases of adults: February 1-2, 1977, San Diego, California. Author: George and Elizabeth Frankel GAP Conference, San Diego, Calif., Feb. 1-2, 1977.; Year: 1958; Atlanta: Research Program,

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Communications, VIIe Congrès international de la mucoviscidose = Proceedings, VIIth International Cystic Fibrosis Congress, Paris, 31 mai, 1, 2, 3 juin 1976. Author: International Cystic Fibrosis (Mucoviscidosis) Association.; Year: 1975; Paris: [s.n.], 1978

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Cystic fibrosis: a comprensive bibliography of the medical literature, 1813-1972 Author: Holsclaw, Douglas S.,; Year: 1976; [Bethesda, Md.]: U. S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health; Atlanta: distributed by

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Cystic fibrosis. Edited by Ruth Porter and Maeve O'Connor. Author: O'Connor, Maeve.; Year: 1969; Boston, Little, Brown, 1968

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Cystic fibrosis; physiology and pathophysiology of serous secretion, clinical investigations and therapy. Proceedings. Geigy-Symposium. Edited by E. Rossi and E. Stoll. Author: Rossi, E. (Ettore); Year: 1969; Basel, New York, Karger, 1967

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Directory of cystic fibrosis care, teaching and research centers and clinical centers. Author: National Cystic Fibrosis Research Foundation (U.S.); Year: 1967; Atlanta [1972?]

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Guide to diagnosis and management of cystic fibrosis: a syllabus for physicians. Author: Cystic Fibrosis Foundation. Professional Education Committee.; Year: 1975; Atlanta: The Foundation, 1971

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Guide to diagnosis and management of cystic fibrosis; a syllabus for physicians. Prepared by the Professional Education Committee. Author: National Cystic Fibrosis Research Foundation (U.S.); Year: 1977; New York [1963]

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Guide to drug therapy in patients with cystic fibrosis. Author: National Cystic Fibrosis Research Foundation (U.S.); Year: 1975; Atlanta: The Foundation, 1974

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Problems in reproductive physiology and anatomy in young adults with cystic fibrosis: [proceedings] February 20-21, 1975, New Orleans, Louisiana. Author: Cystic Fibrosis Foundation. Research Program.; Year: 1973; Atlanta: Research Program,

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Proceedings of the fifth International Cystic Fibrosis Conference, Churchill College, Cambridge, England, September 22nd-26th, 1969. Editor: David Lawson. Author: Lawson, David.; Year: 1969; [London]

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Psychosocial aspects of heterozygote detection in cystic fibrosis; [proceedings] May 14-15, 1975, New Orleans, Louisiana. Author: Cystic Fibrosis Foundation. Research Program.; Year: 1973; Atlanta: Research Program,

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Pulmonary complications in cystic fibrosis. Author: National Cystic Fibrosis Research Foundation (U.S.); Year: 1972; [New York] National

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Research on cystic fibrosis; transactions... Edited by Rustin McIntosh. Author: McIntosh, Rustin,; Year: 1959; [Baltimore, French-Bray, c1960]

Chapters on Cystic Fibrosis In order to find chapters that specifically relate to cystic fibrosis, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and cystic fibrosis using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates

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and language you prefer, and the format option “Book Chapter.” Type “cystic fibrosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on cystic fibrosis: •

Hereditary and Childhood Disorders of the Pancreas, Including Cystic Fibrosis Source: in Feldman, M. Friedman, L.S. Sleisenger, M.H. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 7th ed. [2-volume set]. St. Louis, MO: Saunders. 2002. p. 881-912. Contact: Available from Elsevier. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 545-2522. Fax (800) 568-5136. Website: www.us.elsevierhealth.com. PRICE: $229.00 plus shipping and handling. ISBN: 0721689736. Summary: Understanding the role of developmental genes in human disease remains in its infancy, but emerging evidence suggests that altered function plays a role in developmental malformations and rare congenital disorders. This chapter focuses on recent advances in the understanding of pancreatic disorders associated with mutations in key pancreatic genes and on common acquired pancreatic diseases in children, including cystic fibrosis. The chapter is from a comprehensive and authoritative textbook that covers disorders of the gastrointestinal tract, biliary tree, pancreas, and liver, as well as the related topics of nutrition and peritoneal disorders. Topics include the genetic basis of congenital disorders of morphogenesis, including an overview of embryology, pancreatic agenesis and hypoplasia, agenesis of the dorsal pancreas, agenesis of the ventral pancreas, annular pancreas, and heterotopic pancreatic tissue; ductal abnormalities; inherited syndromes with major pancreatic manifestations, including cystic fibrosis, Shwachman-Diamond syndrome, Johanson-Blizzard syndrome, Pearson's Marrow-Pancreas syndrome, and other rare syndromes affecting the pancreas; gene mutations predisposing to acute and chronic pancreatitis; inherited disorders of metabolism causing pancreatitis; pancreatic insufficiency syndromes; and acquired pancreatic disease in children, including etiology, clinical features, complications, and treatment. The chapter includes a mini-outline with page citations, full-color illustrations, and extensive references. 8 figures. 10 tables. 363 references.

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Toxigenic Diarrheas, Congenital Diarrheas, and Cystic Fibrosis: Disorders of Intestinal Ion Transport Source: in Hoffman, J.F. and De Weer, P., eds. Annual Review of Physiology. Palo Alto, CA: Annual Reviews Inc. 1993. Volume 55: 631-655. Contact: Available from Annual Reviews Inc. 4139 El Camino Way, P.O. Box 10139, Palo Alto, CA 94303-0139. (800) 523-8635. Fax (415) 424-0910. E-mail: [email protected]. PRICE: $46.00. ISBN: 0824303555. ISSN: 00664278. Individual chapter reprints available from Annual Reviews Preprints and Reprints. (800) 347-8007 or (415) 259-5017. Base price $13.50 per article. Summary: This entry from the Annual Review of Physiology discusses the pathophysiology of enterotoxic diarrheas, congenital diarrheas, and cystic fibrosis (CF). The authors begin with a brief summary of the ion transport properties of the intestine as they relate to the active secretion of electrolytes. Other topics include Vibrio Cholerae enterotoxins, including the cholera toxin and the enteric nervous system; heat-stable Escherichia Coli enterotoxin and guanylin; congenital defects of intestinal electrolyte transport; and directions for future research. 3 figures. 128 references.

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Directories In addition to the references and resources discussed earlier in this chapter, a number of directories relating to cystic fibrosis have been published that consolidate information across various sources. The Combined Health Information Database lists the following, which you may wish to consult in your local medical library:12 •

1998-1999 Complete Directory for People with Rare Disorders Source: Lakeville, CT: Grey House Publishing, Inc. 1998. 726 p. Contact: Available from Grey House Publishing, Inc. Pocket Knife Square, Lakeville, CT 06039. (860) 435-0868. Fax (860) 435-0867. PRICE: $190.00. ISBN: 0939300982. Summary: This directory, from the National Organization for Rare Disorders (NORD) provides a wealth of information on diseases and organizations. The directory offers four sections: disease descriptions, disease specific organizations, umbrella organizations, and government agencies. In the first section, the directory includes descriptions of 1,102 rare diseases in alphabetical order. Each entry defines the disorder, then refers readers to the organizations that might be of interest. Diseases related to digestive diseases include achalasia, Addison's disease, Alagille syndrome, Barrett's esophagus, Budd Chiari syndrome, Caroli disease, celiac sprue, cholangitis, cholecystitis, cirrhosis, colitis, Crohn's disease, Cushing syndrome, cystic fibrosis, diverticulitis, Dubin Johnson syndrome, fructose intolerance, galactosemia, gastritis, gastroesophageal reflux, hepatitis, Hirschprung's disease, Hurler syndrome, imperforate anus, irritable bowel syndrome, jejunal atresia, Korsakoff's syndrome, lipodystrophy, maple syrup urine disease, Morquio syndrome, polyposis, porphyria, proctitis, prune belly syndrome, sarcoidosis, Stevens Johnson syndrome, Tropical sprue, tyrosinemia, valinemia, vitamin E deficiency, Whipple's disease, Wilson's disease, and Zollinger Ellison syndrome. Each of the 445 organizations listed in the second section is associated with a specific disease or group of diseases. In addition to contact information, there is a descriptive paragraph about the organization and its primary goals and program activities. Entries include materials published by the organization as well as the diseases the organizations cover, which refer readers to Section I. The third section lists 444 organizations that are more general in nature, serving a wide range of diseases (for example, the American Liver Foundation). The final section describes 74 agencies that are important federal government contacts that serve the diverse needs of individuals with rare disorders. A name and key word index concludes the volume.

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9Health Fair Referral Guide Source: Denver, CO, Nine Health Services, Inc., 216 p., 1994. Contact: Nine Health Services, Inc., 825 East Speer Boulevard, Suite 200, Denver, CO 80218. (303) 698-4455. Summary: 9Health Fair Referral Guide is a publication of Nine Health Services, Inc. in Denver, Colorado, and is primarily used as a resource guide by health professionals at 9Health Fairs across Colorado. The Guide was compiled as a general reference with an

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You will need to limit your search to “Directory” and “cystic fibrosis” using the "Detailed Search" option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find directories, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Select your preferred language and the format option “Directory.” Type “cystic fibrosis” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months.

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emphasis on agencies that serve individuals and families on a limited income. It does, however, have resources for all income levels. Each resource listed in the Referral Guide includes an address, phone number, available services and resources, and cost. Resources are listed in each of the following categories: Crisis and emergency numbers, acquired immune deficiency syndrome (AIDS), alopecia areata, Alzheimer's disease, arthritis, blood pressure screenings, cancer, cardiovascular, cerebral palsy, chiropractic, clinics, cystic fibrosis, dental care, dermatology, diabetes, disabled resources, eating disorders, epilepsy, general consumer information and education, government agencies, hearing, home health care, hospitals in metro Denver, immunizations, intestinal diseases, kidney disease, leukemia, living wills and related issues, lupus, medical societies, mental health, migrant health program, multiple sclerosis, muscular dystrophy, nutrition, orthodontics, ostomies, Parkinson's disease, physical therapy, podiatry, post-polio, prostate and testicular cancer, rehabilitation centers, respiratory diseases, runaways and shelters, safety, senior services, sexuality and family planning, sexually transmitted diseases, sickle cell anemia, shelter, smoking withdrawal and smokeless tobacco, social services agencies, speech and language, sports medicine, stress and grief, substance abuse (including alcohol and drug), suicide prevention, transplant resources, transportation, victim assistance, vision, and weight control. Resources are also listed for the following Colorado regions: Central and Mountain area, Eastern, Northern, Southern, and Western. Information numbers and referral services are also listed.

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CHAPTER 8. MULTIMEDIA ON CYSTIC FIBROSIS Overview In this chapter, we show you how to keep current on multimedia sources of information on cystic fibrosis. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.

Video Recordings An excellent source of multimedia information on cystic fibrosis is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “cystic fibrosis” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Videorecording (videotape, videocassette, etc.).” Type “cystic fibrosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on cystic fibrosis: •

There is a future Source: Durham, NC: Duke University Medical Center. 1990. 1 videotape (14:30 minutes). Contact: Available from Julia Gaskel, Duke University Medical Center, Box 2916, Durham, NC 27710. Telephone: (919) 684-3401. $35.00 , rental $20.00. Summary: This videotape shows interviews of eight adolescents describing their struggles and the uncertainties of living with a chronic illness. The different illnesses include cancer, sickle cell disease, asthma, Hodgkin disease, and cystic fibrosis. These young people talk frankly about their problems and address issues such as friendship, independence, and the possibility of death.

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Health Care Professionals' Guide to Xerostomia Source: Bethesda, MD: Sjogren's Syndrome Foundation, Inc. 1997. (videocassette).

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Contact: Available from Sjogren's Syndrome Foundation, Inc. 8120 Woodmont Avenue, Suite 530, Bethesda MD 20814-1437. (301) 718-0300 or (800) 475-6473. Fax (301) 718-0322. Website: www.sjogrens.org. PRICE: $29.00. Summary: This videotape program reviews xerostomia (dry mouth). The program begins with an overview of the anatomy and physiology of the salivary glands, followed by a discussion of the three functional roles of saliva: digestion (and taste facilitation), lubrication, and protection (including antimicrobial and pH mechanisms). The narrator notes that saliva is also being used more and more as a diagnostic tool to measure systemic health. The program begins with a physician narrating, then includes interviews with two middle age women who have xerostomia; the interviews focus on the impact xerostomia has on quality of life and on the difficulties of obtaining an accurate diagnosis. The program then details the three causes of xerostomia: medical therapies (including drug side effects, radiation therapy, and surgery or trauma of the salivary glands), systemic disorders (including Sjogren's syndrome, HIV, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, graft versus host disease, sarcoidosis, amyloidosis, cystic fibrosis, and neural disease affecting the salivary glands), and dehydration. The program emphasizes that xerostomia is not a natural consequence of the aging process. The program then reviews the clinical signs and oral complications of xerostomia; each is illustrated with a color photograph. Other topics include problems associated with xerostomia, the need for a multidisciplinary team approach to patients with salivary gland dysfunction, diagnostic tests used, treatment options (including chewing activity, oral moisturizing agents, and oral pilocarpine hydrochloride), determining residual salivary gland function, and the behavioral and lifestyle changes that can help patients cope with xerostomia. •

What You Should Know About Xerostomia (Dry Mouth) Source: Fairburn, GA: National Oral Cancer Awareness (NOCAP). 199x. (videocassette). Contact: Available from American Dental Hygienists' Association (ADHA). 444 North Michigan Avenue, Suite 3400, Chicago, IL 60611. (800) 243-2342 (press 2) or (312) 4408900. Fax (312) 467-1806. Website: www.adha.org. PRICE: $18.00. Item Number 3917 COM. Summary: This videocassette program describes the problem of xerostomia (dry mouth). The introduction stresses that the health impact of saliva goes far beyond the mouth and includes eating, talking, tooth maintenance, and tasting. The program then features a person with xerostomia describing how it feels to have problems with dry mouth. A brief description of the chemical makeup of salivary and the anatomy of the salivary glands follow. The next section discusses the potential causes of xerostomia, including radiation therapy, especially for cancer of the head and neck; drug effects, particularly from antihistamines, tranquilizers, and some blood pressure medications; anxiety or depression, even without drug therapy; dehydration; and systemic diseases, including Sjogren's syndrome, lupus, cystic fibrosis, rheumatoid arthritis, and scleroderma. The narrator stresses that aging itself is not necessarily the cause of xerostomia. Complications of xerostomia include dry lips, burning mouth or tongue, constant thirst, difficulty talking or swallowing, impaired taste, dental caries (cavities), candidiasis (a fungal infection), and problems related to dehydration. Viewers are encouraged to work closely with health care providers to obtain an accurate diagnosis and employ strategies to cope with xerostomia. Treatment encompasses three options: eliminating the cause of the xerostomia, if possible; stimulating the salivary glands with sugar-free chewing gum, oral moisturizers, or the prescription drug pilocarpine; and using other measures to get relief, including saliva substitutes, frequent sips of water,

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room humidifiers (especially during winter), and lip balm. The program concludes with a reminder that xerostomia results in the need for increased attention to dental hygiene, including increased dental visits, limiting sugar intake, the use of fluoride, and the prevention of candidiasis. The program encourages viewers to learn about xerostomia, seek help, and improve the quality of their lives.

Bibliography: Multimedia on Cystic Fibrosis The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in cystic fibrosis (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on cystic fibrosis: •

Cystic fibrosis [filmstrip] Source: Trainex Corporation; Year: 1976; Format: Filmstrip; Garden Grove, Calif.: Trainex, c1976

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Cystic fibrosis [slide] Source: Harry Shwachman; Year: 1976; Format: Slide; New York: Medcom, c1976

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Cystic fibrosis [videorecording] Source: [presented by] the University of Texas Medical School at Houston; produced by UT-TV, Houston; Year: 1991; Format: Videorecording; [Houston, Tex.]: UT-TV, Houston, c1991

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Cystic fibrosis population carrier screening [videorecording] Source: [HSTN]; Year: 2003; Format: Videorecording; Carrollton, TX: Primedia Workplace Learning, c2003

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Diagnosing & treating cystic fibrosis [videorecording] Source: a presentation of Films for the Humanities & Sciences; a Leeds University Television production for Shotlist; Year: 1999; Format: Videorecording; Princeton, N.J.: Films for the Humanities & Sciences, c1999

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Diagnosis and management of cystic fibrosis [motion picture] Source: National Institute of Arthritis and Metabolic Diseases and National Cystic Fibrosis Research Foundation; [made by] Sturgis-Grant Productions, inc; Year: 1967; Format: Motion picture; New York: The Foundation; [Atlanta: for loan by National Medical Audiovisual Center], 1967

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Diagnosis of cystic fibrosis in adults [slide] Source: presented by the American Thoracic Society, American Lung Association, ALA/ATS Component Committee on Learning Resources; Year: 1981; Format: Slide; [New York, N.Y.]: The Committee, 1981

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Highlights [electronic resource]: selected proceedings from the Thirteenth Annual North American Cystic Fibrosis Conference, Seattle, Washington, October 7-10, 1999 Source: Cystic Fibrosis Foundation; produced by Med Doc Medical Communications; Year: 1999; Format: Electronic resource; Bloomsbury, NJ: Med Doc Medical Communications, [1999?]

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Living with cystic fibrosis [motion picture] Source: [produced by] Amram Nowak Associates for the National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Public Health Service, the Department of Health and Human Servi; Year: 1980; Format: Motion picture; Rockville, Md.: The Foundation, c1980

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New concepts in managing malabsorption in cystic fibrosis [videorecording] Source: developed and produced for Temple University School of Medicine by GardinerCaldwell SynerMed; Year: 1991; Format: Videorecording; [Califon, N.J.]: GardinerCaldwell SynerMed, c1991

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PKU and cystic fibrosis [slide]: sterilization and artificial insemination Source: coauthored by Garrett E. Bergman, John H. Sorenson; produced by the Medical College of Pennsylvania, Office of Medical Education, Audiovisual Section; Year: 1978; Format: Slide; [Philadelphia]: The Section, c1978

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Sweat testing for cystic fibrosis of the pancreas [videorecording] Source: author, George K. Summer; Year: 1981; Format: Videorecording; Chapel Hill, NC: Health Sciences Consortium, 1981

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The Early diagnosis of cystic fibrosis [slide] Source: American Lung Association, American Thoracic Society; produced by Emerson-Braxton & Co; Year: 1985; Format: Slide; [New York, N.Y.]: American Lung Association, c1985

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CHAPTER 9. PERIODICALS AND NEWS ON CYSTIC FIBROSIS Overview In this chapter, we suggest a number of news sources and present various periodicals that cover cystic fibrosis.

News Services and Press Releases One of the simplest ways of tracking press releases on cystic fibrosis is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “cystic fibrosis” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to cystic fibrosis. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “cystic fibrosis” (or synonyms). The following was recently listed in this archive for cystic fibrosis: •

Adeno-associated virus is safe vector for cystic fibrosis gene therapy Source: Reuters Industry Breifing Date: July 24, 2003 http://www.reutershealth.com/archive/2003/07/24/business/links/20030724drgd001 .html

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Montelukast reduces eosinophilic inflammation in cystic fibrosis patients Source: Reuters Industry Breifing Date: January 01, 2003

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Corus cystic fibrosis drug well tolerated in phase I Source: Reuters Industry Breifing Date: December 11, 2002

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Celltech withdraws from cystic fibrosis collaboration with Targeted Genetics Source: Reuters Industry Breifing Date: December 04, 2002

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Demegen earns US orphan drug designation for peptide to treat cystic fibrosis-related infections Source: Reuters Industry Breifing Date: November 05, 2002

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Inspire wins fast-track status for cystic fibrosis drug, inks partnership Source: Reuters Industry Breifing Date: October 04, 2002

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Antibiotic may help some cystic fibrosis patients Source: Reuters Health eLine Date: September 27, 2002

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Azithromycin may increase FEV1 in children with cystic fibrosis Source: Reuters Industry Breifing Date: September 26, 2002

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Study raises possibility of new cystic fibrosis type Source: Reuters Health eLine Date: August 07, 2002

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Gender gap found in cystic fibrosis diagnosis Source: Reuters Health eLine Date: July 19, 2002

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Oxford GlycoSciences, Cystic Fibrosis Foundation partner on disease detection Source: Reuters Industry Breifing Date: July 12, 2002

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Test could help fight deadly bug in cystic fibrosis Source: Reuters Health eLine Date: June 12, 2002

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Summer camp beneficial for cystic fibrosis patients Source: Reuters Health eLine Date: May 02, 2002

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Blocking bug adaptation might help cystic fibrosis Source: Reuters Health eLine Date: March 25, 2002

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Chronic sinusitis linked to cystic fibrosis gene Source: Reuters Health eLine Date: January 07, 2002

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Repairing defect with pre-mRNA partially corrects cystic fibrosis pathology Source: Reuters Industry Breifing Date: December 21, 2001

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Transplant doesn't help most with cystic fibrosis Source: Reuters Health eLine Date: December 04, 2001

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Altering lung acidity may help in cystic fibrosis Source: Reuters Health eLine Date: November 19, 2001

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Tranzyme, Cystic Fibrosis Foundation affiliate to develop cell lines for CF therapy Source: Reuters Industry Breifing Date: October 09, 2001

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Inhaled tobramycin can clear P. aeruginosa from airways of cystic fibrosis patients Source: Reuters Industry Breifing Date: September 24, 2001

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Development-stage cystic fibrosis drugs look promising Source: Reuters Industry Breifing Date: August 28, 2001

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Australia has best cystic fibrosis screening Source: Reuters Health eLine Date: August 27, 2001

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Demegen gets $1.5 million grant to develop inhalable Cystic Fibrosis treatment Source: Reuters Industry Breifing Date: August 22, 2001

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Study: Poorer cystic fibrosis patients fare worse Source: Reuters Health eLine Date: June 14, 2001

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Cystic fibrosis gene therapy faces many hurdles Source: Reuters Health eLine Date: June 04, 2001

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SciClone cystic fibrosis drug is granted orphan drug status in Europe Source: Reuters Industry Breifing Date: May 22, 2001

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InterMune to co-develop MoliChem investigational cystic fibrosis drug Source: Reuters Industry Breifing Date: May 11, 2001

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Cystic fibrosis patients have positive outlook Source: Reuters Health eLine Date: May 02, 2001

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UK to screen all newborns for cystic fibrosis Source: Reuters Health eLine Date: April 30, 2001

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Height helps measure survival in cystic fibrosis Source: Reuters Health eLine Date: April 13, 2001

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Intravenous pamidronate increases BMD in adults with cystic fibrosis Source: Reuters Industry Breifing Date: March 26, 2001

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Profile Therapeutics and Forum develop inhaled antibiotic for cystic fibrosis Source: Reuters Industry Breifing Date: March 01, 2001

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InterMune begins phase II trial of Actimmune for cystic fibrosis Source: Reuters Industry Breifing Date: February 28, 2001

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Discovery could improve cystic fibrosis treatment Source: Reuters Health eLine Date: February 28, 2001

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Dyax cystic fibrosis candidate enters phase IIa trial Source: Reuters Industry Breifing Date: February 13, 2001

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Internet group helps cystic fibrosis patients Source: Reuters Health eLine Date: February 07, 2001

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Early cystic fibrosis screening can improve health Source: Reuters Health eLine Date: January 08, 2001

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Sensor technology updates sweat test for cystic fibrosis Source: Reuters Industry Breifing Date: December 22, 2000

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Sensors replace lab techs in new cystic fibrosis test Source: Reuters Health eLine Date: December 06, 2000

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Targeted Genetics begins phase II cystic fibrosis drug study Source: Reuters Industry Breifing Date: November 17, 2000

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Fine mist could enhance gene therapy for cystic fibrosis Source: Reuters Health eLine Date: October 23, 2000

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Genentech recalls one lot of cystic fibrosis treatment Pulmozyme Source: Reuters Industry Breifing Date: October 12, 2000

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Bacteria form shield against drugs in cystic fibrosis Source: Reuters Health eLine Date: October 11, 2000

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Chronic sinus infections linked to cystic fibrosis gene Source: Reuters Health eLine Date: October 10, 2000

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Inspire files IND for potential cystic fibrosis treatment Source: Reuters Industry Breifing Date: October 03, 2000

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Affymetrix to develop GeneChip array for cystic fibrosis studies Source: Reuters Industry Breifing Date: September 05, 2000

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Newborn cystic fibrosis screening provides double payoff Source: Reuters Health eLine Date: September 01, 2000

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PathoGenesis receives European patent for cystic fibrosis treatment Source: Reuters Industry Breifing Date: June 01, 2000 The NIH

Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “cystic fibrosis” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “cystic fibrosis” (or synonyms). If you know the name of a company that is relevant to cystic fibrosis, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/.

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BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “cystic fibrosis” (or synonyms).

Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “cystic fibrosis” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on cystic fibrosis: •

Secondary Diabetes in Children Source: On the Cutting Edge. 22(6): 9-10. Winter 2001. Contact: Available from American Dietetic Association. 216 West Jackson Boulevard, Suite 800, Chicago, IL 60606-6995. (800) 877-4746. Summary: Secondary diabetes is diagnosed when glucose levels are elevated as the result of another disorder or medications; this article discusses secondary diabetes in children. The author notes that children diagnosed with secondary diabetes may find it hard to adjust to the daily self care routines needed for good blood glucose (sugar) control while dealing with the reality of not one but two disease states. Individualizing educational plans to allow for flexibility while still promoting good metabolic control is important for these patients. Identifying key dietary changes and sick-day nutritional guidelines for the child can also foster better choices by patients when they are independently making decisions. A meal plan containing 10 to 20 percent of daily calorie intake from protein is encourages and the remainder of calories should be distributed between carbohydrates and fats. The benefits of consistency in meal times as well as portions should be stressed for a child with secondary diabetes. The design of the meal plan may be influenced by the primary diagnosis (e.g., AIDS or cystic fibrosis). 6 references.

Academic Periodicals covering Cystic Fibrosis Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to cystic fibrosis. In addition to these sources, you can search for articles covering cystic fibrosis that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the

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name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

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CHAPTER 10. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for cystic fibrosis. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI® Advice for the Patient® can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with cystic fibrosis. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The

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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to cystic fibrosis: Aminoglycosides •

Systemic - U.S. Brands: Amikin; Garamycin; G-Mycin; Jenamicin; Kantrex; Nebcin; Netromycin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202027.html

Anesthetics •

Dental - U.S. Brands: Anbesol Maximum Strength Gel; Anbesol Maximum Strength Liquid; Anbesol Regular Strength Gel; Anbesol Regular Strength Liquid; Anbesol, Baby; Benzodent; Chloraseptic Lozenges; Chloraseptic Lozenges, Children's; Dentapaine; Dent-Zel-Ite; Hurricaine; Numzi http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202038.html

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Ophthalmic - U.S. Brands: Ak-Taine; Ak-T-Caine; Alcaine; Ocu-Caine; Ophthaine; Ophthetic; Opticaine; Pontocaine; Spectro-Caine http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202039.html

•

Ophthalmic - U.S. Brands: Ak-Taine; Ak-T-Caine; Alcaine; Ocu-Caine; Ophthaine; Ophthetic; Opticaine; Pontocaine; Spectro-Caine http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202057.html

•

Ophthalmic - U.S. Brands: Ak-Taine; Ak-T-Caine; Alcaine; Ocu-Caine; Ophthaine; Ophthetic; Opticaine; Pontocaine; Spectro-Caine http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202221.html

•

Ophthalmic - U.S. Brands: Ak-Taine; Ak-T-Caine; Alcaine; Ocu-Caine; Ophthaine; Ophthetic; Opticaine; Pontocaine; Spectro-Caine http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202654.html

•

Parenteral-Local - U.S. Brands: Carbocaine; Carbocaine with Neo-Cobefrin; Chirocaine; Citanest Forte; Citanest Plain; Dalcaine; Dilocaine; Duranest; Duranest-MPF; Isocaine; L-Caine; Lidoject-1; Lidoject-2; Marcaine; Marcaine Spinal; Nesacaine; Nesacaine-MPF; Novocain; Octocaine; Poloc http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202040.html

•

Rectal - U.S. Brands: Americaine Hemorrhoidal; Fleet Relief; Nupercainal; Pontocaine Cream+; Pontocaine Ointment; ProctoFoam/non-steroid; Tronolane; Tronothane http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202041.html

•

Topical - U.S. Brands: Almay Anti-itch Lotion; Americaine Topical Anesthetic First Aid Ointment; Americaine Topical Anesthetic Spray; Butesin Picrate; DermaFlex; Dermoplast; Lagol; Nupercainal Cream; Nupercainal Ointment; Pontocaine Cream; Pontocaine Ointment; Pramegel; Prax; http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202042.html

Beta-Carotene •

Systemic - U.S. Brands: Lumitene; Max-Caro http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202623.html

Researching Medications 415

Cephalosporins •

Systemic - U.S. Brands: Ancef; Ceclor; Ceclor CD; Cedax; Cefadyl; Cefizox; Cefobid; Cefotan; Ceftin; Cefzil; Ceptaz; Claforan; Duricef; Fortaz; Keflex 20; Keftab 20; Kefurox; Kefzol; Mandol; Maxipime; Mefoxin; Monocid; Omnicef; Rocephin; Suprax; Tazicef; Tazidime; Vantin; Velo http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202119.html

Ciprofloxacin •

Ophthalmic - U.S. Brands: Ciloxan http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202655.html

Corticosteroids •

Dental - U.S. Brands: Kenalog in Orabase; Orabase-HCA; Oracort; Oralone http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202010.html

•

Inhalation - U.S. Brands: AeroBid; AeroBid-M; Azmacort; Beclovent; Decadron Respihaler; Pulmicort Respules; Pulmicort Turbuhaler; Vanceril; Vanceril 84 mcg Double Strength http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202011.html

•

Nasal - U.S. Brands: Beconase; Beconase AQ; Dexacort Turbinaire; Flonase; Nasacort; Nasacort AQ; Nasalide; Nasarel; Nasonex; Rhinocort; Vancenase; Vancenase AQ 84 mcg; Vancenase pockethaler http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202012.html

•

Ophthalmic - U.S. Brands: AK-Dex; AK-Pred; AK-Tate; Baldex; Decadron; Dexair; Dexotic; Econopred; Econopred Plus; Eflone; Flarex; Fluor-Op; FML Forte; FML Liquifilm; FML S.O.P. HMS Liquifilm; Inflamase Forte; Inflamase Mild; I-Pred; Lite Pred; Maxidex; Ocu-Dex; Ocu-Pred; Ocu-Pr http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202013.html

•

Otic - U.S. Brands: Decadron http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202014.html

•

Rectal - U.S. Brands: Anucort-HC; Anu-Med HC; Anuprep HC; Anusol-HC; Anutone-HC; Anuzone-HC; Cort-Dome; Cortenema; Cortifoam; Hemorrhoidal HC; Hemril-HC Uniserts; Proctocort; Proctosol-HC; Rectosol-HC http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203366.html

Dornase Alfa •

Inhalation - U.S. Brands: Pulmozyme http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202710.html

Fluoroquinolones •

Systemic - U.S. Brands: Avelox; Cipro; Cipro I.V. Floxin; Floxin I.V. Levaquin; Maxaquin; Noroxin; Penetrex; Tequin; Zagam http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202656.html

Insulin •

Systemic - U.S. Brands: Humulin 50/50; Humulin 70/30; Humulin 70/30 Pen; Humulin L; Humulin N; Humulin N Pen; Humulin R; Humulin R, Regular U500 (Concentrated); Humulin U; Lente; Lente Iletin II; Novolin 70/30; Novolin 70/30 PenFill; Novolin 70/30 Prefilled; Novolin L; Novoli http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203298.html

416 Cystic Fibrosis

Ipratropium •

Inhalation - U.S. Brands: Atrovent http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202304.html

•

Nasal - U.S. Brands: Atrovent http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202713.html

Pilocarpine •

Ophthalmic - U.S. Brands: Adsorbocarpine; Akarpine; Ocu-Carpine; Pilagan; Pilocar; Piloptic; Piloptic-1; Pilostat http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202465.html

•

Systemic - U.S. Brands: Salagen http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202726.html

Tobramycin •

Ophthalmic - U.S. Brands: AKTob; Tobrex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202570.html

Vancomycin •

Oral - U.S. Brands: Vancocin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202589.html

•

Systemic - U.S. Brands: Vancocin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202590.html

Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.

Mosby’s Drug Consult™ Mosby’s Drug Consult™ database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html.

Researching Medications 417

Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.

Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to cystic fibrosis by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/. Scroll down the page, and on the left toolbar, click on “Orphan Drug Designation Database.” On this page (http://www.rarediseases.org/search/noddsearch.html), type “cystic fibrosis” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for cystic fibrosis: •

2-0-desulfated heparin (trade name: Aeropin) http://www.rarediseases.org/nord/search/nodd_full?code=1

•

recombinant human alpha 1-antitrypsin (rAAT) (trade name: NONE Assigned) http://www.rarediseases.org/nord/search/nodd_full?code=1196

•

Meropenem (trade name: Merrem IV) http://www.rarediseases.org/nord/search/nodd_full?code=1041

•

N-acetylcysteinate (trade name: Nacystelyn Dry Powder) http://www.rarediseases.org/nord/search/nodd_full?code=1078

•

N-acetycsteinate (trade name: Nacystelyn Dry Powder Inhaler) http://www.rarediseases.org/nord/search/nodd_full?code=1089

•

p1-(uridine 5')-p4-(2'-deoxycytidine 5'-) tetrapho http://www.rarediseases.org/nord/search/nodd_full?code=1100

418 Cystic Fibrosis

•

p1-(uridine 5' -)-p4-(2' -deoxcytidine 5' -) tetra http://www.rarediseases.org/nord/search/nodd_full?code=1106

•

aztreonam (trade name: NONE Assigned) http://www.rarediseases.org/nord/search/nodd_full?code=1236

•

carbamic acid, ((4-((30((4-10(4-hydroxypheny1)-1-m http://www.rarediseases.org/nord/search/nodd_full?code=1238

•

p1(uridine 5'-)-p4-(2'-deoxycytidine 5'-) tetrapho (trade name: NONE Assigned) http://www.rarediseases.org/nord/search/nodd_full?code=1190

•

recombinant human alpha-1-antitrypsin (rAAT) (trade name: NONE Assigned) http://www.rarediseases.org/nord/search/nodd_full?code=1230

•

Uridine 5'-triphosphate http://www.rarediseases.org/nord/search/nodd_full?code=229

•

aztreonam http://www.rarediseases.org/nord/search/nodd_full?code=1260

•

carbamic acid, ((4-((3-((4-((1-(4-hydroxypheny1)-1 http://www.rarediseases.org/nord/search/nodd_full?code=1262

•

octavalent Psuedomonas aeruginosa O-polsaccaharide (trade name: Aerugen) http://www.rarediseases.org/nord/search/nodd_full?code=1282

•

Mucoid esopolysaccharide Pseudomonas hyperimmune g (trade name: MEPIG) http://www.rarediseases.org/nord/search/nodd_full?code=166

•

Mucoid exopolysaccharide Pseudomonas hyperimmune g (trade name: Mepig) http://www.rarediseases.org/nord/search/nodd_full?code=170

•

US http://www.rarediseases.org/nord/search/nodd_full?code=221

•

Adeno-associated viral-based vector cystic fibrosi http://www.rarediseases.org/nord/search/nodd_full?code=513

•

Lipid/DNA human cystic fibrosis gene http://www.rarediseases.org/nord/search/nodd_full?code=254

•

Dornase alfa (trade name: Pulmozyme) http://www.rarediseases.org/nord/search/nodd_full?code=285

•

Cystic fibrosis Tr gene therapy (recombinant adeno (trade name: AdGVCFTR.10) http://www.rarediseases.org/nord/search/nodd_full?code=384

•

Cystic fibrosis gene therapy http://www.rarediseases.org/nord/search/nodd_full?code=389

•

Recombinant secretory leucocyte protease inhibitor http://www.rarediseases.org/nord/search/nodd_full?code=392

Researching Medications 419

•

Cystic fibrosis transmembrane conductance regulato http://www.rarediseases.org/nord/search/nodd_full?code=393

•

Cystic fibrosis transmembrane conductance regulato http://www.rarediseases.org/nord/search/nodd_full?code=415

•

DMP 777 http://www.rarediseases.org/nord/search/nodd_full?code=435

•

Recombinant human gelsolin http://www.rarediseases.org/nord/search/nodd_full?code=462

•

Dextran sulfate (inhaled, aerosolized) (trade name: Uendex) http://www.rarediseases.org/nord/search/nodd_full?code=480

•

Amiloride HCL solution for inhalation http://www.rarediseases.org/nord/search/nodd_full?code=534

•

Tobramycin for inhalation (trade name: TOBI) http://www.rarediseases.org/nord/search/nodd_full?code=62

•

8 Cyclopentyl 1,3-dipropylxanthine http://www.rarediseases.org/nord/search/nodd_full?code=830

•

P1, P4-Di(uridine 5'-tetaphosphate), tetrasodium s http://www.rarediseases.org/nord/search/nodd_full?code=944

•

Duramycin http://www.rarediseases.org/nord/search/nodd_full?code=862

If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

421

APPENDICES

423

APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute13: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

•

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

•

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

•

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

•

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

13

These publications are typically written by one or more of the various NIH Institutes.

424 Cystic Fibrosis

•

National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm

•

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

•

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

•

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

•

National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

•

National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/

•

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

•

National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

•

National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

•

National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm

•

National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

•

National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

•

National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

•

Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

•

National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

•

National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

•

Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

•

Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

Physician Resources 425

NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.14 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:15 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

•

Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

•

Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

•

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

•

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

•

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

14

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 15 See http://www.nlm.nih.gov/databases/databases.html.

426 Cystic Fibrosis

•

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

•

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html The Combined Health Information Database

A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to one of the following: Brochure/Pamphlet, Fact Sheet, or Information Package, and “cystic fibrosis” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For the publication date, select “All Years.” Select your preferred language and the format option “Fact Sheet.” Type “cystic fibrosis” (or synonyms) into the “For these words:” box. The following is a sample result: •

Cystic fibrosis and DNA tests: Implications of carrier screening Source: Washington, DC: Office of Technology Assessment, U.S. Congress. 1992. 301 pp. Contact: Available from Superintendent of Documents, U.S. Government Printing Office, P.O. Box 371954, Pittsburgh, PA 15250-7954. Telephone: (202) 512-1991 for public information (D.C. office) or (202) 512-1800 for ordering and publication information (D.C. office) / fax: (202) 512-1293 (public information); (202) 512-2250 (ordering) / Web site: http://www.access.gpo.gov. $29.00. Summary: This report examines the scientific, clinical, legal, economic, and social considerations of widespread carrier screening for cystic fibrosis. Specific topics covered include medical aspects, the state of the art in genetics, quality assurance, education and counseling, financing, discrimination issues, costs and cost-effectiveness, and CF carrier screening in the United Kingdom. Appendices discuss the epidemiology of mutations for cystic fibrosis and cases studies of other carrier screening programs.

•

Introduction to cystic fibrosis for patients and families Source: Bethesda, MD: Cystic Fibrosis Foundation. 1991. 95 pp. Contact: Available from Cystic Fibrosis Foundation, 6931 Arlington Road, Suite 200, Bethesda, MD 20814. Telephone: (301) 951-4422 or (800) 344- 4823 / fax: (301) 951-6378 / e-mail: [email protected] / Web site: http://www.cff.org. Available at no charge. Summary: This book is written to help families of children with cystic fibrosis learn about the disease and identify sources of information and support. Chapters discuss what is cystic fibrosis and how it is diagnosed, how it affects the sweat glands, respiratory system, gastrointestinal system, and the reproductive system, and how to live with cystic fibrosis.

Physician Resources 427

The NLM Gateway16 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.17 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “cystic fibrosis” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 22511 367 122 See Details 8 23008

HSTAT18 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.19 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.20 Simply search by “cystic fibrosis” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists21 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are 16

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

17

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 18 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 19 20

The HSTAT URL is http://hstat.nlm.nih.gov/.

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations. 21 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

428 Cystic Fibrosis

used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.22 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.23 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

The Genome Project and Cystic Fibrosis In the following section, we will discuss databases and references which relate to the Genome Project and cystic fibrosis. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).24 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “cystic fibrosis” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for cystic fibrosis: 22

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 23 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 24 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

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Cystic Fibrosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?219700

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Cystic Fibrosis Modifier 1 Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?603855

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Cystic Fibrosis Transmembrane Conductance Regulator Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?602421

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Cystic Fibrosis with Helicobacter Pylori Gastritis, Megaloblastic Anemia, and Subnormal Mentality Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?219721 Genes and Disease (NCBI - Map)

The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •

Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html

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Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html

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Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html

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Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html

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Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html

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Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html

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Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez

Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •

3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

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Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

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Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

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NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/

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Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide

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OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

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PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

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ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

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Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

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PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

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Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

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Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy

To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then

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select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “cystic fibrosis” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database25 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database26 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “cystic fibrosis” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).

25

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 26 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.

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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on cystic fibrosis can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to cystic fibrosis. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to cystic fibrosis. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “cystic fibrosis”:

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Guides on cystic fibrosis Cystic Fibrosis http://www.nlm.nih.gov/medlineplus/cysticfibrosis.html

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Other Guides Acne http://www.nlm.nih.gov/medlineplus/acne.html Acne http://www.nlm.nih.gov/medlineplus/tutorials/acneloader.html Cystic Fibrosis http://www.nlm.nih.gov/medlineplus/tutorials/cysticfibrosisloader.html Laboratory Tests http://www.nlm.nih.gov/medlineplus/laboratorytests.html Pancreatic Cancer http://www.nlm.nih.gov/medlineplus/pancreaticcancer.html Pancreatic Diseases http://www.nlm.nih.gov/medlineplus/pancreaticdiseases.html Preventing Disease and Staying Healthy http://www.nlm.nih.gov/medlineplus/preventingdiseaseandstayinghealthy.html Pulmonary Fibrosis http://www.nlm.nih.gov/medlineplus/pulmonaryfibrosis.html Respiratory Diseases http://www.nlm.nih.gov/medlineplus/respiratorydiseasesgeneral.html

Within the health topic page dedicated to cystic fibrosis, the following was listed: •

General/Overviews Cystic Fibrosis http://www.nlm.nih.gov/medlineplus/tutorials/cysticfibrosisloader.html Cystic Fibrosis Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DS00287 JAMA Patient Page: Cystic Fibrosis Source: American Medical Association http://www.medem.com/medlb/article_detaillb.cfm?article_ID=ZZZIX1MDUEC &sub_cat=572

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Diagnosis/Symptoms Sweat Testing Source: Cystic Fibrosis Foundation http://www.cff.org/living_with_cf/sweat_testing.cfm Trypsinogen Test Source: American Association for Clinical Chemistry

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http://www.labtestsonline.org/understanding/analytes/trypsinogen/test.html •

Treatment Facts about Lung Transplantation Source: Cystic Fibrosis Foundation http://www.cff.org/living_with_cf/facts_about_lung_transplantation.cfm

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Nutrition Nutrition and Cystic Fibrosis: Changes through Life http://www.cff.org/publications/files/NutritionandCFChangesThroughLife.pdf Pancreatic Enzyme Replacement in People with Cystic Fibrosis Source: Cystic Fibrosis Foundation http://www.cff.org/publications/files/NutritionPancreaticEnzymeReplacement.p df

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Specific Conditions/Aspects Burkholderia Cepacia Frequently Asked Questions Source: Cystic Fibrosis Foundation http://www.cff.org/living_with_cf/B_cepacia_faq.cfm Day-to-Day: Know Your Health Insurance Coverage Source: Cystic Fibrosis Foundation http://www.cff.org/publications/files/DaytoDayKnowYourInsurance.pdf

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Children Cystic Fibrosis Source: Nemours Foundation http://kidshealth.org/kid/health_problems/heart/cystic_fibrosis.html Cystic Fibrosis Source: Nemours Foundation http://kidshealth.org/parent/medical/lungs/cf.html School, Enzymes, and Sports for the Child with Cystic Fibrosis Source: Cystic Fibrosis Foundation http://www.cff.org/publications/files/NutritionSchoolEnzymesSportsandCF.pdf

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From the National Institutes of Health Facts about Cystic Fibrosis Source: National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/health/public/lung/other/cf.htm

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Organizations Cystic Fibrosis Foundation http://www.cff.org/ National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/

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National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov/ •

Prevention/Screening Cystic Fibrosis Testing: The Decision Is Yours Source: American College of Obstetricians and Gynecologists http://www.medem.com/medlb/article_detaillb.cfm?article_ID=ZZZJE8XUUSC& sub_cat=640 Cystic Fibrosis Testing: What Happens If Both My Partner and I Are Carriers? Source: American College of Obstetricians and Gynecologists http://www.medem.com/medlb/article_detaillb.cfm?article_ID=ZZZQRC4JUSC& sub_cat=640

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Research Bacterial Slime Clogs Cystic Fibrosis Lungs Source: National Institute of General Medical Sciences http://www.nigms.nih.gov/news/releases/brief_greenberg.html New Theory Proposed for Cystic Fibrosis Infections Source: National Institute of Allergy and Infectious Diseases http://www.nih.gov/news/pr/nov2001/niaid-19.htm New Treatment for People with CF Significantly Improves Lung Function Source: Cystic Fibrosis Foundation http://www.cff.org/content.cfm?contentID=326

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Teenagers Cystic Fibrosis Source: Nemours Foundation http://kidshealth.org/teen/diseases_conditions/digestive/cystic_fibrosis.html

You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on cystic fibrosis. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive:

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Questions and Facts About Cystic Fibrosis Source: Rockville, MD.: Cystic Fibrosis Foundation. 5 p. Contact: Available from Cystic Fibrosis Foundation. 6000 Executive Boulevard, Suite 309, Rockville, MD 20852. Summary: This brochure describes Cystic Fibrosis (CF), how it occurs and its genetic etiology, identifying CF carriers, symptoms, complications of the disease, age of onset, treatment, and the outlook for the CF patient. Also included is a description of the Cystic Fibrosis Foundation and the programs it supports.

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For adults with cystic fibrosis: Facts on reproduction Source: Madison, WI: Great Lakes Regional Genetics Group, University of Wisconsin Madison. 1993. 12 pp. Contact: Available from National Maternal and Child Health Clearinghouse, 2070 Chain Bridge Road, Suite 450, Vienna, VA 22182-2536. Telephone: (703) 356-1964 or (888) 4344MCH / fax: (703) 821-2098 / e-mail: [email protected] / Web site: http://www.nmchc.org. Available at no charge. Summary: This pamphlet, aimed at adults with cystic fibrosis who want to have a child, describes how the disease might have affected the male and female reproductive organs, how to overcome or circumvent these problems, and the genetics of the disease, so that the couple can make an informed choice. [Funded by the Maternal and Child Health Bureau].

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Cystic fibrosis: Guidelines for care for children with special health care needs Source: Minneapolis, MN: Services for Children with Handicaps, Minnesota Department of Health. 1990. 60 pp. Contact: Available from Minnesota Children with Special Health Care Needs, 717 Delaware Street, S.E., Box 9441, Minneapolis, MN 55440. Telephone: (612) 623-5150 or (800) 728-5420. Summary: This publication was developed for families and health professionals caring for children with cystic fibrosis. The guidelines are aimed at helping families coordinate the health care needed for the optimal growth and development of their child. General information concerning cystic fibrosis is provided along with an overview of the family centered health care team approach to treating a child or adolescent with this metabolic disorder. The publication also outlines the child's needs at various stages of her life in terms of health care, development, school, and child care. A glossary and list of resources are also included. Healthfinder™

Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database:

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Check Your Cystic Fibrosis I.Q. Summary: Test your knowledge of cystic fibrosis. Answer true or false to the statements online and find out what you know or don't know about this respiratory disease. Source: American Association for Respiratory Care http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6169

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Cystic Fibrosis Research Directions Summary: In recent years, the pace of basic research has increased rapidly, and scientists hope to translate new knowledge about the molecular basis of the disease to new therapies to improve the lives of Source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=1135

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Facts About Cystic Fibrosis Summary: Written for consumers, this brochure presents a general overview of cystic fibrosis (CF) -- a chronic, progressive, and frequently fatal genetic disease of the body's mucus glands that primarily Source: National Heart, Lung, and Blood Institute, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=1144

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Find Chapters and Care Centers Summary: Visit this web site to locate a cystic fibrosis chapter or supported-care center in your area accredited by the Cystic Fibrosis Foundation. Source: Cystic Fibrosis Foundation http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=4954

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Gene Therapy and Cystic Fibrosis Summary: A patient education brochure that discusses gene therapy as a potentially a life-saving treatment that tackles the root cause of cystic fibrosis (CF), rather than the symptoms. Source: Cystic Fibrosis Foundation http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=5032

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Sweat Testing Procedure and Commonly Asked Questions Summary: This online fact sheet answers some of the commonly asked questions about the sweat test, a diagnostic procedure for Cystic Fibrosis. Source: Cystic Fibrosis Foundation http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=5014

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The NIH Search Utility The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to cystic fibrosis. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. PEDBASE Similar to NORD, PEDBASE covers relatively rare disorders, limited mainly to pediatric conditions. PEDBASE was designed by Dr. Alan Gandy. To access the database, which is more oriented to researchers than patients, you can view the current list of health topics covered at the following Web site: http://www.icondata.com/health/pedbase/pedlynx.htm. Additional Web Sources

A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

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Family Village: http://www.familyvillage.wisc.edu/specific.htm

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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

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Med Help International: http://www.medhelp.org/HealthTopics/A.html

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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

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WebMD®Health: http://my.webmd.com/health_topics

Associations and Cystic Fibrosis The following is a list of associations that provide information on and resources relating to cystic fibrosis: •

Canadian Cystic Fibrosis Foundation Telephone: (416) 485-9149 Toll-free: (800) 378-2233 Fax: (416) 485-0960 Email: [email protected] Web Site: www.cysticfibrosis.ca

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Background: The Canadian Cystic Fibrosis Foundation (CCFF) is a national not-forprofit organization dedicated to helping individuals with cystic fibrosis (CF) and their family members. Cystic fibrosis is a rare inherited disorder that affects many exocrine ('outward-secreting') glands of the body including the sweat glands, salivary glands, and those within the pancreas and respiratory system. Due to unusually thick secretions of mucus that clog and obstruct air passages of the lungs, affected individuals experience chronic coughing and an increased susceptibility to repeated lung infections. Individuals with CF also exhibit an inability to break down food and absorb fats and nutrients properly; have abnormally salty sweat containing elevated levels of chloride and sodium; and/or may demonstrate other abnormalities. Established in 1960, the Canadian Cystic Fibrosis Foundation is committed to conducting research into improved care and treatment for CF, seeking a cure or control for the disorder, and promoting public awareness. In addition, the Foundation offers support groups, engages in patient advocacy, provides referrals, and promotes patient, professional, and general education. Relevant area(s) of interest: Cystic Fibrosis, Mucoviscidosis, Pancreatic Fibrosis •

Children's Liver Alliance Telephone: (718) 987-6200 Fax: (718) 987-6200 Email: [email protected] Web Site: http://livertx.org Background: The Children's Liver Alliance (formerly the Biliary Atresia and Liver Transplant Network) is an international not-for-profit voluntary health organization that was established in 1995. The mission of the Children s Liver Alliance (CLA) is to empower the hearts and minds of children with liver disease, their families, and the medical professionals who care for them. CLA disseminates educational information about pediatric liver diseases and transplantation via written publications, seminars, and the Internet. CLA provides a support network for families of children with liver disease (both pre- and post-liver transplantation), acts as liaison between families and health care professionals, offers networking services, and promotes the importance of organ donation and tranplantation. CLA s publications include the bimonthly newsletter 'The Biliary Tree.'. Relevant area(s) of interest: Cystic Fibrosis

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Cochrane Cystic Fibrosis and Genetic Disorders Review Group Telephone: (151) 252-5696 Fax: (151) 252-5456 Email: [email protected] Web Site: www.liv.ac.uk/cfgd Background: Cochrane Cystic Fibrosis and Genetic Disorders Review Group is an international network of health care professionals, researchers and consumers preparing, maintaining, and disseminating systematic reviews of randomized control trials in the treatment of cystic fibrosis and other genetic disorders. The group's aim is to help people make well-informed decisions about healthcare with the aid of these reviews. Abstracts (summaries) of these reviews are available free of charge on the

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group's website. The Chochrane Collaboration is a non-profit organization, established as a company, limited by guarantee, and registered as a charity in the UK. Relevant area(s) of interest: Cystic Fibrosis •

Cystic Fibrosis Foundation Telephone: (301) 951-4422 Toll-free: (800) 344-4823 Fax: (301) 951-6378 Email: [email protected] Web Site: http://www.cff.org Background: The Cystic Fibrosis Foundation (CFF) is a voluntary, not-for-profit organization dedicated to raising funds for research to find a cure for cystic fibrosis (CF) and improving the quality of life for individuals with the disease. Cystic fibrosis is a rare inherited disorder that affects many exocrine ('outward-secreting') glands of the body including the sweat glands, salivary glands, and those within the pancreas and respiratory system. Established in 1955 and currently consisting of more than 70 chapters and branch offices across the country, the Cystic Fibrosis Foundation funds its own network of CF research centers at leading universities and medical schools throughout North America. It provides a variety of grants to scientists to fund CF research and finances over 100 CF care centers nationwide. The organization supports clinical trials at its care centers to test new drug therapies for CF and works closely with Congress, the Food and Drug Administration, and pharmaceutical companies to speed the development of new drugs to treat CF. The Foundation offers affected individuals, family members, health care professionals, and the public a variety of informational materials including research updates, regular newsletters, and brochures on several topics such as health insurance and financial assistance programs. Relevant area(s) of interest: Cystic Fibrosis, Fibrocystic Disease of Pancreas, Mucoviscidosis, Pancreatic Fibrosis

•

Cystic Fibrosis Research, Inc Telephone: (650) 404-9975 Fax: (650) 404-9981 Email: [email protected] Web Site: http://www.cfri.org Background: Cystic Fibrosis Research, Inc. (CFRI) is an independent, not-for-profit, voluntary health organization dedicated to offering emotional and educational support to families living with cystic fibrosis (CF). Cystic fibrosis is a genetic disorder that affects many exocrine glands of the body including the sweat glands, salivary glands, and glands within the pancreas and respiratory system. Associated characteristics include susceptibility to repeated lung infections, an impaired ability to absorb fats and other nutrients from food, abnormally salty sweat containing elevated levels of chloride and sodium, and/or other abnormalities. Cystic fibrosis is inherited as an autosomal recessive genetic trait. Established in 1975 and currently consisting of approximately 14,000 members, Cystic Fibrosis Research, Inc. is committed to providing a variety of educational and support programs for affected families including mail and telephone referrals and support services, regular membership meetings, parent support groups, CF support groups for ages 13 to adult, an annual conference, and a family retreat. The organization also funds cystic fibrosis research at major research centers in the U.S.,

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supports ongoing gene therapy research, and offers community educational programs. Cystic Fibrosis Research, Inc. also provides a variety of educational materials, brochures, such as a teacher's guide to CF; a children's newsletter entitled 'Aspirations'; and a regular newsletter for affected families and professionals entitled 'CFRI News.'. •

Cystic Fibrosis Trust Telephone: 020 8646 7211 Fax: 020 8313 0462 Email: [email protected] Background: The Cystic Fibrosis Trust is a voluntary organization in the United Kingdom dedicated to raising funds for hospital and medical research into improved treatment and prevention of cystic fibrosis (CF), a rare inherited disorder that affects many exocrine ('outwardly-secreting') glands of the body including the sweat glands, salivary glands, and those within the pancreas and respiratory system. Established in 1964, the Cystic Fibrosis Trust has approximately 16,000 members in 300 chapters throughout the United Kingdom. The CF Trust provides a network of support groups for affected individuals and family members and offers several materials including brochures, pamphlets, fact sheets, and videos. Relevant area(s) of interest: Cystic Fibrosis, Fibrocystic Disease of Pancreas, Mucosis, Mucoviscidosis, Pancreatic Fibrosis

•

Cystic Fibrosis Worldwide Telephone: +31 492 520241 Fax: +31 492 599068 Email: [email protected], [email protected] Web Site: www.cfww.org Background: Cystic Fibrosis Worldwide works to promote access to appropriate care and education for those people living with the disease in developing countries and to improve the knowledge of cystic fibrosis among medical professionals and governments worldwide. Cystic fibrosis is an inherited disorder that affects several 'outwardly secreting' glands, including respiratory, pancreatic, salivary, and sweat glands. CFW supports the search for a cure and promotes international linkage in the sharing of information. The current organization was created in January 2003 after the merger of International Cystic Fibrosis Adults (IACFA) and International Cystic Fibrosis (Mucoviscidosis) Association (ICFMA). Its philosophy is that people whose lives are affected by cystic fibrosis must have equal opportunities to participate in their society no matter where they live. Relevant area(s) of interest: Cystic Fibrosis

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International Association of Cystic Fibrosis Adults Telephone: (978) 456-8387 Fax: (978) 456-8387 Email: [email protected] Web Site: http://www.ourworld.compuserve.com/homepages/fantognini/iacfa.htm

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Background: The International Association of Cystic Fibrosis Adults (IACFA) is a nonprofit organization that provides information and support to individuals over the age of 18 who are diagnosed with cystic fibrosis, their families, allied health workers, and medical professionals. Cystic fibrosis (CF) is a rare inherited disorder that affects many exocrine ('outward-secreting') glands of the body including the sweat glands, salivary glands, and those within the pancreas and respiratory system. Due to unusually thick secretions of mucus that clog and obstruct air passages of the lungs, affected individuals experience chronic coughing and an increased susceptibility to repeated lung infections. Individuals with CF also exhibit an inability to break down food and absorb fats and nutrients properly; have abnormally salty sweat containing elevated levels of chloride and sodium; and/or may demonstrate other abnormalities. IACFA was established in 1982 and its mission is to assist in improving the quality of life by identifying common problems, attempting to define possible solutions, and enhancing the exchange of information in the world community of CF. The Association also endeavors to cooperate with the CF community in defining the new needs arising in the treatment of adults with CF and in raising the awareness of the medical profession to adults with CF as having specific requirements. IACFA publishes a quarterly self-titled newsletter and, every two years, sponsors an international conference open to adults with cystic fibrosis and their partners and siblings. Relevant area(s) of interest: Cystic Fibrosis, Fibrocystic Disease of Pancreas, Mucosis, Mucoviscidosis, Pancreatic Fibrosis •

March of Dimes Birth Defects Foundation Telephone: (914) 428-7100 Toll-free: (888) 663-4637 Fax: (914) 997-4763 Email: [email protected] Web Site: http://www.marchofdimes.com Background: The March of Dimes Birth Defects Foundation is a national not-for-profit organization that was established in 1938. The mission of the Foundation is to improve the health of babies by preventing birth defects and infant mortality. The March of Dimes funds programs of research, community services, education, and advocacy. Educational programs that seek to prevent birth defects are important to the Foundation and to that end it also produces a wide variety of printed informational materials and videos. The Pregnancy and Newborn Health Education Center staffs trained health information specialists who provide researched information on pregnancy issues, complications and risks, newborn care, birth defects, genetic diseases and related topics as well as referrals to relevant organizations and support groups. Relevant area(s) of interest: Cystic Fibrosis

•

National Kidney Foundation Telephone: (212) 889-2210 Toll-free: (800) 622-9010 Fax: (212) 689-9261 Web Site: http://www.kidney.org Background: Established in 1950, the National Kidney Foundation is a voluntary notfor-profit organization dedicated to preventing kidney and urinary tract diseases, improving the health and well-being of individuals and families affected by these diseases, and increasing the availability of organs for transplantation. The Foundation is

444 Cystic Fibrosis

committed to gaining adequate support for research and research training; fostering continuing education of health care professionals; expanding and developing patient services and community resources; increasing public awareness of kidney diseases; monitoring health policy development; and increasing fund-raising for new programs and research. In addition, the Foundation supports and promotes medical research into the causes, prevention, and treatment of kidney diseases. A wide variety of educational materials is produced and distributed by the Foundation. These materials are listed in a booklet entitled Public and Professional Education Materials. •

Second Wind Lung Transplant Association, Inc Telephone: Toll-free: (888) 222-2690 Fax: (727) 442-9762 Email: [email protected] Web Site: http://www.2ndwind.org Background: Second Wind Lung Transplant Association, Inc. is a not-for-profit organization dedicated to improving the quality of life for lung transplant recipients, lung surgery candidates, people with related pulmonary concerns, and their families. The Association provides support, advocacy, education, information, and guidance through a spirit of service, 'adding years to their lives and life to their years.' Established in 1995 by a group of lung transplant recipients, candidates, and their families, Second Wind has quarterly support group meetings to provide educational programs (e.g., on nutrition, effects of medications and exercise, physical therapy) for both lung transplant candidates and recipients; to share experiences; and to enjoy social activities. In addition, the organization provides educational programs; seeks to increase Organ Donor Awareness; and provides a quarterly newsletter entitled 'AirWays' to its members. Relevant area(s) of interest: Cystic Fibrosis

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to cystic fibrosis. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with cystic fibrosis. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about cystic fibrosis. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797.

Patient Resources 445

Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “cystic fibrosis” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “cystic fibrosis”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “cystic fibrosis” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “cystic fibrosis” (or a synonym) into the search box, and click “Submit Query.”

447

APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.27

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

27

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

448 Cystic Fibrosis

libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)28: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

•

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

28

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

Finding Medical Libraries 449

•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

•

Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

•

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

•

Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

•

Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

•

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

•

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

•

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

•

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

•

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

•

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

•

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

•

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

450 Cystic Fibrosis

•

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

•

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

•

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

•

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

•

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

•

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

•

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

•

Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

•

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

Finding Medical Libraries 451

•

Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

•

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

•

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

•

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

•

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

•

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

•

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

•

Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

•

Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

452 Cystic Fibrosis

•

South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

•

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

453

ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

•

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

•

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on cystic fibrosis: •

Basic Guidelines for Cystic Fibrosis Cystic fibrosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000107.htm Cystic fibrosis - nutritional considerations Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002437.htm Cystic fibrosis - resources Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002176.htm

•

Signs & Symptoms for Cystic Fibrosis Abdominal distention Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003122.htm Abdominal pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003120.htm

454 Cystic Fibrosis

Breathing difficulty Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003075.htm Clubbing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003282.htm Cough Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003072.htm Coughing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003072.htm Delayed growth Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003021.htm Diarrhea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003126.htm Discouraged Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003213.htm Dyspnea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003075.htm Easy fatigue Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Fatigue Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Foul smelling stools Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003132.htm Hemoptysis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003073.htm Lung disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000066.htm Osteoarthropathy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003282.htm Stools, pale or clay colored Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003129.htm Stress Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Tachypnea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003071.htm

Online Glossaries 455

Weight loss Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003107.htm Wheezing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003070.htm •

Diagnostics and Tests for Cystic Fibrosis Albumin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003480.htm ALT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003473.htm ANA Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003535.htm CAT scan Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm Chest CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003788.htm Chest X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm Diffusing capacity Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003854.htm Echocardiogram Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm Fecal fat Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003588.htm Pulmonary function Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003443.htm Pulmonary function tests Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003853.htm Secretin stimulation test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003892.htm Sweat chloride Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003630.htm

456 Cystic Fibrosis

Sweat test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003630.htm Trypsin and chymotrypsin in stool Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003594.htm Upper GI and small bowel series Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003816.htm X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003337.htm •

Nutrition for Cystic Fibrosis Fat Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002468.htm Fats Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002468.htm Normal growth and development Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002456.htm Protein Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002467.htm Vitamins Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002399.htm Yogurt Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002463.htm

•

Surgery and Procedures for Cystic Fibrosis Lung transplant Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003010.htm

•

Background Topics for Cystic Fibrosis Bile Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002237.htm Chronic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002312.htm Cystic fibrosis - support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002176.htm Distal Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002346.htm

Online Glossaries 457

Meconium Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002262.htm Pain reliever Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002123.htm Percussion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002281.htm Respiratory Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002290.htm Support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002150.htm

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

459

CYSTIC FIBROSIS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 1-phosphate: A drug that halts cell suicide in human white blood cells. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetaminophen: Analgesic antipyretic derivative of acetanilide. It has weak antiinflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH] Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH]

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Adenosine Monophosphate: Adenylic acid. Adenine nucleotide containing one phosphate group esterified to the sugar moiety in the 2'-, 3'-, or 5'-position. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of cyclic AMP and pyrophosphate from ATP. EC 4.6.1.1. [NIH] Adenylate Kinase: An enzyme that catalyzes the phosphorylation of AMP to ADP in the presence of ATP or inorganic triphosphate. EC 2.7.4.3. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adrenergic Agents: Drugs that act on adrenergic receptors or affect the life cycle of adrenergic transmitters. Included here are adrenergic agonists and antagonists and agents that affect the synthesis, storage, uptake, metabolism, or release of adrenergic transmitters. [NIH]

Adrenergic Agonists: Drugs that bind to and activate adrenergic receptors. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]

Aetiology: Study of the causes of disease. [EU] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH]

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Agenesis: Lack of complete or normal development; congenital absence of an organ or part. [NIH]

Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Airway Obstruction: Any hindrance to the passage of air into and out of the lungs. [NIH] AK: Enzyme of the biosynthetic pathway. [NIH] Albuterol: A racemic mixture with a 1:1 ratio of the r-isomer, levalbuterol, and s-albuterol. It is a short-acting beta 2-adrenergic agonist with its main clinical use in asthma. [NIH] Aldehydes: Organic compounds containing a carbonyl group in the form -CHO. [NIH] Alendronate: A nonhormonal medication for the treatment of postmenopausal osteoporosis in women. This drug builds healthy bone, restoring some of the bone loss as a result of osteoporosis. [NIH] Alfalfa: A deep-rooted European leguminous plant (Medicago sativa) widely grown for hay and forage. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alkalosis: A pathological condition that removes acid or adds base to the body fluids. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergens: Antigen-type substances (hypersensitivity, immediate). [NIH]

that

produce

immediate

hypersensitivity

Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha 1-Antitrypsin: Plasma glycoprotein member of the serpin superfamily which inhibits trypsin, neutrophil elastase, and other proteolytic enzymes. Commonly referred to as alpha 1-proteinase inhibitor (A1PI), it exists in over 30 different biochemical variant forms known collectively as the PI (protease inhibitor) system. Hereditary A1PI deficiency is associated with pulmonary emphysema. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alpha-fetoprotein: AFP. A protein normally produced by a developing fetus. AFP levels are usually undetectable in the blood of healthy nonpregnant adults. An elevated level of AFP suggests the presence of either a primary liver cancer or germ cell tumor. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments.

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Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alveolar Process: The thickest and spongiest part of the maxilla and mandible hollowed out into deep cavities for the teeth. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Amber: A yellowish fossil resin, the gum of several species of coniferous trees, found in the alluvial deposits of northeastern Germany. It is used in molecular biology in the analysis of organic matter fossilized in amber. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amylase: An enzyme that helps the body digest starches. [NIH] Amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. [NIH] Anabolic: Relating to, characterized by, or promoting anabolism. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]

Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a,

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C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Anode: Electrode held at a positive potential with respect to a cathode. [NIH] Anomalies: Birth defects; abnormalities. [NIH] Anorectal: Pertaining to the anus and rectum or to the junction region between the two. [EU] Antiarrhythmic: An agent that prevents or alleviates cardiac arrhythmia. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antifungal: Destructive to fungi, or suppressing their reproduction or growth; effective against fungal infections. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage

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causes immune complex diseases. [NIH] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Apheresis: Components being separated out, as leukapheresis, plasmapheresis, plateletpheresis. [NIH] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Appendicitis: Acute inflammation of the vermiform appendix. [NIH] Aptitude: The ability to acquire general or special types of knowledge or skill. [NIH] Apyrase: A calcium-activated enzyme that catalyzes the hydrolysis of ATP to yield AMP and orthophosphate. It can also act on ADP and other nucleoside triphosphates and diphosphates. EC 3.6.1.5. [NIH] Aqueous: Having to do with water. [NIH] Arachidonate 12-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 12-hydroperoxyarachidonate (12-HPETE) which is itself rapidly converted by a peroxidase to 12-hydroxy-5,8,10,14-eicosatetraenoate (12-HETE). The 12-hydroperoxides are preferentially formed in platelets. EC 1.13.11.31. [NIH] Arachidonate 15-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 15-hydroperoxyarachidonate (15-HPETE) which is rapidly converted to 15-hydroxy5,8,11,13-eicosatetraenoate (15-HETE). The 15-hydroperoxides are preferentially formed in neutrophils and lymphocytes. EC 1.13.11.33. [NIH] Arachidonate Lipoxygenases: Enzymes catalyzing the oxidation of arachidonic acid to hydroperoxyarachidonates (HPETES). These products are then rapidly converted by a peroxidase to hydroxyeicosatetraenoic acids (HETES). The positional specificity of the enzyme reaction varies from tissue to tissue. The final lipoxygenase pathway leads to the leukotrienes. EC 1.13.11.- . [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatic: Having a spicy odour. [EU]

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Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Articular: Of or pertaining to a joint. [EU] Ascending Colon: The part of the colon on the right side of the abdomen. [NIH] Ascites: Accumulation or retention of free fluid within the peritoneal cavity. [NIH] Ascorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [NIH] Aspergillosis: Infections with fungi of the genus Aspergillus. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atelectasis: Incomplete expansion of the lung. [NIH] ATP: ATP an abbreviation for adenosine triphosphate, a compound which serves as a carrier of energy for cells. [NIH] Atresia: Lack of a normal opening from the esophagus, intestines, or anus. [NIH] Atrial: Pertaining to an atrium. [EU] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Atropine: A toxic alkaloid, originally from Atropa belladonna, but found in other plants, mainly Solanaceae. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autogenic: A type of succession when the developing vegetation itself is the cause for the succession. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign

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and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autopsy: Postmortem examination of the body. [NIH] Azithromycin: A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. [NIH] Azoospermia: Absence of spermatozoa in the semen, or failure of formation of spermatozoa. [EU] Aztreonam: A monocyclic beta-lactam antibiotic originally isolated from Chromobacterium violaceum. It is resistant to beta-lactamases and is used in gram-negative infections, especially of the meninges, bladder, and kidneys. It may cause a superinfection with grampositive organisms. [NIH] Bacillus: A genus of Bacillaceae that are spore-forming, rod-shaped cells. Most species are saprophytic soil forms with only a few species being pathogenic. [NIH] Bacteremia: The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacteriostatic: 1. Inhibiting the growth or multiplication of bacteria. 2. An agent that inhibits the growth or multiplication of bacteria. [EU] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Base Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH]

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Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Bereavement: Refers to the whole process of grieving and mourning and is associated with a deep sense of loss and sadness. [NIH] Beta-Lactamases: Enzymes found in many bacteria which catalyze the hydrolysis of the amide bond in the beta-lactam ring. Well known antibiotics destroyed by these enzymes are penicillins and cephalosporins. EC 3.5.2.6. [NIH] Beta-Thromboglobulin: A platelet-specific protein which is released when platelets aggregate. Elevated plasma levels have been reported after deep venous thrombosis, preeclampsia, myocardial infarction with mural thrombosis, and myeloproliferative disorders. Measurement of beta-thromboglobulin in biological fluids by radioimmunoassay is used for the diagnosis and assessment of progress of thromboembolic disorders. [NIH] Bezoars: Concretions of swallowed hair, fruit or vegetable fibers, or similar substances found in the alimentary canal. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile Ducts: Tubes that carry bile from the liver to the gallbladder for storage and to the small intestine for use in digestion. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Atresia: Atresia of the biliary tract, most commonly of the extrahepatic bile ducts. [NIH]

Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU]

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Biofilms: Films of bacteria or other microbial organisms, usually embedded in extracellular polymers such as implanted medical devices, which adhere to surfaces submerged in, or subjected to, aquatic environments (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed). Biofilms consist of multilayers of microbial cells glued together to form microbial communities which are highly resistant to both phagocytes and antibiotics. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bivalent: Pertaining to a group of 2 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [NIH] Bladder: The organ that stores urine. [NIH] Blastomycosis: A fungal infection that may appear in two forms: 1) a primary lesion characterized by the formation of a small cutaneous nodule and small nodules along the lymphatics that may heal within several months; and 2) chronic granulomatous lesions characterized by thick crusts, warty growths, and unusual vascularity and infection in the middle or upper lobes of the lung. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Body Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Regions: Anatomical areas of the body. [NIH] Bolus: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus infusion. [NIH] Bolus infusion: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus. [NIH]

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Bone Density: The amount of mineral per square centimeter of bone. This is the definition used in clinical practice. Actual bone density would be expressed in grams per milliliter. It is most frequently measured by photon absorptiometry or x-ray computed tomography. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Boron: A trace element with the atomic symbol B, atomic number 5, and atomic weight 10.81. Boron-10, an isotope of boron, is used as a neutron absorber in boron neutron capture therapy. [NIH] Boron Neutron Capture Therapy: A technique for the treatment of neoplasms, especially gliomas and melanomas in which boron-10, an isotope, is introduced into the target cells followed by irradiation with thermal neutrons. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU]

Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchiectasis: Persistent abnormal dilatation of the bronchi. [NIH] Bronchiseptica: A small, gram-negative, motile bacillus. A normal inhabitant of the respiratory tract in man, dogs, and pigs, but is also associated with canine infectious tracheobronchitis and atrophic rhinitis in pigs. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Bronchoalveolar Lavage: Washing out of the lungs with saline or mucolytic agents for diagnostic or therapeutic purposes. It is very useful in the diagnosis of diffuse pulmonary infiltrates in immunosuppressed patients. [NIH] Bronchoalveolar Lavage Fluid: Fluid obtained by washout of the alveolar compartment of

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the lung. It is used to assess biochemical and inflammatory changes in and effects of therapy on the interstitial lung tissue. [NIH] Bronchodilator: A drug that relaxes the smooth muscles in the constricted airway. [NIH] Bronchopulmonary: Pertaining to the lungs and their air passages; both bronchial and pulmonary. [EU] Bronchopulmonary Dysplasia: A chronic lung disease appearing in certain newborn infants treated for respiratory distress syndrome with mechanical ventilation and elevated concentration of inspired oxygen. [NIH] Bronchoscopy: Endoscopic examination, therapy or surgery of the bronchi. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Bupivacaine: A widely used local anesthetic agent. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Candidiasis: Infection with a fungus of the genus Candida. It is usually a superficial infection of the moist cutaneous areas of the body, and is generally caused by C. albicans; it most commonly involves the skin (dermatocandidiasis), oral mucous membranes (thrush, def. 1), respiratory tract (bronchocandidiasis), and vagina (vaginitis). Rarely there is a systemic infection or endocarditis. Called also moniliasis, candidosis, oidiomycosis, and formerly blastodendriosis. [EU] Candidosis: An infection caused by an opportunistic yeasts that tends to proliferate and become pathologic when the environment is favorable and the host resistance is weakened. [NIH]

Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capillary Permeability: Property of blood capillary walls that allows for the selective exchange of substances. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas (tight junctions) which may limit large molecule movement. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboxy: Cannabinoid. [NIH] Carcinogenic: Producing carcinoma. [EU]

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Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carotenoids: Substance found in yellow and orange fruits and vegetables and in dark green, leafy vegetables. May reduce the risk of developing cancer. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheters: A small, flexible tube that may be inserted into various parts of the body to inject or remove liquids. [NIH] Cathode: An electrode, usually an incandescent filament of tungsten, which emits electrons in an X-ray tube. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Caustic: An escharotic or corrosive agent. Called also cauterant. [EU] Cecum: The beginning of the large intestine. The cecum is connected to the lower part of the small intestine, called the ileum. [NIH] Ceftazidime: Semisynthetic, broad-spectrum antibacterial derived from cephaloridine and used especially for Pseudomonas and other gram-negative infections in debilitated patients. [NIH]

Celiac Disease: A disease characterized by intestinal malabsorption and precipitated by gluten-containing foods. The intestinal mucosa shows loss of villous structure. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids,

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proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell motility: The ability of a cell to move. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cephaloridine: A cephalosporin antibiotic. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemical Warfare: Tactical warfare using incendiary mixtures, smokes, or irritant, burning, or asphyxiating gases. [NIH] Chemical Warfare Agents: Chemicals that are used to cause the disturbance, disease, or death of humans during war. [NIH] Chemoprotective: A quality of some drugs used in cancer treatment. Chemoprotective agents protect healthy tissue from the toxic effects of anticancer drugs. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chenodeoxycholic Acid: A bile acid, usually conjugated with either glycine or taurine. It acts as a detergent to solubilize fats for intestinal absorption and is reabsorbed by the small

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intestine. It is used as cholagogue, a choleretic laxative, and to prevent or dissolve gallstones. [NIH] Chest wall: The ribs and muscles, bones, and joints that make up the area of the body between the neck and the abdomen. [NIH] Child Care: Care of children in the home or institution. [NIH] Chiropractic: A system of treating bodily disorders by manipulation of the spine and other parts, based on the belief that the cause is the abnormal functioning of a nerve. [NIH] Chloride Channels: Cell membrane glycoproteins selective for chloride ions. [NIH] Chlorine: A greenish-yellow, diatomic gas that is a member of the halogen family of elements. It has the atomic symbol Cl, atomic number 17, and atomic weight 70.906. It is a powerful irritant that can cause fatal pulmonary edema. Chlorine is used in manufacturing, as a reagent in synthetic chemistry, for water purification, and in the production of chlorinated lime, which is used in fabric bleaching. [NIH] Cholangiography: Radiographic examination of the bile ducts. [NIH] Cholangitis: Inflammation of a bile duct. [NIH] Cholecystectomy: Surgical removal of the gallbladder. [NIH] Cholecystitis: Inflammation of the gallbladder. [NIH] Cholelithiasis: Presence or formation of gallstones. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Cholera Toxin: The enterotoxin from Vibrio cholerae. It is a protein that consists of two major components, the heavy (H) or A peptide and the light (L) or B peptide or choleragenoid. The B peptide anchors the protein to intestinal epithelial cells, while the A peptide, enters the cytoplasm, and activates adenylate cyclase, and production of cAMP. Increased levels of cAMP are thought to modulate release of fluid and electrolytes from intestinal crypt cells. [NIH] Choleretic: A choleretic agent. [EU] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla. [NIH]

Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH]

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Chronic Obstructive Pulmonary Disease: emphysema. [NIH]

Collective term for chronic bronchitis and

Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Chymotrypsin: A serine endopeptidase secreted by the pancreas as its zymogen, chymotrypsinogen and carried in the pancreatic juice to the duodenum where it is activated by trypsin. It selectively cleaves aromatic amino acids on the carboxyl side. [NIH] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Cimetidine: A histamine congener, it competitively inhibits histamine binding to H2 receptors. Cimetidine has a range of pharmacological actions. It inhibits gastric acid secretion, as well as pepsin and gastrin output. It also blocks the activity of cytochrome P450. [NIH] Ciprofloxacin: A carboxyfluoroquinoline antimicrobial agent that is effective against a wide range of microorganisms. It has been successfully and safely used in the treatment of resistant respiratory, skin, bone, joint, gastrointestinal, urinary, and genital infections. [NIH] Citrus: Any tree or shrub of the Rue family or the fruit of these plants. [NIH] Clarithromycin: A semisynthetic macrolide antibiotic derived from erythromycin that is active against a variety of microorganisms. It can inhibit protein synthesis in bacteria by reversibly binding to the 50S ribosomal subunits. This inhibits the translocation of aminoacyl transfer-RNA and prevents peptide chain elongation. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Clubbing: A proliferative change in the soft tissues about the terminal phalanges of the fingers or toes, with no constant osseous changes. [NIH] Cobalt: A trace element that is a component of vitamin B12. It has the atomic symbol Co, atomic number 27, and atomic weight 58.93. It is used in nuclear weapons, alloys, and pigments. Deficiency in animals leads to anemia; its excess in humans can lead to erythrocytosis. [NIH] Cod Liver Oil: Oil obtained from fresh livers of the cod family, Gadidae. It is a source of

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vitamins A and D. [NIH] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Cognitive restructuring: A method of identifying and replacing fear-promoting, irrational beliefs with more realistic and functional ones. [NIH] Colic: Paroxysms of pain. This condition usually occurs in the abdominal region but may occur in other body regions as well. [NIH] Colistin: Cyclic polypeptide antibiotic from Bacillus colistinus. It is composed of Polymyxins E1 and E2 (or Colistins A, B, and C) which act as detergents on cell membranes. Colistin is less toxic than Polymyxin B, but otherwise similar; the methanesulfonate is used orally. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colloidal: Of the nature of a colloid. [EU] Colonopathy: Any disease or disorder of the colon. [EU] Colonoscopy: Endoscopic examination, therapy or surgery of the luminal surface of the colon. [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Common Bile Duct: The largest biliary duct. It is formed by the junction of the cystic duct and the hepatic duct. [NIH] Compassionate: A process for providing experimental drugs to very sick patients who have no treatment options. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols

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C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU]

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Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Conjugated: Acting or operating as if joined; simultaneous. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Cor pulmonale: Heart disease that results from resistance to the passage of blood through the lungs; it often leads to right heart failure. [NIH] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corpuscle: A small mass or body; a sensory nerve end bulb; a cell, especially that of the blood or the lymph. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the

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internal substance. [EU] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Critical Care: Health care provided to a critically ill patient during a medical emergency or crisis. [NIH] Cryptosporidiosis: Parasitic intestinal infection with severe diarrhea caused by a protozoan, Cryptosporidium. It occurs in both animals and humans. [NIH] Crystallization: The formation of crystals; conversion to a crystalline form. [EU] Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyanosis: A bluish or purplish discoloration of the skin and mucous membranes due to an increase in the amount of deoxygenated hemoglobin in the blood or a structural defect in the hemoglobin molecule. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cystic Duct: The tube that carries bile from the gallbladder into the common bile duct and the small intestine. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, ... New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Cytomegalovirus Infections: Infection with Cytomegalovirus, characterized by enlarged cells bearing intranuclear inclusions. Infection may be in almost any organ, but the salivary glands are the most common site in children, as are the lungs in adults. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytotoxic: Cell-killing. [NIH]

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Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decompensation: Failure of compensation; cardiac decompensation is marked by dyspnea, venous engorgement, and edema. [EU] Decontamination: The removal of contaminating material, such as radioactive materials, biological materials, or chemical warfare agents, from a person or object. [NIH] Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH]

Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydration: The condition that results from excessive loss of body water. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Care: The total of dental diagnostic, preventive, and restorative services provided to meet the needs of a patient (from Illustrated Dictionary of Dentistry, 1982). [NIH] Dental Caries: Localized destruction of the tooth surface initiated by decalcification of the enamel followed by enzymatic lysis of organic structures and leading to cavity formation. If left unchecked, the cavity may penetrate the enamel and dentin and reach the pulp. The three most prominent theories used to explain the etiology of the disase are that acids produced by bacteria lead to decalcification; that micro-organisms destroy the enamel protein; or that keratolytic micro-organisms produce chelates that lead to decalcification. [NIH]

Deoxycytidine: A drug that protects healthy tissues from the toxic effects of anticancer drugs. [NIH] Deoxyribonuclease I: An enzyme capable of hydrolyzing highly polymerized DNA by splitting phosphodiester linkages, preferentially adjacent to a pyrimidine nucleotide. This catalyzes endonucleolytic cleavage of DNA yielding 5'-phosphodi- and oligonucleotide endproducts. The enzyme has a preference for double-stranded DNA. EC 3.1.21.1 (formerly EC 3.1.4.5). [NIH] Dermatology: A medical specialty concerned with the skin, its structure, functions, diseases, and treatment. [NIH] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Desmosine:

4-(4-Amino-4-carboxybutyl)-1-(5-amino-5-carboxypentyl)-3,5-bis(3-amino-3-

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carboxypropyl)pyridinium. A rare amino acid found in elastin, formed by condensation of four molecules of lysine into a pyridinium ring. [NIH] Detergents: Purifying or cleansing agents, usually salts of long-chain aliphatic bases or acids, that exert cleansing (oil-dissolving) and antimicrobial effects through a surface action that depends on possessing both hydrophilic and hydrophobic properties. [NIH] Developing Countries: Countries in the process of change directed toward economic growth, that is, an increase in production, per capita consumption, and income. The process of economic growth involves better utilization of natural and human resources, which results in a change in the social, political, and economic structures. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diarrhoea: Abnormal frequency and liquidity of faecal discharges. [EU] Diastole: Period of relaxation of the heart, especially the ventricles. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Dietary Fats: Fats present in food, especially in animal products such as meat, meat products, butter, ghee. They are present in lower amounts in nuts, seeds, and avocados. [NIH]

Dietary Fiber: The remnants of plant cell walls that are resistant to digestion by the alimentary enzymes of man. It comprises various polysaccharides and lignins. [NIH] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Dilatation: The act of dilating. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Diphosphates: Inorganic salts of phosphoric acid that contain two phosphate groups. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disparity: Failure of the two retinal images of an object to fall on corresponding retinal points. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or

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in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Distention: The state of being distended or enlarged; the act of distending. [EU] Diuretic: A drug that increases the production of urine. [NIH] Diverticula: Plural form of diverticulum. [NIH] Diverticulitis: Inflammation of a diverticulum or diverticula. [NIH] Diverticulum: A pathological condition manifested as a pouch or sac opening from a tubular or sacular organ. [NIH] DNA Topoisomerase: An enzyme catalyzing ATP-independent breakage of singlestranded DNA, followed by passage and rejoining of another single-stranded DNA. This enzyme class brings about the conversion of one topological isomer of DNA into another, e.g., the relaxation of superhelical turns in DNA, the interconversion of simple and knotted rings of single-stranded DNA, and the intertwisting of single-stranded rings of complementary sequences. (From Enzyme Nomenclature, 1992) EC 5.99.1.2. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] Double-blinded: A clinical trial in which neither the medical staff nor the person knows which of several possible therapies the person is receiving. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Design: The molecular designing of drugs for specific purposes (such as DNAbinding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH]

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Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dyslexia: Partial alexia in which letters but not words may be read, or in which words may be read but not understood. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eating Disorders: A group of disorders characterized by physiological and psychological disturbances in appetite or food intake. [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

Emboli: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embolization: The blocking of an artery by a clot or foreign material. Embolization can be done as treatment to block the flow of blood to a tumor. [NIH] Embryo:

The prenatal stage of mammalian development characterized by rapid

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morphological changes and the differentiation of basic structures. [NIH] Embryology: The study of the development of an organism during the embryonic and fetal stages of life. [NIH] Emollient: Softening or soothing; called also malactic. [EU] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Enamel: A very hard whitish substance which covers the dentine of the anatomical crown of a tooth. [NIH] Encopresis: Incontinence of feces not due to organic defect or illness. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocarditis: Exudative and proliferative inflammatory alterations of the endocardium, characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary disorder or as a complication of or in association with another disease. [EU] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocrinologist: A doctor that specializes in diagnosing and treating hormone disorders. [NIH]

Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]

Endometrium: The layer of tissue that lines the uterus. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endoscopic retrograde cholangiopancreatography: ERCP. A procedure to x-ray the pancreatic duct, hepatic duct, common bile duct, duodenal papilla, and gallbladder. In this procedure, a thin, lighted tube (endoscope) is passed through the mouth and down into the first part of the small intestine (duodenum). A smaller tube (catheter) is then inserted through the endoscope into the bile and pancreatic ducts. A dye is injected through the catheter into the ducts, and an x-ray is taken. [NIH] Endoscopy: Endoscopic examination, therapy or surgery performed on interior parts of the body. [NIH]

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Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enteral Nutrition: Nutritional support given via the alimentary canal or any route connected to the gastrointestinal system (i.e., the enteral route). This includes oral feeding, sip feeding, and tube feeding using nasogastric, gastrostomy, and jejunostomy tubes. [NIH] Enteric Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Enteric-coated: A term designating a special coating applied to tablets or capsules which prevents release and absorption of their contents until they reach the intestines. [EU] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [NIH]

Enterotoxins: Substances that are toxic to the intestinal tract causing vomiting, diarrhea, etc.; most common enterotoxins are produced by bacteria. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH] Environmental tobacco smoke: ETS. Smoke that comes from the burning of a tobacco product and smoke that is exhaled by smokers (second-hand smoke). Inhaling ETS is called involuntary or passive smoking. [NIH] Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Eosinophilic: A condition found primarily in grinding workers caused by a reaction of the

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pulmonary tissue, in particular the eosinophilic cells, to dust that has entered the lung. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]

Erythrocyte Membrane: The semipermeable outer portion of the red corpuscle. It is known as a 'ghost' after hemolysis. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythromycin: A bacteriostatic antibiotic substance produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. [NIH] Escalation: Progressive use of more harmful drugs. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Esophageal Atresia: Congenital failure of the full esophageal lumen to develop that commonly occurs with tracheoesophageal fistula. Symptoms include excessive salivation, gagging, cyanosis, and dyspnea. [NIH] Esophageal Motility Disorders: Disorders affecting the motor function of the upper or lower esophageal sphincters, the esophageal body, or a combination of these parts. The failure of the sphincters to maintain a tonic pressure may result in the impeding of the passage of food, regurgitation of food, or reflux of gastric acid into the esophagus. [NIH] Esophageal Varices: Stretched veins in the esophagus that occur when the liver is not

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working properly. If the veins burst, the bleeding can cause death. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estrogen: One of the two female sex hormones. [NIH] Ethmoid: An unpaired cranial bone which helps form the medial walls of the orbits and contains the themoidal air cells which drain into the nose. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evacuation: An emptying, as of the bowels. [EU] Excipients: Usually inert substances added to a prescription in order to provide suitable consistency to the dosage form; a binder, matrix, base or diluent in pills, tablets, creams, salves, etc. [NIH] Exercise Test: Controlled physical activity, more strenuous than at rest, which is performed in order to allow assessment of physiological functions, particularly cardiovascular and pulmonary, but also aerobic capacity. Maximal (most intense) exercise is usually required but submaximal exercise is also used. The intensity of exercise is often graded, using criteria such as rate of work done, oxygen consumption, and heart rate. Physiological data obtained from an exercise test may be used for diagnosis, prognosis, and evaluation of disease severity, and to evaluate therapy. Data may also be used in prescribing exercise by determining a person's exercise capacity. [NIH] Exercise Tolerance: The exercise capacity of an individual as measured by endurance (maximal exercise duration and/or maximal attained work load) during an exercise test. [NIH]

Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Exotoxin: Toxic substance excreted by living bacterial cells. [NIH] Expiration: The act of breathing out, or expelling air from the lungs. [EU] Expiratory: The volume of air which leaves the breathing organs in each expiration. [NIH] External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Facial: Of or pertaining to the face. [EU] Facial Nerve: The 7th cranial nerve. The facial nerve has two parts, the larger motor root which may be called the facial nerve proper, and the smaller intermediate or sensory root. Together they provide efferent innervation to the muscles of facial expression and to the lacrimal and salivary glands, and convey afferent information for taste from the anterior two-thirds of the tongue and for touch from the external ear. [NIH]

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Faecal: Pertaining to or of the nature of feces. [EU] Failure to Thrive: A condition in which an infant or child's weight gain and growth are far below usual levels for age. [NIH] Fallopian Tubes: Two long muscular tubes that transport ova from the ovaries to the uterus. They extend from the horn of the uterus to the ovaries and consist of an ampulla, an infundibulum, an isthmus, two ostia, and a pars uterina. The walls of the tubes are composed of three layers: mucosal, muscular, and serosal. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Famotidine: A competitive histamine H2-receptor antagonist. Its main pharmacodynamic effect is the inhibition of gastric secretion. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Fatty Liver: The buildup of fat in liver cells. The most common cause is alcoholism. Other causes include obesity, diabetes, and pregnancy. Also called steatosis. [NIH] Febrile: Pertaining to or characterized by fever. [EU] Fecal Incontinence: Failure of voluntary control of the anal sphincters, with involuntary passage of feces and flatus. [NIH] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Fetoprotein: Transabdominal aspiration of fluid from the amniotic sac with a view to detecting increases of alpha-fetoprotein in maternal blood during pregnancy, as this is an important indicator of open neural tube defects in the fetus. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fish Oils: Oils high in unsaturated fats extracted from the bodies of fish or fish parts, especially the livers. Those from the liver are usually high in vitamin A. The oils are used as dietary supplements, in soaps and detergents, as protective coatings, and as a base for other food products such as vegetable shortenings. [NIH] Fistula: Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. [NIH] Flatus: Gas passed through the rectum. [NIH] Fluid Therapy: Therapy whose basic objective is to restore the volume and composition of the body fluids to normal with respect to water-electrolyte balance. Fluids may be administered intravenously, orally, by intermittent gavage, or by hypodermoclysis. [NIH] Fluorine: A nonmetallic, diatomic gas that is a trace element and member of the halogen family. It is used in dentistry as flouride to prevent dental caries. [NIH] Flutter: A rapid vibration or pulsation. [EU]

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Foetoplacental: Pertaining to the fetus and placenta. [EU] Fold: A plication or doubling of various parts of the body. [NIH] Forced Expiratory Volume: Measure of the maximum amount of air during a forced vital capacity determination that can be expelled in a given number of seconds. It is usually given as FEV followed by a subscript indicating the number of seconds over which the measurement is made, although it is sometimes given as a percentage of forced vital capacity. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fosfomycin: An antibiotic produced by Streptomyces fradiae. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Friction: Surface resistance to the relative motion of one body against the rubbing, sliding, rolling, or flowing of another with which it is in contact. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has calories. [NIH] Fructose Intolerance: An autosomal recessive fructose metabolism disorder due to deficient fructose-1-phosphate aldolase (EC 2.1.2.13) activity, resulting in accumulation of fructose-1phosphate. The accumulated fructose-1-phosphate inhibits glycogenolysis and gluconeogenesis, causing severe hypoglycemia following ingestion of fructose. Prolonged fructose ingestion in infants leads ultimately to hepatic failure and death. Patients develop a strong distaste for sweet food, and avoid a chronic course of the disease by remaining on a fructose- and sucrose-free diet. [NIH] Fucose: Deoxysugar. [NIH] Fucosyltransferases: Enzymes catalyzing the transfer of fucose from a nucleoside diphosphate fucose to an acceptor molecule which is frequently another carbohydrate, a glycoprotein, or a glycolipid molecule. Elevated activity of some fucosyltransferases in human serum may serve as an indicator of malignancy. The class includes EC 2.4.1.65; EC 2.4.1.68; EC 2.4.1.69; EC 2.4.1.89. [NIH] Fulminant Hepatic Failure: Liver failure that occurs suddenly in a previously healthy person. The most common causes of FHF are acute hepatitis, acetaminophen overdose, and liver damage from prescription drugs. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Galactosemia: Buildup of galactose in the blood. Caused by lack of one of the enzymes needed to break down galactose into glucose. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and

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stored in the gallbladder. [NIH] Gallstones: The solid masses or stones made of cholesterol or bilirubin that form in the gallbladder or bile ducts. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Ganciclovir: Acyclovir analog that is a potent inhibitor of the Herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from AIDS-associated cytomegalovirus infections. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Acid: Hydrochloric acid present in gastric juice. [NIH] Gastric Juices: Liquids produced in the stomach to help break down food and kill bacteria. [NIH]

Gastric Mucosa: Surface epithelium in the stomach that invaginates into the lamina propria, forming gastric pits. Tubular glands, characteristic of each region of the stomach (cardiac, gastric, and pyloric), empty into the gastric pits. The gastric mucosa is made up of several different kinds of cells. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastritis: Inflammation of the stomach. [EU] Gastroduodenal: Pertaining to or communicating with the stomach and duodenum, as a gastroduodenal fistula. [EU] Gastroenterology: A subspecialty of internal medicine concerned with the study of the physiology and diseases of the digestive system and related structures (esophagus, liver, gallbladder, and pancreas). [NIH] Gastroesophageal Reflux: Reflux of gastric juice and/or duodenal contents (bile acids, pancreatic juice) into the distal esophagus, commonly due to incompetence of the lower esophageal sphincter. Gastric regurgitation is an extension of this process with entry of fluid into the pharynx or mouth. [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal Hemorrhage: Bleeding in the gastrointestinal tract. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gastrointestinal Transit: Passage of food (sometimes in the form of a test meal) through the gastrointestinal tract as measured in minutes or hours. The rate of passage through the intestine is an indicator of small bowel function. [NIH] Gastrostomy: Creation of an artificial external opening into the stomach for nutritional support or gastrointestinal compression. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in

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pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gels: Colloids with a solid continuous phase and liquid as the dispersed phase; gels may be unstable when, due to temperature or other cause, the solid phase liquifies; the resulting colloid is called a sol. [NIH] Gelsolin: A 90-kD protein produced by macrophages that severs actin filaments and forms a cap on the newly exposed filament end. Gelsolin is activated by calcium ions and participates in the assembly and disassembly of actin, thereby increasing the motility of some cells. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Counseling: Advising families of the risks involved pertaining to birth defects, in order that they may make an informed decision on current or future pregnancies. [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Screening: Searching a population or individuals for persons possessing certain genotypes or karyotypes that: (1) are already associated with disease or predispose to disease; (2) may lead to disease in their descendants; or (3) produce other variations not known to be associated with disease. Genetic screening may be directed toward identifying phenotypic expression of genetic traits. It includes prenatal genetic screening. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genistein: An isoflavonoid derived from soy products. It inhibits protein-tyrosine kinase and topoisomerase-ii (dna topoisomerase (atp-hydrolysing)) activity and is used as an antineoplastic and antitumor agent. Experimentally, it has been shown to induce G2 phase arrest in human and murine cell lines. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Giant Cells: Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. [NIH] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically

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active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH]

Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glanders: A contagious disease of horses that can be transmitted to humans. It is caused by Pseudomonas mallei and characterized by ulceration of the respiratory mucosa and an eruption of nodules on the skin. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Gluconeogenesis: The process by which glucose is formed from a non-carbohydrate source. [NIH]

Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH] Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

Gluten: The protein of wheat and other grains which gives to the dough its tough elastic character. [EU] Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]

Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions

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are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Gonadal: Pertaining to a gonad. [EU] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Government Agencies: Administrative units of government responsible for policy making and management of governmental activities in the U.S. and abroad. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-Negative Bacteria: Bacteria which lose crystal violet stain but are stained pink when treated by Gram's method. [NIH] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram's method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitat: An area considered in terms of its environment, particularly as this determines the type and quality of the vegetation the area can carry. [NIH] Haematoma: A localized collection of blood, usually clotted, in an organ, space, or tissue,

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due to a break in the wall of a blood vessel. [EU] Haemorrhage: The escape of blood from the vessels; bleeding. Small haemorrhages are classified according to size as petechiae (very small), purpura (up to 1 cm), and ecchymoses (larger). The massive accumulation of blood within a tissue is called a haematoma. [EU] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the major histocompatibility complex. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Health Policy: Decisions, usually developed by government policymakers, for determining present and future objectives pertaining to the health care system. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heart-Lung Transplantation: The simultaneous, or near simultaneous, transference of heart and lungs from one human or animal to another. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematuria: Presence of blood in the urine. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemoptysis: Bronchial hemorrhage manifested with spitting of blood. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver,

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lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatic: Refers to the liver. [NIH] Hepatic Duct, Common: Predominantly extrahepatic bile duct which is formed by the junction of the right and left hepatic ducts, which are predominantly intrahepatic, and, in turn, joins the cystic duct to form the common bile duct. [NIH] Hepatic Encephalopathy: A condition that may cause loss of consciousness and coma. It is usually the result of advanced liver disease. Also called hepatic coma. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatobiliary: Pertaining to the liver and the bile or the biliary ducts. [EU] Hepatocyte: A liver cell. [NIH] Hepatocyte Growth Factor: Multifunctional growth factor which regulates both cell growth and cell motility. It exerts a strong mitogenic effect on hepatocytes and primary epithelial cells. Its receptor is proto-oncogene protein C-met. [NIH] Hepatomegaly: Enlargement of the liver. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Hernia: Protrusion of a loop or knuckle of an organ or tissue through an abnormal opening. [NIH]

Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH] Heterotrophic: Pertaining to organisms that are consumers and dependent on other organisms for their source of energy (food). [NIH] Heterozygote: An individual having different alleles at one or more loci in homologous chromosome segments. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH]

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Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH] Horny layer: The superficial layer of the epidermis containing keratinized cells. [NIH] Hospice: Institution dedicated to caring for the terminally ill. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [NIH]

Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolases: Any member of the class of enzymes that catalyze the cleavage of the substrate and the addition of water to the resulting molecules, e.g., esterases, glycosidases (glycoside hydrolases), lipases, nucleotidases, peptidases (peptide hydrolases), and phosphatases (phosphoric monoester hydrolases). EC 3. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersecretion: Excessive secretion. [EU] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypersensitivity, Immediate: Hypersensitivity reactions which occur within minutes of exposure to challenging antigen due to the release of histamine which follows the antigenantibody reaction and causes smooth muscle contraction and increased vascular permeability. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH]

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Hypnotic: A drug that acts to induce sleep. [EU] Hypoglycemia: Abnormally low blood sugar [NIH] Hypokalaemia: Abnormally low potassium concentration in the blood; it may result from potassium loss by renal secretion or by the gastrointestinal route, as by vomiting or diarrhoea. It may be manifested clinically by neuromuscular disorders ranging from weakness to paralysis, by electrocardiographic abnormalities (depression of the T wave and elevation of the U wave), by renal disease, and by gastrointestinal disorders. [EU] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypoxemia: Deficient oxygenation of the blood; hypoxia. [EU] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Ibuprofen: A nonsteroidal anti-inflammatory agent with analgesic properties used in the therapy of rheumatism and arthritis. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Ileum: The lower end of the small intestine. [NIH] Ileus: Obstruction of the intestines. [EU] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune response: (antigens). [NIH]

The activity of the immune system against foreign substances

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic effects of foreign microorganisms or to the toxic effect of antigenic substances. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Imperforate Anus: A birth defect in which the anal canal fails to develop. The condition is treated with an operation. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH]

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Incisive: 1. Having the power or quality of cutting. 2. Pertaining to the incisor teeth. [EU] Incisor: Anything adapted for cutting; any one of the four front teeth in each jaw. [NIH] Incompetence: Physical or mental inadequacy or insufficiency. [EU] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU]

Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infant Mortality: Perinatal, neonatal, and infant deaths in a given population. [NIH] Infantile: Pertaining to an infant or to infancy. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infection Control: Programs of disease surveillance, generally within health care facilities, designed to investigate, prevent, and control the spread of infections and their causative microorganisms. [NIH] Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]

Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and

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then cemented into the cavity. [NIH] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Intelligence Tests: Standardized tests that measure the present general ability or aptitude for intellectual performance. [NIH] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]

Intensive Care Units: Hospital units providing continuous surveillance and care to acutely ill patients. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Interleukin-8: A cytokine that activates neutrophils and attracts neutrophils and Tlymphocytes. It is released by several cell types including monocytes, macrophages, Tlymphocytes, fibroblasts, endothelial cells, and keratinocytes by an inflammatory stimulus. IL-8 is a member of the beta-thromboglobulin superfamily and structurally related to platelet factor 4. [NIH] Interleukin-9: Factor that is thought to be a regulator of hematopoiesis. It has been shown to enhance the growth of human mast cells and megakaryoblastic leukemic cells as well as murine helper t-cell clones. IL-9 is a glycoprotein with a molecular weight of 32-39 that is derived from T-cells, and maps to human chromosome 5. [NIH] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intervention Studies: Epidemiologic investigations designed to test a hypothesized causeeffect relation by modifying the supposed causal factor(s) in the study population. [NIH] Intestinal: Having to do with the intestines. [NIH] Intestinal Obstruction: Any impairment, arrest, or reversal of the normal flow of intestinal contents toward the anus. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH]

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Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intrahepatic: Within the liver. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Introns: Non-coding, intervening sequences of DNA that are transcribed, but are removed from within the primary gene transcript and rapidly degraded during maturation of messenger RNA. Most genes in the nuclei of eukaryotes contain introns, as do mitochondrial and chloroplast genes. [NIH] Intussusception: A rare disorder. A part of the intestines folds into another part of the intestines, causing blockage. Most common in infants. Can be treated with an operation. [NIH]

Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ion Exchange: Reversible chemical reaction between a solid, often an ION exchange resin, and a fluid whereby ions may be exchanged from one substance to another. This technique is used in water purification, in research, and in industry. [NIH] Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active or passive. Passive ion transport (facilitated diffusion) derives its energy from the concentration gradient of the ion itself and allows the transport of a single solute in one direction (uniport). Active ion transport is usually coupled to an energy-yielding chemical or photochemical reaction such as ATP hydrolysis. This form of primary active transport is called an ion pump. Secondary active transport utilizes the voltage and ion gradients produced by the primary transport to drive the cotransport of other ions or molecules. These may be transported in the same (symport) or opposite (antiport) direction. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Iontophoresis: Therapeutic introduction of ions of soluble salts into tissues by means of electric current. In medical literature it is commonly used to indicate the process of increasing the penetration of drugs into surface tissues by the application of electric current. It has nothing to do with ion exchange, air ionization nor phonophoresis, none of which requires current. [NIH] Ipratropium: A muscarinic antagonist structurally related to atropine but often considered safer and more effective for inhalation use. It is used for various bronchial disorders, in rhinitis, and as an antiarrhythmic. [NIH]

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Irritable Bowel Syndrome: A disorder that comes and goes. Nerves that control the muscles in the GI tract are too active. The GI tract becomes sensitive to food, stool, gas, and stress. Causes abdominal pain, bloating, and constipation or diarrhea. Also called spastic colon or mucous colitis. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoelectric: Separation of amphoteric substances, dissolved in water, based on their isoelectric behavior. The amphoteric substances are a mixture of proteins to be separated and of auxiliary "carrier ampholytes". [NIH] Isoelectric Focusing: Electrophoresis in which a pH gradient is established in a gel medium and proteins migrate until they reach the site (or focus) at which the pH is equal to their isoelectric point. [NIH] Isoelectric Point: The pH in solutions of proteins and related compounds at which the dipolar ions are at a maximum. [NIH] Isoflavones: 3-Phenylchromones. Isomeric form of flavones in which the benzene group is attached to the 3 position of the benzopyran ring instead of the 2 position. [NIH] Isotonic: A biological term denoting a solution in which body cells can be bathed without a net flow of water across the semipermeable cell membrane. Also, denoting a solution having the same tonicity as some other solution with which it is compared, such as physiologic salt solution and the blood serum. [EU] Itraconazole: An antifungal agent that has been used in the treatment of histoplasmosis, blastomycosis, cryptococcal meningitis, and aspergillosis. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

Jejunostomy: Surgical formation of an opening through the abdominal wall into the jejunum, usually for enteral hyperalimentation. [NIH] Jejunum: That portion of the small intestine which extends from the duodenum to the ileum; called also intestinum jejunum. [EU] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kallidin: A decapeptide bradykinin homolog produced by the action of tissue and glandular kallikreins on low-molecular-weight kininogen. It is a smooth-muscle stimulant and hypotensive agent that functions through vasodilatation. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Keratolytic: An agent that promotes keratolysis. [EU] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2.

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Chemically unstable. [EU] Lactation: The period of the secretion of milk. [EU] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Larynx: An irregularly shaped, musculocartilaginous tubular structure, lined with mucous membrane, located at the top of the trachea and below the root of the tongue and the hyoid bone. It is the essential sphincter guarding the entrance into the trachea and functioning secondarily as the organ of voice. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Learning Disorders: Conditions characterized by a significant discrepancy between an individual's perceived level of intellect and their ability to acquire new language and other cognitive skills. These disorders may result from organic or psychological conditions. Relatively common subtypes include dyslexia, dyscalculia, and dysgraphia. [NIH] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH]

Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leukaemia: An acute or chronic disease of unknown cause in man and other warmblooded animals that involves the blood-forming organs, is characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood, and is classified according of the type leucocyte most prominently involved. [EU] Leukapheresis: The preparation of leukocyte concentrates with the return of red cells and leukocyte-poor plasma to the donor. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Levofloxacin: A substance used to treat bacterial infections. It belongs to the family of drugs called quinolone antibiotics. [NIH] Library Services: circulation. [NIH]

Services offered to the library user. They include reference and

Lidocaine: A local anesthetic and cardiac depressant used as an antiarrhythmia agent. Its actions are more intense and its effects more prolonged than those of procaine but its duration of action is shorter than that of bupivacaine or prilocaine. [NIH] Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Life Expectancy: A figure representing the number of years, based on known statistics, to

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which any person of a given age may reasonably expect to live. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lip: Either of the two fleshy, full-blooded margins of the mouth. [NIH] Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. (From Dorland, 27th ed) EC 3.1.1.3. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipodystrophy: A collection of rare conditions resulting from defective fat metabolism and characterized by atrophy of the subcutaneous fat. They include total, congenital or acquired, partial, abdominal infantile, and localized lipodystrophy. [NIH] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Lipoxygenase: An enzyme of the oxidoreductase class that catalyzes reactions between linoleate and other fatty acids and oxygen to form hydroperoxy-fatty acid derivatives. Related enzymes in this class include the arachidonate lipoxygenases, arachidonate 5lipoxygenase, arachidonate 12-lipoxygenase, and arachidonate 15-lipoxygenase. EC 1.13.11.12. [NIH] Lithotripsy: The destruction of a calculus of the kidney, ureter, bladder, or gallbladder by physical forces, including crushing with a lithotriptor through a catheter. Focused percutaneous ultrasound and focused hydraulic shock waves may be used without surgery. Lithotripsy does not include the dissolving of stones by acids or litholysis. Lithotripsy by laser is laser lithotripsy. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver cancer: A disease in which malignant (cancer) cells are found in the tissues of the liver. [NIH] Liver Cirrhosis: Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules. [NIH]

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Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [NIH] Living will: A health care directive that tells others how a person would like to be treated if they lose their capacity to make decisions about health care; it contains instructions about the person's choices of medical treatment and it is prepared in advance. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Locomotor: Of or pertaining to locomotion; pertaining to or affecting the locomotive apparatus of the body. [EU] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lower Esophageal Sphincter: The muscle between the esophagus and stomach. When a person swallows, this muscle relaxes to let food pass from the esophagus to the stomach. It stays closed at other times to keep stomach contents from flowing back into the esophagus. [NIH]

Lubricants: Oily or slippery substances. [NIH] Lubrication: The application of a substance to diminish friction between two surfaces. It may refer to oils, greases, and similar substances for the lubrication of medical equipment but it can be used for the application of substances to tissue to reduce friction, such as lotions for skin and vaginal lubricants. [NIH] Lumen: The cavity or channel within a tube or tubular organ. [EU] Lung Transplantation: The transference of either one or both of the lungs from one human or animal to another. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of

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connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphoblastic: One of the most aggressive types of non-Hodgkin lymphoma. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malabsorption syndrome: A group of symptoms such as gas, bloating, abdominal pain, and diarrhea resulting from the body's inability to properly absorb nutrients. [NIH] Malformation: A morphologic defect resulting from an intrinsically abnormal developmental process. [EU] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mandible: The largest and strongest bone of the face constituting the lower jaw. It supports the lower teeth. [NIH] Maple Syrup Urine Disease: A genetic disorder involving deficiency of an enzyme necessary in the metabolism of branched-chain amino acids, and named for the characteristic odor of the urine. [NIH] Marital Status: A demographic parameter indicating a person's status with respect to marriage, divorce, widowhood, singleness, etc. [NIH] Mass Screening: Organized periodic procedures performed on large groups of people for the purpose of detecting disease. [NIH] Maxillary: Pertaining to the maxilla : the irregularly shaped bone that with its fellow forms

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the upper jaw. [EU] Maxillary Sinus: One of the paired paranasal sinuses, located in the body of the maxilla, communicating with the middle meatus of the nasal cavity. [NIH] Maximum Tolerated Dose: The highest dose level eliciting signs of toxicity without having major effects on survival relative to the test in which it is used. [NIH] Meatus: A canal running from the internal auditory foramen through the petrous portion of the temporal bone. It gives passage to the facial and auditory nerves together with the auditory branch of the basilar artery and the internal auditory veins. [NIH] Mechanical ventilation: Use of a machine called a ventilator or respirator to improve the exchange of air between the lungs and the atmosphere. [NIH] Meconium: The thick green-to-black mucilaginous material found in the intestines of a fullterm fetus. It consists of secretions of the intestinal glands, bile pigments, fatty acids, amniotic fluid, and intrauterine debris. It constitutes the first stools passed by a newborn. [NIH]

Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Medical Records: illnesses. [NIH]

Recording of pertinent information concerning patient's illness or

Medical Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megestrol: 17-Hydroxy-6-methylpregna-3,6-diene-3,20-dione. A progestational hormone used most commonly as the acetate ester. As the acetate, it is more potent than progesterone both as a progestagen and as an ovulation inhibitor. It has also been used in the palliative treatment of breast cancer. [NIH] Megestrol Acetate: A drug that belongs to the group of hormones called progestins, used as hormone therapy to block estrogen and to suppress the effects of estrogen and androgens. [NIH]

Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melioidosis: A disease of humans and animals that resembles glanders. It is caused by Burkholderia pseudomallei and may range from a dormant infection to a condition that causes multiple abscesses, pneumonia, and bacteremia. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They

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include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Menopause: Permanent cessation of menstruation. [NIH] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metaphase: The second phase of cell division, in which the chromosomes line up across the equatorial plane of the spindle prior to separation. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Micelles: Electrically charged colloidal particles or ions consisting of oriented molecules; aggregates of a number of molecules held loosely together by secondary bonds. [NIH] Miconazole: An imidazole antifungal agent that is used topically and by intravenous infusion. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Micronutrients: Essential dietary elements or organic compounds that are required in only small quantities for normal physiologic processes to occur. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microscopy: The application of microscope magnification to the study of materials that

Dictionary 507

cannot be properly seen by the unaided eye. [NIH] Microspheres: Small uniformly-sized spherical particles frequently labeled with radioisotopes or various reagents acting as tags or markers. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller than a quart and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same. [NIH] Miotic: 1. Pertaining to, characterized by, or producing miosis : contraction of the pupil. 2. An agent that causes the pupil to contract. 3. Meiotic: characterized by cell division. [EU] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular mass: The sum of the atomic masses of all atoms in a molecule, based on a scale in which the atomic masses of hydrogen, carbon, nitrogen, and oxygen are 1, 12, 14, and 16, respectively. For example, the molecular mass of water, which has two atoms of hydrogen and one atom of oxygen, is 18 (i.e., 2 + 16). [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocyte: A type of white blood cell. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monophosphate: So called second messenger for neurotransmitters and hormones. [NIH]

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Monotherapy: A therapy which uses only one drug. [EU] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]

Morphological: Relating to the configuration or the structure of live organs. [NIH] Motility: The ability to move spontaneously. [EU] Mucilaginous: Pertaining to or secreting mucus. [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucociliary: Pertaining to or affecting the mucus membrane and hairs (including eyelashes, nose hair, ...): mucociliary clearing: the clearance of mucus by ciliary movement ( particularly in the respiratory system). [EU] Mucociliary Clearance: Rate of ciliary and secretory activity of the respiratory submucosal glands. It is a non-specific host defense mechanism, measurable in vivo by mucus transfer, ciliary beat frequency, and clearance of radioactive tracers. [NIH] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]

Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Musculature: The muscular apparatus of the body, or of any part of it. [EU] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mycobacterium: A genus of gram-positive, aerobic bacteria. Most species are free-living in

Dictionary 509

soil and water, but the major habitat for some is the diseased tissue of warm-blooded hosts. [NIH]

Myelin: The fatty substance that covers and protects nerves. [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Nasal Cavity: The proximal portion of the respiratory passages on either side of the nasal septum, lined with ciliated mucosa, extending from the nares to the pharynx. [NIH] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] Nasal Polyps: Focal accumulations of edema fluid in the nasal mucosa accompanied by hyperplasia of the associated submucosal connective tissue. Polyps may be neoplasms, foci of inflammation, degenerative lesions, or malformations. [NIH] Nasogastric: The process of passing a small, flexible plastic tube through the nose or mouth into the stomach or small intestine. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Nebramycin: A complex of antibiotic substances produced by Streptomyces tenebrarius. [NIH]

Nebulizer: A device used to turn liquid into a fine spray. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neonatal Hepatitis: Irritation of the liver with no known cause. Occurs in newborn babies. Symptoms include jaundice and liver cell changes. [NIH] Neonatal Screening: The identification of selected parameters in newborn infants by various tests, examinations, or other procedures. Screening may be performed by clinical or laboratory measures. A screening test is designed to sort out healthy neonates from those not well, but the screening test is not intended as a diagnostic device, rather instead as epidemiologic. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU]

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Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuraminidase: An enzyme that catalyzes the hydrolysis of alpha-2,3, alpha-2,6-, and alpha-2,8-glycosidic linkages (at a decreasing rate, respectively) of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid, and synthetic substrate. (From Enzyme Nomenclature, 1992) EC 3.2.1.18. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU]

Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neurotransmitters: Endogenous signaling molecules that alter the behavior of neurons or effector cells. Neurotransmitter is used here in its most general sense, including not only messengers that act directly to regulate ion channels, but also those that act through second messenger systems, and those that act at a distance from their site of release. Included are neuromodulators, neuroregulators, neuromediators, and neurohumors, whether or not acting at synapses. [NIH] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Nickel: A trace element with the atomic symbol Ni, atomic number 28, and atomic weight 58.69. It is a cofactor of the enzyme urease. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal

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transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nosocomial: Pertaining to or originating in the hospital, said of an infection not present or incubating prior to admittance to the hospital, but generally occurring 72 hours after admittance; the term is usually used to refer to patient disease, but hospital personnel may also acquire nosocomial infection. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleotidases: A class of enzymes that catalyze the conversion of a nucleotide and water to a nucleoside and orthophosphate. EC 3.1.3.-. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Nutritional Support: The administration of nutrients for assimilation and utilization by a patient by means other than normal eating. It does not include fluid therapy which normalizes body fluids to restore water-electrolyte balance. [NIH] Oestrogen: A generic term for oestrus-producing steroid compounds; the female sex hormones. In humans, oestrogen is formed in the ovary, possibly the adrenal cortex, the testis, and the foetoplacental unit; it has various functions in both sexes. It is responsible for the development of the female secondary sex characteristics, and during the menstrual cycle it acts on the female genitalia to produce an environment suitable for the fertilization, implantation, and nutrition of the early embryo. Oestrogen is used in oral contraceptives and as a palliative in cancer of the breast after menopause and cancer of the prostate; other uses include the relief of the discomforts of menopause, inhibition of lactation, and treatment of osteoporosis, threatened abortion, and various functional ovarian disorders. [EU]

Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Oligosaccharides: Carbohydrates consisting of between two and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. [NIH] Omega-3 fatty acid: A type of fat obtained in the diet and involved in immunity. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an

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environmental exposure to carcinogens. [NIH] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Opium: The air-dried exudate from the unripe seed capsule of the opium poppy, Papaver somniferum, or its variant, P. album. It contains a number of alkaloids, but only a few morphine, codeine, and papaverine - have clinical significance. Opium has been used as an analgesic, antitussive, antidiarrheal, and antispasmodic. [NIH] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Oral Hygiene: The practice of personal hygiene of the mouth. It includes the maintenance of oral cleanliness, tissue tone, and general preservation of oral health. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Orthodontics: A dental specialty concerned with the prevention and correction of dental and oral anomalies (malocclusion). [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]

Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

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Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Paediatric: Of or relating to the care and medical treatment of children; belonging to or concerned with paediatrics. [EU] Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pamidronate: A drug that belongs to the family of drugs called bisphosphonates. Pamidronate is used as treatment for abnormally high levels of calcium in the blood. [NIH] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancreatic Ducts: Ducts that collect pancreatic juice from the pancreas and supply it to the duodenum. [NIH] Pancreatic enzymes: A group of proteins secreted by the pancreas which aid in the digestion of food. [NIH] Pancreatic Extracts: Extracts prepared from pancreatic tissue that may contain the pancreatic enzymes or other specific uncharacterized factors or proteins with specific activities. Pancreatin is a specific extract containing digestive enzymes and used to treat pancreatic insufficiency. [NIH] Pancreatic Fistula: Abnormal passage communicating with the pancreas. [NIH] Pancreatic Function Tests: Tests based on the biochemistry and physiology of the exocrine pancreas and involving analysis of blood, duodenal contents, feces, or urine for products of pancreatic secretion. [NIH] Pancreatic Insufficiency: Absence of or reduced pancreatic exocrine secretion into the duodenum and resultant poor digestion of lipids, vitamins, nitrogen, and carbohydrates. [NIH]

Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH] Pancreatin: A mammalian pancreatic extract composed of enzymes with protease, amylase and lipase activities. It is used as a digestant in pancreatic malfunction. [NIH] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic

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or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease; less commonly it may be associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] Pancrelipase: A preparation of hog pancreatic enzymes standardized for lipase content. [NIH]

Papilla: A small nipple-shaped elevation. [NIH] Paralysis: Loss of ability to move all or part of the body. [NIH] Paranasal Sinuses: Air-filled extensions of the respiratory part of the nasal cavity into the frontal, ethmoid, sphenoid, and maxillary cranial bones. They vary in size and form in different individuals and are lined by the ciliated mucous membranes of the nasal cavity. [NIH]

Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Parasitic Diseases: Infections or infestations with parasitic organisms. They are often contracted through contact with an intermediate vector, but may occur as the result of direct exposure. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parenteral Nutrition: The administering of nutrients for assimilation and utilization by a patient who cannot maintain adequate nutrition by enteral feeding alone. Nutrients are administered by a route other than the alimentary canal (e.g., intravenously, subcutaneously). [NIH] Parotid: The space that contains the parotid gland, the facial nerve, the external carotid artery, and the retromandibular vein. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Paternity: Establishing the father relationship of a man and a child. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Advocacy: Promotion and protection of the rights of patients, frequently through a legal process. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

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Peer Review: An organized procedure carried out by a select committee of professionals in evaluating the performance of other professionals in meeting the standards of their specialty. Review by peers is used by editors in the evaluation of articles and other papers submitted for publication. Peer review is used also in the evaluation of grant applications. It is applied also in evaluating the quality of health care provided to patients. [NIH] Pelvic: Pertaining to the pelvis. [EU] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Pepsin A: Formed from pig pepsinogen by cleavage of one peptide bond. The enzyme is a single polypeptide chain and is inhibited by methyl 2-diaazoacetamidohexanoate. It cleaves peptides preferentially at the carbonyl linkages of phenylalanine or leucine and acts as the principal digestive enzyme of gastric juice. [NIH] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU] Peptic Ulcer: Ulcer that occurs in those portions of the alimentary tract which come into contact with gastric juice containing pepsin and acid. It occurs when the amount of acid and pepsin is sufficient to overcome the gastric mucosal barrier. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide Chain Elongation: The process whereby an amino acid is joined through a substituted amide linkage to a chain of peptides. [NIH] Peptide Hydrolases: A subclass of enzymes from the hydrolase class that catalyze the hydrolysis of peptide bonds. Exopeptidases and endopeptidases make up the sub-subclasses for this group. EC 3.4. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and

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covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Petechiae: Pinpoint, unraised, round red spots under the skin caused by bleeding. [NIH] Petrolatum: A colloidal system of semisolid hydrocarbons obtained from petroleum. It is used as an ointment base, topical protectant, and lubricant. [NIH] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [NIH] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenolphthalein: An acid-base indicator which is colorless in acid solution, but turns pink to red as the solution becomes alkaline. It is used medicinally as a cathartic. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phenylbutyrate: An anticancer drug that belongs to the family of drugs called differentiating agents. [NIH] Phonophoresis: Use of ultrasound to increase the percutaneous adsorption of drugs. [NIH] Phosphates: Inorganic salts of phosphoric acid. [NIH]

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Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [NIH] Phosphodiesterase Inhibitors: Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphoric Monoester Hydrolases: A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate. EC 3.1.3. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physical Fitness: A state of well-being in which performance is optimal, often as a result of physical conditioning which may be prescribed for disease therapy. [NIH] Physical Therapy: The restoration of function and the prevention of disability following disease or injury with the use of light, heat, cold, water, electricity, ultrasound, and exercise. [NIH]

Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pilocarpine: A slowly hydrolyzed muscarinic agonist with no nicotinic effects. Pilocarpine is used as a miotic and in the treatment of glaucoma. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasmapheresis: Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness,

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aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelet Factor 4: A high-molecular-weight proteoglycan-platelet factor complex which is released from blood platelets by thrombin. It acts as a mediator in the heparin-neutralizing capacity of the blood and plays a role in platelet aggregation. At high ionic strength (I=0.75), the complex dissociates into the active component (molecular weight 29,000) and the proteoglycan carrier (chondroitin 4-sulfate, molecular weight 350,000). The molecule exists in the form of a dimer consisting of 8 moles of platelet factor 4 and 2 moles of proteoglycan. [NIH]

Plateletpheresis: The preparation of platelet concentrates with the return of red cells and platelet-poor plasma to the donor. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Podiatry: A specialty concerned with the diagnosis and treatment of foot disorders and injuries and anatomic defects of the foot. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Policy Making: The decision process by which individuals, groups or institutions establish policies pertaining to plans, programs or procedures. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polylysine: A peptide which is a homopolymer of lysine. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polyp: A growth that protrudes from a mucous membrane. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH]

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Porins: Protein molecules situated in the outer membrane of gram-negative bacteria that, in dimeric or trimeric form, constitute a water-filled transmembrane channel allowing passage of ions and other small molecules. Porins are also found in bacterial cell walls, and in plant, fungal, mammalian and other vertebrate cell and mitochondrial membranes. [NIH] Porphyria: A group of disorders characterized by the excessive production of porphyrins or their precursors that arises from abnormalities in the regulation of the porphyrin-heme pathway. The porphyrias are usually divided into three broad groups, erythropoietic, hepatic, and erythrohepatic, according to the major sites of abnormal porphyrin synthesis. [NIH]

Porphyrins: A group of compounds containing the porphin structure, four pyrrole rings connected by methine bridges in a cyclic configuration to which a variety of side chains are attached. The nature of the side chain is indicated by a prefix, as uroporphyrin, hematoporphyrin, etc. The porphyrins, in combination with iron, form the heme component in biologically significant compounds such as hemoglobin and myoglobin. [NIH] Positive End-Expiratory Pressure: A method of mechanical ventilation in which pressure is maintained to increase the volume of gas remaining in the lung at the end of expiration, thus keeping the alveoli open and improving gas exchange. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Postprandial: Occurring after dinner, or after a meal; postcibal. [EU] Postprandial Blood Glucose: Blood taken 1-2 hours after eating to see the amount of glucose (sugar) in the blood. [NIH] Postural: Pertaining to posture or position. [EU] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precipitation: The act or process of precipitating. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prevalence: The total number of cases of a given disease in a specified population at a

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designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Procaine: A local anesthetic of the ester type that has a slow onset and a short duration of action. It is mainly used for infiltration anesthesia, peripheral nerve block, and spinal block. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1016). [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Prognostic factor: A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease, or the chance of the disease recurring (coming back). [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Progressive disease: Cancer that is increasing in scope or severity. [NIH] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH]

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Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Protein-Tyrosine Kinase: An enzyme that catalyzes the phosphorylation of tyrosine residues in proteins with ATP or other nucleotides as phosphate donors. EC 2.7.1.112. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Prune Belly Syndrome: A syndrome characterized by abdominal wall musculature deficiency, cryptorchism, and urinary tract abnormalities. The syndrome derives its name from its characteristic distended abdomen with wrinkled skin. [NIH] Pruritus: An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. [NIH] Pseudomonas: A genus of gram-negative, aerobic, rod-shaped bacteria widely distributed in nature. Some species are pathogenic for humans, animals, and plants. [NIH] Pseudomonas aeruginosa: A species of gram-negative, aerobic, rod-shaped bacteria commonly isolated from clinical specimens (wound, burn, and urinary tract infections). It is also found widely distributed in soil and water. P. aeruginosa is a major agent of nosocomial infection. [NIH] Pseudomonas Infections: Infections with bacteria of the genus Pseudomonas. [NIH] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary congestion: Fluid accumulation in the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH]

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Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulmonary Ventilation: The total volume of gas per minute inspired or expired measured in liters per minute. [NIH] Pulsation: A throb or rhythmical beat, as of the heart. [EU] Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Pyloric Stenosis: Obstruction of the pyloric canal. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiologist: A doctor who specializes in creating and interpreting pictures of areas inside the body. The pictures are produced with x-rays, sound waves, or other types of energy. [NIH]

Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that

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the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Reabsorption: 1. The act or process of absorbing again, as the selective absorption by the kidneys of substances (glucose, proteins, sodium, etc.) already secreted into the renal tubules, and their return to the circulating blood. 2. Resorption. [EU] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Rebound effect: The characteristic of a drug to produce reverse effects when either the effect of the drug has passed, or when the patient no longer responds to the drug. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recessive gene: A gene that is phenotypically expressed only when homozygous. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Reconstitution: 1. A type of regeneration in which a new organ forms by the rearrangement of tissues rather than from new formation at an injured surface. 2. The restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectal Prolapse: Protrusion of the rectal mucous membrane through the anus. There are various degrees: incomplete with no displacement of the anal sphincter muscle; complete with displacement of the anal sphincter muscle; complete with no displacement of the anal sphincter muscle but with herniation of the bowel; and internal complete with rectosigmoid or upper rectum intussusception into the lower rectum. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflux: The term used when liquid backs up into the esophagus from the stomach. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regurgitation: A backward flowing, as the casting up of undigested food, or the backward flowing of blood into the heart, or between the chambers of the heart when a valve is incompetent. [EU] Rehabilitation Centers: Facilities which provide programs for rehabilitating the mentally or physically disabled individuals. [NIH]

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Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Reproductive system: In women, this system includes the ovaries, the fallopian tubes, the uterus (womb), the cervix, and the vagina (birth canal). The reproductive system in men includes the prostate, the testes, and the penis. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respirator: A mechanical device that helps a patient breathe; a mechanical ventilator. [NIH] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Respiratory failure: Inability of the lungs to conduct gas exchange. [NIH] Respiratory Physiology: Functions and activities of the respiratory tract as a whole or of any of its parts. [NIH] Respiratory System: The tubular and cavernous organs and structures, by means of which pulmonary ventilation and gas exchange between ambient air and the blood are brought about. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoids: Derivatives of vitamin A. Used clinically in the treatment of severe cystic acne, psoriasis, and other disorders of keratinization. Their possible use in the prophylaxis and treatment of cancer is being actively explored. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retrograde: 1. Moving backward or against the usual direction of flow. 2. Degenerating,

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deteriorating, or catabolic. [EU] Retrospective: Looking back at events that have already taken place. [NIH] Retrospective study: A study that looks backward in time, usually using medical records and interviews with patients who already have or had a disease. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Rheology: The study of the deformation and flow of matter, usually liquids or fluids, and of the plastic flow of solids. The concept covers consistency, dilatancy, liquefaction, resistance to flow, shearing, thixotrophy, and viscosity. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rheumatology: A subspecialty of internal medicine concerned with the study of inflammatory or degenerative processes and metabolic derangement of connective tissue structures which pertain to a variety of musculoskeletal disorders, such as arthritis. [NIH] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Ristocetin: An antibiotic mixture of two components, A and B, obtained from Nocardia lurida (or the same substance produced by any other means). It is no longer used clinically because of its toxicity. It causes platelet agglutination and blood coagulation and is used to assay those functions in vitro. [NIH] Rod: A reception for vision, located in the retina. [NIH] Role-play: In this method, a conflict is artificially constructed, and the trainee is given a strategic position in it. [NIH] Rubber: A high-molecular-weight polymeric elastomer derived from the milk juice (latex) of Hevea brasiliensis and other trees. It is a substance that can be stretched at room temperature to atleast twice its original length and after releasing the stress, retractrapidly, and recover its original dimensions fully. Synthetic rubber is made from many different chemicals, including styrene, acrylonitrile, ethylene, propylene, and isoprene. [NIH] Saline: A solution of salt and water. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Salivation: 1. The secretion of saliva. 2. Ptyalism (= excessive flow of saliva). [EU]

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Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sarcoidosis: An idiopathic systemic inflammatory granulomatous disorder comprised of epithelioid and multinucleated giant cells with little necrosis. It usually invades the lungs with fibrosis and may also involve lymph nodes, skin, liver, spleen, eyes, phalangeal bones, and parotid glands. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Scleroderma: A chronic disorder marked by hardening and thickening of the skin. Scleroderma can be localized or it can affect the entire body (systemic). [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Scoliosis: A lateral curvature of the spine. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Scrotum: In males, the external sac that contains the testicles. [NIH] Secretin: A hormone made in the duodenum. Causes the stomach to make pepsin, the liver to make bile, and the pancreas to make a digestive juice. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an

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essential component of glutathione peroxidase. [NIH] Self Care: Performance of activities or tasks traditionally performed by professional health care providers. The concept includes care of oneself or one's family and friends. [NIH] Self-Help Groups: Organizations which provide an environment encouraging social interactions through group activities or individual relationships especially for the purpose of rehabilitating or supporting patients, individuals with common health problems, or the elderly. They include therapeutic social clubs. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Seminal vesicles: Glands that help produce semen. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] Sequence Analysis: A multistage process that includes the determination of a sequence (protein, carbohydrate, etc.), its fragmentation and analysis, and the interpretation of the resulting sequence information. [NIH] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: female or male. [NIH]

The biological characteristics which distinguish human beings as

Sexually Transmitted Diseases: Diseases due to or propagated by sexual contact. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock.

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[NIH]

Short Bowel Syndrome: A malabsorption syndrome resulting from extensive operative resection of small bowel. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Sigma Factor: A protein which is a subunit of RNA polymerase. It effects initiation of specific RNA chains from DNA. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Sinusitis: An inflammatory process of the mucous membranes of the paranasal sinuses that occurs in three stages: acute, subacute, and chronic. Sinusitis results from any condition causing ostial obstruction or from pathophysiologic changes in the mucociliary transport mechanism. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Sludge: A clump of agglutinated red blood cells. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Soaps: Sodium or potassium salts of long chain fatty acids. These detergent substances are obtained by boiling natural oils or fats with caustic alkali. Sodium soaps are harder and are used as topical anti-infectives and vehicles in pills and liniments; potassium soaps are soft, used as vehicles for ointments and also as topical antimicrobials. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Support: Support systems that provide assistance and encouragement to individuals with physical or emotional disabilities in order that they may better cope. Informal social support is usually provided by friends, relatives, or peers, while formal assistance is provided by churches, groups, etc. [NIH] Social Work: The use of community resources, individual case work, or group work to promote the adaptive capacities of individuals in relation to their social and economic environments. It includes social service agencies. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Sodium Channels: Cell membrane glycoproteins selective for sodium ions. Fast sodium current is associated with the action potential in neural membranes. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH]

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Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Soybean Oil: Oil from soybean or soybean plant. [NIH] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spermatozoa: Mature male germ cells that develop in the seminiferous tubules of the testes. Each consists of a head, a body, and a tail that provides propulsion. The head consists mainly of chromatin. [NIH] Sphenoid: An unpaired cranial bone with a body containing the sphenoid sinus and forming the posterior part of the medial walls of the orbits. [NIH] Sphincter: A ringlike band of muscle fibres that constricts a passage or closes a natural orifice; called also musculus sphincter. [EU] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinal Cord Injuries: Penetrating and non-penetrating injuries to the spinal cord resulting from traumatic external forces (e.g., wounds, gunshot; whiplash injuries; etc.). [NIH] Spinous: Like a spine or thorn in shape; having spines. [NIH] Spirometry: Measurement of volume of air inhaled or exhaled by the lung. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Spontaneous Abortion: The non-induced birth of an embryo or of fetus prior to the stage of viability at about 20 weeks of gestation. [NIH]

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Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Sports Medicine: The field of medicine concerned with physical fitness and the diagnosis and treatment of injuries sustained in sports activities. [NIH] Sprue: A non febrile tropical disease of uncertain origin. [NIH] Sputa: The material expelled from the respiratory passages by coughing or clearing the throat. [NIH] Sputum: The material expelled from the respiratory passages by coughing or clearing the throat. [NIH] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. [NIH] Steatorrhea: A condition in which the body cannot absorb fat. Causes a buildup of fat in the stool and loose, greasy, and foul bowel movements. [NIH] Steatosis: Fatty degeneration. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Sterilization: The destroying of all forms of life, especially microorganisms, by heat, chemical, or other means. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stethoscopes: An instrument used for the detection and study of sounds within the body that conveyed to the ears of the observer through rubber tubing. [NIH] Stimulants: Any drug or agent which causes stimulation. [NIH] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stress management: A set of techniques used to help an individual cope more effectively with difficult situations in order to feel better emotionally, improve behavioral skills, and often to enhance feelings of control. Stress management may include relaxation exercises, assertiveness training, cognitive restructuring, time management, and social support. It can

Dictionary 531

be delivered either on a one-to-one basis or in a group format. [NIH] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH]

Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Superinfection: A frequent complication of drug therapy for microbial infection. It may result from opportunistic colonization following immunosuppression by the primary pathogen and can be influenced by the time interval between infections, microbial physiology, or host resistance. Experimental challenge and in vitro models are sometimes used in virulence and infectivity studies. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]

Survival Analysis: A class of statistical procedures for estimating the survival function (function of time, starting with a population 100% well at a given time and providing the percentage of the population still well at later times). The survival analysis is then used for making inferences about the effects of treatments, prognostic factors, exposures, and other covariates on the function. [NIH] Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [NIH] Sweat Glands: Sweat-producing structures that are embedded in the dermis. Each gland consists of a single tube, a coiled body, and a superficial duct. [NIH] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatic treatment: Therapy that eases symptoms without addressing the cause of disease. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU]

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Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thoracic: Having to do with the chest. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH]

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Tic: An involuntary compulsive, repetitive, stereotyped movement, resembling a purposeful movement because it is coordinated and involves muscles in their normal synergistic relationships; tics usually involve the face and shoulders. [EU] Time Management: Planning and control of time to improve efficiency and effectiveness. [NIH]

Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tobacco Mosaic Virus: The type species of tobamovirus which causes mosaic disease of tobacco. Transmission occurs by mechanical inoculation. [NIH] Tobamovirus: A genus of plant viruses in which the virion is a rigid filament. Transmission is by mechanical inoculation or seed. The type species is tobacco mosaic virus. [NIH] Tobramycin: An aminoglycoside, broad-spectrum antibiotic produced by Streptomyces tenebrarius. It is effective against gram-negative bacteria, especially the Pseudomonas species. It is a 10% component of the antibiotic complex, nebramycin, produced by the same species. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tonic: 1. Producing and restoring the normal tone. 2. Characterized by continuous tension. 3. A term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU] Tonicity: The normal state of muscular tension. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Toxoplasmosis: The acquired form of infection by Toxoplasma gondii in animals and man. [NIH]

Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH]

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Tracheoesophageal Fistula: Abnormal communication between the esophagus and the trachea, acquired or congenital, often associated with esophageal atresia. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Trees: Woody, usually tall, perennial higher plants (Angiosperms, Gymnosperms, and some Pterophyta) having usually a main stem and numerous branches. [NIH] Tricuspid Atresia: Absence of the orifice between the right atrium and ventricle, with the presence of an atrial defect through which all the systemic venous return reaches the left heart. As a result, there is left ventricular hypertrophy because the right ventricle is absent or not functional. [NIH] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tungsten: A metallic element with the atomic symbol W, atomic number 74, and atomic weight 183.85. It is used in many manufacturing applications, including increasing the

Dictionary 535

hardness, toughness, and tensile strength of steel; manufacture of filaments for incandescent light bulbs; and in contact points for automotive and electrical apparatus. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] Ultrasonography: The visualization of deep structures of the body by recording the reflections of echoes of pulses of ultrasonic waves directed into the tissues. Use of ultrasound for imaging or diagnostic purposes employs frequencies ranging from 1.6 to 10 megahertz. [NIH] Ultrasound test: A test that bounces sound waves off tissues and internal organs and changes the echoes into pictures (sonograms). [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Unsaturated Fats: A type of fat. [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Uraemia: 1. An excess in the blood of urea, creatinine, and other nitrogenous end products of protein and amino acids metabolism; more correctly referred to as azotemia. 2. In current usage the entire constellation of signs and symptoms of chronic renal failure, including nausea, vomiting anorexia, a metallic taste in the mouth, a uraemic odour of the breath, pruritus, uraemic frost on the skin, neuromuscular disorders, pain and twitching in the muscles, hypertension, edema, mental confusion, and acid-base and electrolyte imbalances. [EU]

Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureter: One of a pair of thick-walled tubes that transports urine from the kidney pelvis to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Uridine Triphosphate: Uridine 5'-(tetrahydrogen triphosphate). A uracil nucleotide containing three phosphate groups esterified to the sugar moiety. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [NIH]

Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU]

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Ursodeoxycholic Acid: An epimer of chenodeoxycholic acid. It is a mammalian bile acid found first in the bear and is apparently either a precursor or a product of chenodeoxycholate. Its administration changes the composition of bile and may dissolve gallstones. It is used as a cholagogue and choleretic. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Vaginitis: Inflammation of the vagina characterized by pain and a purulent discharge. [NIH] Valves: Flap-like structures that control the direction of blood flow through the heart. [NIH] Vanadium: Vanadium. A metallic element with the atomic symbol V, atomic number 23, and atomic weight 50.94. It is used in the manufacture of vanadium steel. Prolonged exposure can lead to chronic intoxication caused by absorption usually via the lungs. [NIH] Vancomycin: Antibacterial obtained from Streptomyces orientalis. It is a glycopeptide related to ristocetin that inhibits bacterial cell wall assembly and is toxic to kidneys and the inner ear. [NIH] Varices: Stretched veins such as those that form in the esophagus from cirrhosis. [NIH] Vas Deferens: The excretory duct of the testes that carries spermatozoa. It rises from the scrotum and joins the seminal vesicles to form the ejaculatory duct. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasoactive Intestinal Peptide: A highly basic, single-chain polypeptide isolated from the intestinal mucosa. It has a wide range of biological actions affecting the cardiovascular, gastrointestinal, and respiratory systems. It is also found in several parts of the central and peripheral nervous systems and is a neurotransmitter. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventilator: A breathing machine that is used to treat respiratory failure by promoting ventilation; also called a respirator. [NIH] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU]

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Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vibrio: A genus of Vibrionaceae, made up of short, slightly curved, motile, gram-negative rods. Various species produce cholera and other gastrointestinal disorders as well as abortion in sheep and cattle. [NIH] Vibrio cholerae: The etiologic agent of cholera. [NIH] Video Recording: The storing or preserving of video signals for television to be played back later via a transmitter or receiver. Recordings may be made on magnetic tape or discs (videodisc recording). [NIH] Videodisc Recording: The storing of visual and usually sound signals on discs for later reproduction on a television screen or monitor. [NIH] Villous: Of a surface, covered with villi. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Hepatitis: Hepatitis caused by a virus. Five different viruses (A, B, C, D, and E) most commonly cause this form of hepatitis. Other rare viruses may also cause hepatitis. [NIH] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virulent: A virus or bacteriophage capable only of lytic growth, as opposed to temperate phages establishing the lysogenic response. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Vital Capacity: The volume of air that is exhaled by a maximal expiration following a maximal inspiration. [NIH] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH]

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Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Vocal cord: The vocal folds of the larynx. [NIH] Voriconazole: A drug that treats infections caused by fungi. [NIH] Weight Gain: Increase in body weight over existing weight. [NIH] Weight Perception: Recognition and discrimination of the heaviness of a lifted object. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wounds, Gunshot: Disruption of structural continuity of the body as a result of the discharge of firearms. [NIH] Xanthine: An urinary calculus. [NIH] Xerostomia: Decreased salivary flow. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

539

INDEX 1 1-phosphate, 459, 488 A Abdomen, 388, 459, 465, 468, 469, 473, 485, 498, 502, 513, 516, 521, 529, 530, 532, 537 Abdominal, 6, 386, 387, 388, 453, 459, 475, 500, 502, 504, 513, 514, 515, 516, 521, 535 Abdominal Pain, 386, 387, 388, 459, 500, 504, 535 Aberrant, 378, 379, 459 Acceptor, 459, 488, 502, 512, 534 Acetaminophen, 459, 488 Acetylcholine, 459, 473, 510 Acne, 434, 459, 524 Actin, 128, 459, 490 Acute lymphoblastic leukemia, 311, 459 Acute lymphocytic leukemia, 459 Acute renal, 459, 493 Adaptation, 320, 321, 407, 459, 508 Adenine, 459, 460, 522 Adenosine, 123, 356, 367, 368, 381, 459, 460, 465, 517 Adenosine Monophosphate, 460 Adenovirus, 123, 129, 276, 336, 337, 460 Adenylate Cyclase, 460, 473 Adenylate Kinase, 301, 460 Adjustment, 319, 322, 459, 460 Adjuvant, 313, 460, 489 Adolescence, 386, 390, 460 Adrenal Cortex, 460, 511, 520 Adrenal Glands, 460, 462 Adrenergic, 122, 360, 376, 460, 461, 481, 485 Adrenergic Agents, 376, 460 Adrenergic Agonists, 360, 460 Adverse Effect, 389, 460, 528 Aerobic, 460, 486, 507, 508, 521 Aerosol, 276, 292, 313, 341, 361, 460 Aetiology, 460 Affinity, 367, 381, 460, 461, 528 Age of Onset, 437, 460 Agenesis, 398, 461 Agonist, 360, 461, 481, 517 Airway, 122, 123, 125, 127, 128, 129, 130, 136, 276, 277, 278, 280, 286, 319, 320, 337, 341, 348, 349, 352, 356, 366, 375, 380, 461, 470 Airway Obstruction, 348, 349, 375, 461

Albuterol, 335, 461 Aldehydes, 371, 461 Alendronate, 328, 461 Alfalfa, 461 Algorithms, 387, 461, 468 Alimentary, 289, 461, 467, 480, 484, 514, 515 Alkaline, 461, 462, 470, 516 Alkaloid, 461, 465, 508 Alkalosis, 461 Alleles, 124, 367, 372, 376, 377, 461, 494 Allergens, 461 Alopecia, 400, 461 Alpha 1-Antitrypsin, 299, 417, 461 Alpha Particles, 461, 522 Alpha-1, 418, 461 Alpha-fetoprotein, 298, 461, 487 Alternative medicine, 410, 461 Alveolar Process, 462, 524 Alveoli, 462, 519, 536 Amber, 353, 462 Amino Acid Sequence, 462, 463, 486, 490 Amino Acids, 346, 369, 370, 462, 474, 475, 485, 490, 504, 515, 518, 521, 525, 527, 534, 535 Ammonia, 462, 491, 531, 535 Amniotic Fluid, 462, 505 Ampulla, 462, 473, 483, 487 Amylase, 462, 513 Amyloidosis, 402, 462 Anabolic, 462 Anaesthesia, 462, 497 Anal, 462, 487, 496, 503, 523 Analgesic, 459, 462, 496, 508, 512 Analog, 462, 489 Analogous, 462, 481, 534 Analytes, 435, 462 Anaphylatoxins, 462, 476 Anaplasia, 463 Anatomical, 362, 463, 465, 468, 483, 496, 526 Androgens, 460, 463, 505 Anemia, 300, 400, 429, 430, 463, 474 Anesthesia, 461, 463, 520 Anions, 463, 499 Annealing, 463, 518 Anode, 365, 463 Anomalies, 386, 387, 388, 463, 512

540 Cystic Fibrosis

Anorectal, 388, 463 Antiarrhythmic, 463, 499 Antibacterial, 463, 471, 529, 536 Antibodies, 137, 346, 355, 463, 493, 495, 507, 517 Antibody, 290, 364, 365, 460, 463, 475, 485, 493, 494, 495, 496, 497, 507, 522, 529 Anticoagulant, 463, 520 Antifungal, 463, 500, 506 Antigen, 460, 461, 463, 476, 490, 494, 495, 496, 497 Antigen-Antibody Complex, 463, 476 Anti-inflammatory, 274, 459, 464, 496 Antineoplastic, 464, 490 Antioxidant, 274, 301, 464, 465, 512, 513 Antiviral, 464, 515 Anus, 462, 463, 464, 465, 469, 498, 523 Anxiety, 327, 339, 402, 464 Apheresis, 332, 464 Apolipoproteins, 464, 502 Apoptosis, 133, 464 Appendicitis, 386, 387, 464 Aptitude, 464, 498 Apyrase, 464 Aqueous, 363, 373, 464, 466, 478, 483, 495, 502 Arachidonate 12-Lipoxygenase, 464, 502 Arachidonate 15-Lipoxygenase, 464, 502 Arachidonate Lipoxygenases, 464, 502 Arginine, 462, 464, 510, 534 Aromatic, 464, 474, 516 Arterial, 465, 473, 477, 495, 521, 532 Arteries, 465, 468, 477, 503, 506, 522 Arteriolar, 465, 469 Arterioles, 465, 468, 470, 506 Articular, 465 Ascending Colon, 5, 465 Ascites, 386, 387, 465 Ascorbic Acid, 363, 373, 465 Aspergillosis, 465, 500 Assay, 130, 349, 465, 525 Asymptomatic, 364, 365, 465, 513 Ataxia, 429, 430, 465, 532 Atelectasis, 465 ATP, 122, 130, 136, 137, 297, 460, 464, 465, 481, 490, 499, 517, 521, 534 Atresia, 399, 465, 467 Atrial, 465, 477, 534 Atrioventricular, 465, 477 Atrium, 465, 477, 534, 537 Atrophy, 277, 429, 465, 502 Atropine, 465, 499

Atypical, 330, 336, 395, 465 Autodigestion, 465, 514 Autogenic, 286, 287, 310, 465 Autoimmune disease, 465, 466, 508 Autoimmunity, 466 Autopsy, 466 Azithromycin, 406, 466 Azoospermia, 466 Aztreonam, 418, 466 B Bacillus, 466, 469, 475 Bacteremia, 466, 505 Bacteria, 125, 127, 131, 138, 329, 335, 338, 372, 374, 380, 409, 463, 466, 467, 468, 474, 479, 482, 484, 486, 487, 489, 492, 493, 506, 508, 521, 529, 534, 535, 536 Bacterial Infections, 338, 347, 349, 466, 501 Bacterial Physiology, 459, 466 Bactericidal, 466 Bacteriophage, 466, 534, 537 Bacteriostatic, 466, 485 Bacterium, 133, 466, 493 Basal Ganglia, 465, 466 Basal Ganglia Diseases, 465, 466 Base, 378, 398, 459, 461, 466, 479, 486, 487, 488, 490, 500, 516, 535 Base Sequence, 466, 488, 490 Basophils, 467, 492, 501 Benign, 467, 509, 522 Benzene, 467, 500 Bereavement, 390, 467 Beta-Lactamases, 466, 467 Beta-Thromboglobulin, 467, 498 Bezoars, 386, 467 Bilateral, 395, 467 Bile Acids, 467, 489, 530, 532 Bile Acids and Salts, 467 Bile Ducts, 386, 467, 473, 489 Bile Pigments, 467, 500, 505 Biliary, 4, 331, 385, 387, 388, 398, 440, 467, 473, 475, 494, 514 Biliary Atresia, 440, 467 Biliary Tract, 385, 387, 467, 514 Bilirubin, 467, 489, 495 Binding Sites, 285, 467 Bioavailability, 328, 331, 334, 467 Biochemical, 294, 302, 333, 349, 357, 364, 461, 467, 470, 492, 501, 527 Biofilms, 355, 468 Biological therapy, 468, 492 Biopsy, 6, 330, 468, 515

Index 541

Biosynthesis, 133, 352, 354, 468, 517, 520, 527 Biotechnology, 122, 396, 410, 425, 428, 429, 430, 468 Bivalent, 136, 468 Bladder, 466, 468, 497, 502, 508, 520, 535 Blastomycosis, 468, 500 Bloating, 468, 500, 504 Blood Coagulation, 468, 470, 525, 532 Blood Glucose, 7, 8, 411, 468, 493, 498 Blood pressure, 400, 402, 468, 495, 507, 522, 528 Blood vessel, 468, 469, 471, 477, 484, 493, 500, 503, 515, 528, 531, 532, 536 Body Composition, 287, 468 Body Fluids, 364, 461, 468, 482, 487, 511, 528 Body Regions, 468, 475 Bolus, 468 Bolus infusion, 468 Bone Density, 469 Bone Marrow, 459, 467, 469, 504 Bone scan, 469, 526 Boron, 363, 373, 469 Boron Neutron Capture Therapy, 469 Bowel, 386, 388, 456, 462, 469, 480, 489, 497, 498, 516, 523, 528, 530, 535 Bowel Movement, 469, 480, 530 Brachytherapy, 469, 498, 522 Bradykinin, 291, 469, 500, 510 Branch, 441, 451, 469, 505, 514, 521, 529, 532 Breakdown, 469, 480, 489 Broad-spectrum, 469, 471, 533 Bronchi, 355, 363, 375, 469, 470, 485, 533 Bronchiectasis, 128, 129, 331, 357, 376, 469 Bronchiseptica, 134, 469 Bronchitis, 352, 357, 363, 375, 397, 469, 474 Bronchoalveolar Lavage, 128, 331, 340, 375, 469 Bronchoalveolar Lavage Fluid, 128, 375, 469 Bronchodilator, 335, 470 Bronchopulmonary, 299, 470 Bronchopulmonary Dysplasia, 470 Bronchoscopy, 331, 470 Buccal, 470, 503 Bupivacaine, 470, 501 C Calcium, 124, 274, 286, 294, 320, 356, 464, 470, 476, 490, 513 Candidiasis, 402, 470

Candidosis, 470 Capillary, 125, 351, 469, 470, 537 Capillary Permeability, 469, 470 Capsules, 5, 340, 470, 484, 490 Carbohydrate, 5, 8, 299, 388, 470, 488, 491, 492, 527 Carbon Dioxide, 470, 489, 524 Carboxy, 369, 470 Carcinogenic, 389, 467, 470, 497, 530 Carcinogens, 471, 512 Carcinoma, 470, 471 Cardiac, 277, 311, 463, 471, 477, 479, 482, 483, 485, 489, 501, 509, 530 Cardiorespiratory, 471 Cardiovascular, 279, 389, 400, 471, 486, 527, 536 Carnitine, 303, 471 Carotene, 287, 294, 295, 303, 304, 309, 310, 414, 471, 524 Carotenoids, 311, 471 Case report, 8, 299, 309, 471, 474 Catecholamine, 471, 481, 516 Catheters, 471, 496, 498 Cathode, 365, 463, 471, 482 Cations, 471, 499 Causal, 471, 493, 498 Cause of Death, 349, 379, 471 Caustic, 386, 387, 471, 528 Cecum, 471, 501 Ceftazidime, 126, 131, 135, 471 Celiac Disease, 386, 471 Cell Death, 125, 464, 471, 490, 509 Cell Division, 429, 466, 471, 472, 492, 505, 506, 507, 517, 520 Cell membrane, 347, 357, 367, 372, 381, 471, 473, 475, 499, 500, 517, 519, 528 Cell motility, 472, 494 Cell proliferation, 361, 472 Cell Respiration, 472, 507, 524 Cell Survival, 472, 492 Cellulose, 472, 488, 517 Central Nervous System, 459, 467, 472, 489, 491, 508, 527 Centrifugation, 332, 472 Cephaloridine, 471, 472 Cerebellar, 465, 472, 523 Cerebral, 400, 465, 466, 472, 485, 529 Cerebral Palsy, 400, 472, 529 Cerebrum, 472, 534 Cervical, 389, 472 Cervix, 472, 524 Character, 472, 479, 491

542 Cystic Fibrosis

Chemical Warfare, 472, 479 Chemical Warfare Agents, 472, 479 Chemoprotective, 361, 472 Chemotactic Factors, 472, 476 Chenodeoxycholic Acid, 472, 536 Chest wall, 473 Child Care, 437, 473 Chiropractic, 400, 473 Chloride Channels, 124, 130, 347, 350, 359, 371, 372, 473 Chlorine, 356, 473 Cholangiography, 386, 473 Cholangitis, 279, 386, 387, 399, 473 Cholecystectomy, 386, 387, 473 Cholecystitis, 386, 387, 399, 473 Cholelithiasis, 6, 473 Cholera, 361, 398, 473, 537 Cholera Toxin, 398, 473 Choleretic, 473, 536 Cholestasis, 6, 334, 473 Cholesterol, 288, 386, 467, 473, 474, 489, 502, 503, 530 Cholesterol Esters, 473, 502 Cholinergic, 360, 473 Chromatin, 464, 473, 485, 529 Chromosomal, 350, 359, 371, 373, 473, 525 Chromosome, 355, 360, 473, 493, 494, 498, 502 Chronic Disease, 320, 473, 501 Chronic Obstructive Pulmonary Disease, 382, 396, 474 Chronic renal, 474, 518, 535 Chylomicrons, 474, 502 Chymotrypsin, 456, 474 Ciliary, 278, 311, 474, 508 Cimetidine, 288, 303, 313, 474 Ciprofloxacin, 126, 134, 135, 415, 474 Citrus, 465, 474 Clarithromycin, 474 Clear cell carcinoma, 474, 479 Clinical Medicine, 474, 519 Clinical study, 474, 477 Clinical trial, 309, 325, 342, 425, 441, 474, 477, 481, 508, 521, 522 Clone, 474 Cloning, 126, 350, 359, 371, 372, 468, 474 Clubbing, 454, 474 Cobalt, 363, 373, 474 Cod Liver Oil, 474, 483 Codon, 353, 475, 490 Coenzyme, 465, 475 Cofactor, 475, 510, 521, 532

Cognition, 389, 475 Cognitive restructuring, 475, 530 Colic, 386, 475 Colistin, 131, 475 Colitis, 399, 475, 500 Collagen, 475, 487, 489, 518, 520 Colloidal, 475, 482, 506, 516 Colonopathy, 275, 298, 475 Colonoscopy, 475 Colorectal, 361, 475 Colorectal Cancer, 361, 475 Common Bile Duct, 386, 475, 478, 494 Compassionate, 390, 475 Complement, 303, 462, 475, 476, 490, 504 Complementary and alternative medicine, 283, 284, 317, 476 Complementary medicine, 284, 476 Complementation, 276, 295, 357, 476 Computational Biology, 425, 428, 476 Computed tomography, 330, 469, 476, 526 Computerized axial tomography, 476, 526 Computerized tomography, 326, 333, 476 Conception, 476, 487, 530 Concomitant, 7, 476 Conduction, 123, 379, 477 Congestion, 477 Conjugated, 467, 472, 477, 478 Connective Tissue, 465, 469, 475, 477, 487, 489, 504, 509, 525, 532 Consciousness, 462, 477, 481, 494 Constipation, 386, 387, 388, 477, 500 Constriction, 477, 500 Consumption, 477, 480, 511, 513 Contraindications, ii, 477 Control group, 7, 477 Controlled clinical trial, 477 Coordination, 477, 508 Cor, 357, 477 Cor pulmonale, 357, 477 Corneum, 477, 485 Coronary, 477, 506 Coronary Thrombosis, 477, 506 Corpuscle, 477, 485 Cortex, 465, 477, 523 Corticosteroids, 280, 415, 478 Cranial, 478, 486, 514, 515, 529 Cryptosporidiosis, 466, 478 Crystallization, 386, 478 Cues, 339, 478 Curative, 478, 532 Cutaneous, 468, 470, 478, 503 Cyanosis, 478, 485

Index 543

Cyclic, 297, 360, 366, 460, 475, 478, 492, 510, 517, 519 Cystic Duct, 475, 478, 494 Cytochrome, 349, 474, 478 Cytokine, 123, 365, 478, 498 Cytomegalovirus, 478, 489 Cytomegalovirus Infections, 478, 489 Cytoplasm, 464, 467, 471, 473, 478, 485, 492, 525 Cytotoxic, 4, 478, 522 Cytotoxicity, 129, 479 D Databases, Bibliographic, 425, 479 De novo, 329, 479 Decompensation, 4, 479 Decontamination, 479 Defense Mechanisms, 479 Degenerative, 363, 373, 479, 494, 509, 525 Dehydration, 402, 473, 479 Deletion, 367, 377, 464, 479 Denaturation, 479, 518 Density, 295, 301, 338, 469, 472, 479, 502, 512, 529 Dental Care, 400, 479 Dental Caries, 402, 479, 487 Deoxycytidine, 417, 418, 479 Deoxyribonuclease I, 479 Dermatology, 330, 400, 479 DES, 462, 479 Desmosine, 479 Detergents, 475, 480, 487 Developing Countries, 442, 480 Diabetes Mellitus, 7, 277, 283, 480, 491, 493 Diagnostic procedure, 345, 410, 438, 480 Diarrhea, 138, 386, 454, 478, 480, 484, 500, 504 Diarrhoea, 480, 496 Diastole, 480 Diastolic, 480, 495 Dietary Fats, 480, 502 Dietary Fiber, 480 Diffusion, 126, 470, 480, 499 Digestion, 356, 402, 461, 467, 469, 480, 498, 502, 513, 515, 530 Digestive system, 343, 385, 386, 480, 489 Dilatation, 469, 480, 520 Dilation, 469, 480 Diphosphates, 464, 480 Diploid, 476, 480, 517 Direct, iii, 4, 6, 327, 350, 357, 359, 371, 373, 413, 474, 480, 481, 514, 523

Discrimination, 128, 426, 480, 538 Disparity, 480 Dissociation, 460, 480, 499 Distal, 5, 353, 382, 456, 481, 482, 489, 521 Distention, 453, 481 Diuretic, 361, 481 Diverticula, 481 Diverticulitis, 399, 481 Diverticulum, 481 DNA Topoisomerase, 481, 490 Dopamine, 481, 516 Dorsal, 398, 481, 519 Dorsum, 481 Double-blinded, 481 Drive, ii, vii, 3, 4, 273, 386, 387, 388, 398, 481, 499 Drug Design, 406, 417, 481 Drug Interactions, 416, 481 Drug Resistance, 369, 481, 482 Drug Tolerance, 481, 482, 533 Duct, 4, 124, 287, 360, 362, 386, 462, 473, 475, 482, 483, 486, 494, 525, 531, 536 Duodenum, 388, 467, 474, 482, 483, 489, 500, 513, 526, 530 Dyskinesia, 278, 311, 482 Dyslexia, 482, 501 Dysplasia, 430, 482 Dyspnea, 357, 454, 479, 482, 485 Dystrophy, 400, 429, 482 E Eating Disorders, 386, 387, 400, 482 Edema, 479, 482, 509, 535 Effector, 329, 459, 475, 482, 510, 517 Elastin, 475, 480, 482 Elective, 482 Electrode, 391, 396, 463, 471, 482 Electrolyte, 350, 358, 359, 371, 372, 380, 394, 398, 482, 487, 511, 519, 528, 535 Electrons, 464, 466, 471, 482, 499, 512, 522 Electrophoresis, 125, 288, 364, 482, 500 Emboli, 482 Embolization, 482 Embryo, 482, 497, 511, 529 Embryology, 398, 483 Emollient, 483, 491, 511 Emphysema, 461, 474, 483 Emulsion, 284, 313, 314, 483 Enamel, 479, 483 Encopresis, 386, 483 Endemic, 473, 483, 530 Endocarditis, 470, 483 Endocrine System, 483, 510

544 Cystic Fibrosis

Endocrinologist, 7, 483 Endometrial, 275, 483 Endometrium, 483, 506 Endopeptidases, 483, 515, 520 Endoscope, 483 Endoscopic, 6, 275, 279, 321, 386, 387, 470, 475, 483 Endoscopic retrograde cholangiopancreatography, 387, 483 Endoscopy, 387, 483 Endothelial cell, 484, 498, 532 Endothelium, 299, 484, 510 Endothelium, Lymphatic, 484 Endothelium, Vascular, 484 Endothelium-derived, 484, 510 Endotoxic, 484, 502 Endotoxin, 484, 534 End-stage renal, 474, 484, 518 Enhancer, 484 Enteral Nutrition, 279, 292, 299, 386, 484 Enteric Nervous System, 398, 484 Enteric-coated, 5, 484 Enteropeptidase, 484, 534 Enterotoxins, 398, 484 Environmental Exposure, 484, 512 Environmental Health, 424, 426, 484 Environmental tobacco smoke, 389, 484 Enzymatic, 315, 470, 471, 476, 479, 484, 494, 518, 524 Eosinophilic, 406, 484 Eosinophils, 485, 492, 501 Epidemic, 128, 140, 485, 530 Epidemiological, 129, 485 Epidermis, 477, 485, 495, 500, 522 Epigastric, 485, 513 Epinephrine, 460, 481, 485, 510, 535 Epitope, 485 Erythrocyte Membrane, 308, 485 Erythrocytes, 274, 463, 469, 485, 493, 523 Erythromycin, 466, 474, 485 Escalation, 485 Esophageal, 4, 387, 485, 534 Esophageal Atresia, 387, 485, 534 Esophageal Motility Disorders, 387, 485 Esophageal Varices, 4, 485 Esophagus, 386, 388, 399, 465, 480, 485, 486, 489, 503, 516, 523, 530, 534, 536 Essential Tremor, 429, 486 Estrogen, 296, 486, 505 Ethmoid, 486, 514 Eukaryotic Cells, 486, 512, 535 Evacuation, 477, 486

Excipients, 363, 373, 486 Exercise Test, 486 Exercise Tolerance, 301, 486 Exocrine, 5, 7, 277, 279, 315, 348, 349, 350, 351, 355, 356, 357, 359, 360, 363, 368, 371, 372, 377, 379, 394, 395, 440, 441, 442, 443, 486, 513 Exogenous, 341, 486 Exon, 139, 359, 371, 486 Exotoxin, 329, 486 Expiration, 296, 486, 519, 524, 537 Expiratory, 327, 486 External-beam radiation, 486, 522 Extracellular, 136, 297, 320, 468, 477, 486, 487, 528 Eye Infections, 460, 486 F Facial, 486, 505, 514 Facial Nerve, 486, 514 Faecal, 293, 297, 480, 487 Failure to Thrive, 386, 387, 487 Fallopian Tubes, 487, 524 Family Planning, 400, 425, 487 Famotidine, 315, 487 Fatigue, 454, 487, 493 Fatty acids, 276, 289, 291, 297, 298, 487, 492, 502, 505, 528 Fatty Liver, 6, 487 Febrile, 487, 530 Fecal Incontinence, 388, 487, 497 Feces, 477, 483, 487, 513, 530 Fetoprotein, 487 Fetus, 461, 487, 488, 505, 519, 529, 536 Fibroblasts, 487, 498 Fish Oils, 278, 306, 487 Fistula, 487, 489 Flatus, 487, 489 Fluid Therapy, 487, 511 Fluorine, 363, 373, 487 Flutter, 310, 487 Foetoplacental, 488, 511 Fold, 132, 301, 352, 366, 488 Forced Expiratory Volume, 488 Forearm, 468, 488 Fosfomycin, 488 Frameshift, 354, 488 Friction, 488, 503 Fructose, 399, 488, 492 Fructose Intolerance, 399, 488 Fucose, 488 Fucosyltransferases, 488 Fulminant Hepatic Failure, 387, 388, 488

Index 545

Fungi, 131, 463, 465, 486, 488, 506, 538 Fungus, 470, 488 G Galactosemia, 399, 488 Gallbladder, 385, 386, 387, 459, 467, 473, 478, 480, 483, 488, 489, 502 Gallstones, 386, 387, 467, 473, 489, 536 Gamma Rays, 489, 522 Ganciclovir, 278, 489 Ganglia, 459, 466, 484, 489, 510, 515 Gas, 462, 470, 473, 480, 487, 489, 495, 500, 504, 510, 519, 522, 524, 536 Gas exchange, 489, 519, 524, 536 Gastric, 5, 386, 465, 471, 474, 485, 487, 489, 494, 515 Gastric Acid, 474, 485, 489 Gastric Juices, 489, 515 Gastric Mucosa, 489, 515 Gastrin, 474, 489, 494 Gastritis, 387, 399, 429, 489 Gastroduodenal, 388, 489 Gastroesophageal Reflux, 276, 387, 388, 399, 489 Gastrointestinal Hemorrhage, 386, 489 Gastrointestinal tract, 5, 7, 360, 361, 377, 387, 388, 398, 489, 527 Gastrointestinal Transit, 280, 489 Gastrostomy, 305, 321, 484, 489 Gelatin, 489, 492, 532 Gels, 365, 490 Gelsolin, 419, 490 Gene Expression, 127, 334, 430, 490 Genetic Code, 378, 490, 511 Genetic Counseling, 338, 394, 490 Genetic Engineering, 468, 474, 490 Genetic Screening, 490 Genetic testing, 490, 518 Genistein, 284, 285, 290, 298, 302, 311, 312, 314, 325, 358, 490 Genital, 347, 474, 490, 535 Genitourinary, 358, 368, 490, 535 Genotype, 4, 136, 296, 490, 516 Germ Cells, 490, 505, 512, 529, 532 Gestation, 490, 515, 529 Giant Cells, 490, 526 Ginseng, 317, 490 Glanders, 491, 505 Glomerular, 491, 524 Gluconeogenesis, 329, 488, 491 Glucose Intolerance, 480, 491 Glucose tolerance, 7, 8, 341, 491 Glucose Tolerance Test, 7, 491

Glucuronic Acid, 491, 493 Glutamic Acid, 491, 520 Glutamine, 491 Glutathione Peroxidase, 491, 527 Gluten, 471, 491 Glycerol, 363, 373, 378, 491, 492, 517 Glycerophospholipids, 491, 517 Glycine, 363, 373, 467, 472, 492, 527 Glycoprotein, 321, 346, 369, 370, 377, 461, 488, 490, 492, 498, 508, 532, 534 Glycoside, 492, 495, 526 Glycosidic, 492, 510, 511 Glycosylation, 130, 132, 492 Gonadal, 492, 530 Governing Board, 492, 519 Government Agencies, 399, 400, 492, 519 Gp120, 492, 515 Graft, 402, 492, 495 Gram-negative, 466, 469, 471, 484, 492, 519, 521, 533, 537 Gram-Negative Bacteria, 484, 492, 519, 533 Gram-positive, 466, 492, 508 Granulocytes, 306, 492, 501, 538 Growth, 5, 6, 276, 277, 287, 294, 301, 305, 311, 320, 326, 328, 355, 362, 388, 429, 437, 454, 456, 460, 463, 464, 466, 471, 472, 480, 487, 492, 494, 498, 504, 509, 511, 512, 517, 518, 532, 537 Growth factors, 492 Guanylate Cyclase, 492, 510 H Habitat, 492, 509 Haematoma, 492, 493 Haemorrhage, 493 Haploid, 493, 517 Haplotypes, 493 Haptens, 460, 493 Health Policy, 444, 493 Heart failure, 477, 493 Heart-Lung Transplantation, 493 Hematopoiesis, 493, 498 Hematuria, 493 Heme, 467, 478, 493, 519 Hemochromatosis, 387, 493 Hemoglobin, 463, 478, 485, 493, 501, 519 Hemoglobinuria, 429, 493 Hemolysis, 485, 493 Hemolytic, 493 Hemoptysis, 454, 493 Hemorrhage, 493, 522, 531 Heparin, 417, 493, 518

546 Cystic Fibrosis

Hepatic, 4, 329, 341, 378, 379, 387, 388, 475, 483, 488, 491, 494, 502, 519 Hepatic Duct, Common, 483, 494 Hepatic Encephalopathy, 387, 494 Hepatitis, 386, 387, 399, 488, 494, 537 Hepatobiliary, 6, 123, 330, 368, 494 Hepatocyte, 351, 473, 494 Hepatocyte Growth Factor, 351, 494 Hepatomegaly, 303, 494 Hereditary, 362, 363, 387, 394, 398, 461, 494, 524 Heredity, 388, 490, 494 Hernia, 386, 494 Heterogeneity, 130, 131, 373, 460, 494 Heterotrophic, 488, 494 Heterozygote, 360, 373, 397, 494 Histamine, 462, 474, 487, 494, 495 Histology, 5, 494 Homeostasis, 274, 286, 388, 494 Homogeneous, 135, 352, 494 Homologous, 131, 461, 468, 494 Homozygotes, 364, 494 Hormonal, 465, 494 Hormone therapy, 495, 505 Horny layer, 485, 495 Hospice, 390, 495 Host, 380, 393, 402, 466, 470, 495, 508, 525, 531, 536, 537 Hybrid, 474, 495 Hybridomas, 346, 355, 495, 498 Hydrogen, 300, 459, 466, 470, 479, 491, 495, 502, 507, 510, 511, 512, 516, 521 Hydrogen Bonding, 495, 511 Hydrogen Peroxide, 491, 495, 502 Hydrolases, 378, 495, 517 Hydrolysis, 136, 464, 467, 495, 499, 510, 515, 517, 518, 521, 534 Hydrophobic, 480, 491, 495, 502 Hyperbilirubinemia, 495, 500 Hyperplasia, 495, 509 Hypersecretion, 375, 495 Hypersensitivity, 300, 461, 495, 525 Hypersensitivity, Immediate, 461, 495 Hypertension, 4, 6, 387, 388, 495, 535 Hypertrophy, 477, 495, 534 Hypnotic, 283, 496 Hypoglycemia, 488, 496 Hypokalaemia, 496 Hypoplasia, 398, 496 Hypoxemia, 357, 496 Hypoxia, 496, 532

I Ibuprofen, 340, 496 Id, 281, 315, 434, 439, 450, 452, 496 Idiopathic, 496, 526 Ileum, 279, 471, 496, 500 Ileus, 4, 303, 305, 357, 496 Imidazole, 494, 496, 506 Immune response, 334, 460, 463, 466, 493, 496, 504, 531, 536, 537 Immune system, 329, 380, 466, 468, 496, 508, 509, 516, 536, 538 Immunity, 137, 283, 496, 511 Immunodeficiency, 429, 496 Immunogenic, 496, 502 Immunoglobulin, 463, 496, 507 Immunologic, 364, 472, 496, 522 Immunology, 295, 393, 394, 460, 496 Impairment, 6, 286, 368, 465, 473, 482, 486, 496, 498, 506 Imperforate Anus, 399, 496 Implant radiation, 496, 498, 522 Implantation, 476, 496, 511 In vitro, 125, 131, 355, 496, 518, 525, 531, 533 In vivo, 125, 127, 132, 138, 334, 378, 494, 496, 508, 512 Incision, 496, 499 Incisive, 497 Incisor, 497 Incompetence, 489, 497 Incontinence, 136, 387, 483, 497 Incubation, 378, 497 Indicative, 355, 390, 497, 514, 536 Induction, 463, 497 Infancy, 349, 398, 497 Infant Mortality, 443, 497 Infantile, 497, 502 Infarction, 467, 477, 497, 506 Infection Control, 497 Infertility, 360, 497 Inflammatory bowel disease, 387, 388, 497 Infusion, 134, 284, 314, 497, 506 Ingestion, 127, 386, 387, 488, 491, 497, 518 Initiation, 497, 528 Inlay, 497, 524 Inner ear, 498, 536 Inorganic, 367, 381, 460, 480, 498, 508, 516 Insulator, 498, 508 Insulin, 7, 8, 274, 341, 415, 491, 498 Insulin-dependent diabetes mellitus, 498 Insulin-like, 498 Intelligence Tests, 327, 498

Index 547

Intensive Care, 126, 498 Intensive Care Units, 126, 498 Interleukin-6, 498 Interleukin-8, 365, 366, 498 Interleukin-9, 498 Internal Medicine, 489, 498, 525 Internal radiation, 498, 522 Interstitial, 469, 470, 498, 524 Intervention Studies, 283, 498 Intestinal Obstruction, 5, 388, 498 Intestine, 347, 349, 362, 377, 386, 398, 467, 469, 475, 489, 498, 501 Intoxication, 499, 536, 538 Intracellular, 123, 277, 279, 307, 368, 378, 381, 497, 499, 505, 510, 519, 526 Intracellular Membranes, 499, 505 Intrahepatic, 279, 494, 499 Intramuscular, 499, 514 Intravenous, 284, 302, 313, 338, 386, 408, 497, 499, 506, 514 Intrinsic, 132, 378, 460, 499 Introns, 359, 371, 499 Intussusception, 5, 499, 523 Invasive, 6, 277, 340, 496, 499, 504 Involuntary, 466, 484, 486, 487, 499, 509, 533 Ion Channels, 368, 381, 499, 510 Ion Exchange, 472, 499 Ion Transport, 307, 337, 350, 356, 357, 358, 359, 371, 372, 378, 379, 395, 398, 499 Ionization, 499 Iontophoresis, 360, 499 Ipratropium, 416, 499 Irritable Bowel Syndrome, 399, 500 Ischemia, 465, 500 Isoelectric, 311, 365, 500 Isoelectric Focusing, 311, 365, 500 Isoelectric Point, 365, 500 Isoflavones, 348, 377, 500 Isotonic, 360, 366, 500, 507 Itraconazole, 131, 138, 500 J Jaundice, 386, 387, 388, 495, 500, 509 Jejunostomy, 484, 500 Jejunum, 123, 500 Joint, 330, 465, 474, 500, 531, 532 K Kallidin, 469, 500 Kb, 424, 500 Keratinocytes, 498, 500 Keratolytic, 479, 500

Kidney Disease, 331, 332, 334, 335, 337, 342, 343, 400, 424, 430, 436, 438, 444, 500 Kinetic, 349, 500 L Labile, 475, 500 Lactation, 501, 511 Large Intestine, 361, 471, 475, 480, 498, 501, 523, 528 Larynx, 501, 533, 538 Latent, 501, 519 Learning Disorders, 328, 501 Lectin, 124, 501, 506 Lesion, 277, 468, 501, 503 Lethal, 5, 326, 347, 349, 354, 362, 364, 366, 376, 377, 466, 501 Leucine, 501, 515 Leucocyte, 418, 461, 501, 504 Leukaemia, 285, 501 Leukapheresis, 464, 501 Leukemia, 353, 400, 429, 501 Leukocytes, 467, 469, 472, 485, 492, 501, 534 Levofloxacin, 501 Library Services, 450, 501 Lidocaine, 501 Life cycle, 460, 488, 501 Life Expectancy, 8, 326, 348, 362, 372, 501 Ligament, 502, 520 Ligands, 382, 502 Ligation, 502 Linkage, 321, 376, 442, 502, 515 Lip, 403, 502 Lipase, 5, 279, 289, 317, 502, 513, 514 Lipid A, 292, 502 Lipid Peroxidation, 293, 294, 311, 502, 513 Lipodystrophy, 399, 502 Lipopolysaccharide, 139, 314, 492, 502 Lipoprotein, 301, 492, 502, 503 Liposome, 333, 334, 337, 502 Lipoxygenase, 306, 464, 502 Lithotripsy, 386, 502 Liver cancer, 461, 502 Liver Cirrhosis, 316, 502 Liver scan, 503, 526 Liver Transplantation, 4, 6, 275, 386, 387, 388, 440, 503 Living will, 400, 503 Localization, 131, 503 Localized, 355, 462, 479, 492, 497, 502, 503, 517, 526 Locomotion, 503, 517 Locomotor, 363, 373, 503

548 Cystic Fibrosis

Longitudinal study, 503 Loop, 494, 503 Low-density lipoprotein, 502, 503 Lower Esophageal Sphincter, 485, 489, 503 Lubricants, 503, 516 Lubrication, 402, 503 Lumen, 351, 362, 484, 485, 503 Lupus, 400, 402, 503, 532 Lymph, 472, 477, 484, 503, 504, 526 Lymph node, 472, 503, 504, 526 Lymphatic, 484, 497, 503, 504, 529 Lymphoblastic, 285, 504 Lymphoblasts, 459, 504 Lymphoid, 394, 463, 478, 501, 504 Lymphoma, 429, 504 Lysine, 480, 504, 518, 534 Lytic, 504, 537 M Magnetic Resonance Imaging, 330, 504, 526 Maintenance therapy, 348, 504 Major Histocompatibility Complex, 493, 504 Malabsorption syndrome, 387, 388, 504, 528 Malformation, 504 Malignancy, 488, 504 Malignant, 429, 464, 502, 504, 509, 522 Malnutrition, 308, 465, 504, 508 Mandible, 462, 504, 524 Maple Syrup Urine Disease, 399, 504 Marital Status, 327, 504 Mass Screening, 357, 504 Maxillary, 504, 505, 514 Maxillary Sinus, 505 Maximum Tolerated Dose, 334, 335, 482, 505 Meatus, 505 Mechanical ventilation, 470, 505, 519 Meconium, 4, 303, 305, 357, 457, 505 Mediate, 123, 362, 481, 505 Medical Records, 505, 525 Medical Staff, 481, 505 Medicament, 365, 375, 505 MEDLINE, 425, 428, 430, 505 Megestrol, 505 Megestrol Acetate, 505 Meiosis, 468, 505 Melanin, 505, 516, 535 Melanocytes, 505 Melanoma, 429, 469, 505 Melioidosis, 126, 505

Membrane, 123, 124, 127, 132, 140, 284, 286, 296, 307, 315, 346, 347, 350, 356, 359, 362, 367, 370, 371, 372, 377, 381, 382, 471, 476, 486, 492, 499, 501, 505, 508, 509, 512, 517, 518, 519, 523, 525, 534 Membrane Glycoproteins, 505 Membrane Proteins, 382, 505 Meninges, 466, 472, 506 Meningitis, 500, 506 Menopause, 506, 511, 519 Menstrual Cycle, 506, 511, 520 Menstruation, 506 Mental Disorders, 343, 506, 521 Mental Health, v, 343, 400, 424, 427, 506, 521 Metabolic disorder, 437, 506 Metaphase, 468, 506 Metastasis, 283, 506 MI, 313, 350, 366, 372, 457, 506 Micelles, 506 Miconazole, 131, 506 Microbe, 506, 533 Microcirculation, 502, 506 Micronutrients, 506 Microorganism, 475, 506, 514, 538 Micro-organism, 479, 506 Microscopy, 288, 506 Microspheres, 5, 507 Migration, 507 Milliliter, 469, 507 Miotic, 507, 517 Mitochondria, 349, 507, 512 Mitochondrial Swelling, 507, 509 Mitosis, 464, 507 Mobility, 330, 507 Modeling, 481, 507 Modification, 291, 347, 490, 507, 522 Molecular mass, 382, 507 Monitor, 334, 507, 511, 537 Monoclonal, 355, 495, 507, 522 Monoclonal antibodies, 355, 507 Monocyte, 366, 507 Mononuclear, 507, 534 Monophosphate, 356, 507 Monotherapy, 508 Morphine, 508, 509, 512 Morphogenesis, 398, 508 Morphological, 483, 488, 505, 508 Motility, 386, 490, 508, 527 Mucilaginous, 505, 508 Mucins, 508, 525 Mucociliary, 365, 508, 528

Index 549

Mucociliary Clearance, 365, 508 Mucolytic, 366, 469, 508 Mucosa, 340, 471, 489, 491, 503, 508, 509, 536 Multicenter study, 508 Multidrug resistance, 307, 508 Multiple sclerosis, 400, 508 Muscle Fibers, 508 Muscular Atrophy, 429, 508 Muscular Dystrophies, 482, 508 Musculature, 508, 521 Mutagenesis, 508 Mutagens, 508 Mycobacterium, 129, 330, 336, 466, 508, 534 Myelin, 508, 509 Myocardium, 506, 509 Myotonic Dystrophy, 429, 509 N Naive, 509 Narcotic, 508, 509 Nasal Cavity, 505, 509, 514 Nasal Mucosa, 125, 509 Nasal Polyps, 509 Nasogastric, 484, 509 NCI, 1, 342, 423, 509 Nebramycin, 509, 533 Nebulizer, 8, 330, 335, 509 Necrosis, 277, 464, 497, 506, 509, 526 Neonatal, 305, 332, 388, 497, 509 Neonatal Hepatitis, 388, 509 Neonatal Screening, 305, 332, 509 Neoplasia, 429, 509 Neoplasm, 509 Neoplastic, 361, 463, 495, 504, 509 Nephropathy, 500, 510 Nerve, 460, 463, 465, 473, 477, 484, 486, 508, 510, 520, 526, 530, 534 Nervous System, 429, 472, 510, 515 Neural, 402, 487, 510, 528 Neuraminidase, 297, 510 Neuroendocrine, 510 Neuromuscular, 459, 496, 510, 535 Neuronal, 510 Neurons, 489, 510 Neurotransmitters, 507, 510 Neutrons, 461, 469, 510, 522 Neutrophil, 295, 304, 306, 339, 340, 461, 510 Nickel, 363, 373, 510 Nitric Oxide, 278, 298, 300, 510 Nitrogen, 340, 461, 463, 491, 507, 510, 513

Norepinephrine, 460, 481, 510 Nosocomial, 387, 511, 521 Nuclear, 466, 474, 482, 486, 489, 509, 511 Nuclei, 461, 482, 490, 499, 504, 507, 510, 511, 521 Nucleic acid, 372, 466, 490, 508, 510, 511, 522 Nucleic Acid Hybridization, 372, 511 Nucleotidases, 495, 511 Nucleus, 464, 466, 467, 473, 478, 485, 486, 489, 505, 507, 510, 511, 520, 521, 530, 532 Nutritional Status, 5, 6, 7, 292, 306, 309, 511 Nutritional Support, 388, 489, 511 O Oestrogen, 280, 314, 511 Ointments, 366, 511, 528 Oligosaccharides, 510, 511 Omega-3 fatty acid, 278, 292, 301, 306, 312, 313, 511 Oncogene, 429, 494, 511 Oocytes, 130, 275, 298, 379, 512 Opacity, 479, 512 Opium, 508, 512 Opportunistic Infections, 380, 512 Oral Health, 8, 512 Oral Hygiene, 8, 512 Organ Culture, 512, 533 Organ Transplantation, 512 Organelles, 472, 478, 505, 512 Orthodontics, 400, 512 Osteoporosis, 275, 278, 286, 326, 328, 461, 511, 512 Ovaries, 487, 512, 524, 527 Ovary, 511, 512 Overdose, 488, 512 Ovulation, 505, 512 Oxidants, 278, 365, 512 Oxidation, 295, 301, 459, 464, 478, 491, 502, 512, 513 Oxidation-Reduction, 512, 513 Oxidative Stress, 3, 513 Oxygen Consumption, 486, 513, 524 Oxygenation, 496, 513 P Paediatric, 275, 276, 309, 513 Palate, 330, 513 Palliative, 295, 378, 505, 511, 513, 532 Pamidronate, 408, 513 Pancreatic cancer, 387, 429, 513 Pancreatic Ducts, 358, 483, 513

550 Cystic Fibrosis

Pancreatic enzymes, 5, 6, 275, 331, 513, 514 Pancreatic Extracts, 5, 293, 513 Pancreatic Fistula, 387, 513 Pancreatic Function Tests, 348, 513 Pancreatic Juice, 474, 489, 513 Pancreatin, 289, 513 Pancreatitis, 279, 355, 386, 387, 388, 398, 513 Pancrelipase, 340, 514 Papilla, 483, 514 Paralysis, 496, 514, 529 Paranasal Sinuses, 505, 514, 528 Parasite, 514 Parasitic, 387, 388, 478, 514 Parasitic Diseases, 387, 514 Parenteral, 292, 299, 386, 387, 388, 414, 514 Parenteral Nutrition, 387, 514 Parotid, 288, 514, 526 Paroxysmal, 429, 514 Particle, 502, 514, 529, 534 Patch, 514 Paternity, 514 Pathogen, 276, 380, 497, 514, 531 Pathogenesis, 127, 132, 139, 314, 322, 386, 387, 514 Pathologic, 464, 468, 470, 477, 495, 514, 524 Pathologic Processes, 464, 514 Pathophysiology, 279, 397, 398, 514 Patient Advocacy, 440, 514 Patient Education, 8, 290, 436, 438, 448, 450, 457, 514 Peer Review, 273, 389, 515 Pelvic, 515, 520 Penis, 515, 524 Pepsin, 474, 515, 526 Pepsin A, 474, 515 Peptic, 309, 387, 388, 515 Peptic Ulcer, 309, 387, 388, 515 Peptide, 130, 133, 362, 382, 406, 473, 474, 483, 484, 495, 515, 518, 520, 521 Peptide Chain Elongation, 474, 515 Peptide Hydrolases, 483, 495, 515 Peptide T, 406, 515 Percutaneous, 321, 502, 515, 516 Perfusion, 496, 515 Pericardium, 515, 532 Perinatal, 389, 497, 515 Peripheral Nervous System, 515, 531, 536 Peritoneal, 398, 465, 515, 516 Peritoneal Cavity, 465, 516 Peritoneum, 515, 516

Peroxide, 295, 300, 516 Petechiae, 493, 516 Petrolatum, 366, 483, 516 Petroleum, 516 PH, 125, 138, 469, 516 Phagocyte, 278, 327, 512, 516 Phagocytosis, 354, 355, 516 Pharmacodynamic, 131, 487, 516 Pharmacokinetic, 134, 278, 516 Pharmacologic, 463, 516, 533 Pharmacotherapy, 126, 307, 353, 516 Pharynx, 489, 509, 516 Phenolphthalein, 483, 516 Phenylalanine, 367, 377, 382, 515, 516, 535 Phenylbutyrate, 285, 325, 516 Phonophoresis, 499, 516 Phosphates, 516 Phosphodiesterase, 366, 517 Phosphodiesterase Inhibitors, 366, 517 Phospholipids, 297, 487, 502, 517 Phosphoric Monoester Hydrolases, 495, 517 Phosphorus, 470, 517 Phosphorylation, 136, 346, 369, 370, 382, 460, 517, 521 Physical Examination, 331, 517 Physical Fitness, 389, 517, 530 Physical Therapy, 289, 312, 374, 396, 400, 444, 517 Physiologic, 334, 461, 468, 500, 506, 517, 523, 524 Pigment, 386, 467, 505, 517 Pilocarpine, 360, 402, 416, 517 Pilot study, 313, 517 Plants, 366, 461, 465, 470, 474, 490, 491, 492, 501, 511, 517, 521, 526, 533, 534 Plasma cells, 463, 517 Plasmapheresis, 464, 517 Platelet Activation, 517 Platelet Aggregation, 462, 510, 518 Platelet Factor 4, 498, 518 Plateletpheresis, 464, 518 Platelets, 464, 467, 510, 517, 518, 527 Podiatry, 400, 518 Poisoning, 310, 499, 518 Policy Making, 492, 518 Polycystic, 430, 518 Polylysine, 518 Polymerase, 518, 528 Polymerase Chain Reaction, 518 Polymers, 365, 366, 468, 518, 521 Polymorphism, 3, 125, 128, 376, 518

Index 551

Polyp, 295, 518 Polypeptide, 353, 367, 378, 381, 382, 462, 475, 515, 518, 520, 536, 538 Polyposis, 399, 475, 518 Porins, 286, 519 Porphyria, 399, 519 Porphyrins, 519 Positive End-Expiratory Pressure, 519 Posterior, 462, 465, 481, 513, 519, 529 Postmenopausal, 461, 512, 519 Postnatal, 389, 519 Postoperative, 519 Postprandial, 8, 519 Postprandial Blood Glucose, 8, 519 Postural, 287, 296, 304, 519 Potassium, 128, 296, 363, 373, 496, 519, 528 Potassium Channels, 128, 519 Practice Guidelines, 427, 519 Precipitation, 365, 519 Precursor, 382, 481, 482, 484, 510, 516, 519, 535, 536 Predisposition, 519 Prenatal, 338, 349, 350, 359, 371, 372, 395, 482, 490, 519 Prevalence, 7, 124, 131, 336, 362, 373, 389, 519 Probe, 140, 308, 315, 520 Procaine, 501, 520 Progesterone, 505, 520, 530 Prognostic factor, 520, 531 Progression, 366, 520 Progressive, 357, 368, 438, 474, 481, 482, 485, 492, 508, 509, 517, 520, 524 Progressive disease, 368, 520 Projection, 479, 511, 520, 523 Proline, 375, 475, 520 Prophase, 468, 512, 520 Prophylaxis, 520, 524, 536 Prospective study, 503, 520 Prostate, 400, 429, 511, 520, 524 Protease, 139, 294, 418, 461, 513, 520 Protease Inhibitors, 294, 520 Protein C, 136, 321, 372, 378, 462, 464, 466, 475, 502, 520, 535 Protein Conformation, 136, 462, 520 Protein S, 378, 396, 430, 468, 474, 485, 490, 520, 521, 525 Protein-Tyrosine Kinase, 490, 521 Proteolytic, 300, 320, 461, 476, 484, 521 Protocol, 521 Protons, 461, 495, 521, 522 Proximal, 380, 481, 509, 521

Prune Belly Syndrome, 399, 521 Pruritus, 334, 521, 535 Pseudomonas Infections, 332, 521 Psychiatry, 287, 521, 536 Public Health, 322, 397, 403, 427, 521 Public Policy, 425, 521 Publishing, 5, 6, 122, 399, 521 Pulmonary Artery, 468, 521, 537 Pulmonary congestion, 362, 521 Pulmonary Edema, 473, 521 Pulmonary hypertension, 357, 477, 522 Pulmonary Ventilation, 522, 524 Pulsation, 487, 522 Purifying, 346, 365, 370, 480, 522 Purines, 466, 522, 527 Purpura, 493, 522 Purulent, 357, 366, 522, 536 Pyloric Stenosis, 522 Q Quaternary, 520, 522 R Race, 461, 507, 522 Radiation, 402, 484, 486, 489, 498, 522, 526, 538 Radiation therapy, 402, 486, 498, 522 Radioactive, 469, 479, 495, 496, 498, 499, 503, 507, 508, 511, 522, 526 Radiolabeled, 339, 522 Radiologist, 386, 522 Radiotherapy, 469, 522 Randomized clinical trial, 333, 522 Reabsorption, 364, 523 Reagent, 473, 523 Rebound effect, 340, 523 Recessive gene, 332, 350, 359, 366, 371, 441, 523 Recombinant, 132, 136, 326, 334, 350, 359, 369, 371, 372, 417, 418, 419, 523, 536 Reconstitution, 352, 523 Rectal, 5, 414, 415, 523 Rectal Prolapse, 5, 523 Rectum, 361, 463, 464, 469, 475, 480, 487, 489, 497, 501, 520, 523 Red blood cells, 485, 493, 523, 526, 528 Red Nucleus, 465, 523 Refer, 1, 399, 470, 475, 488, 503, 509, 510, 511, 523 Reflux, 386, 485, 489, 523 Refraction, 523, 529 Regeneration, 523 Regimen, 320, 328, 482, 516, 523 Regurgitation, 485, 489, 523

552 Cystic Fibrosis

Rehabilitation Centers, 400, 523 Remission, 504, 524 Renal failure, 524 Reproductive system, 362, 426, 524 Resection, 524, 528 Resorption, 360, 523, 524 Respiration, 276, 279, 298, 349, 393, 394, 470, 507, 524 Respirator, 505, 524, 536 Respiratory distress syndrome, 470, 524 Respiratory failure, 352, 376, 379, 524, 536 Respiratory System, 348, 349, 365, 368, 380, 426, 440, 441, 442, 443, 508, 524, 536 Restoration, 358, 517, 523, 524 Retinal, 480, 524 Retinoblastoma, 429, 524 Retinoids, 524, 537 Retinol, 309, 312, 524 Retrograde, 296, 524 Retrospective, 279, 525 Retrospective study, 525 Retrovirus, 356, 525 Rheology, 310, 525 Rheumatism, 496, 525 Rheumatoid, 402, 512, 525 Rheumatoid arthritis, 402, 525 Rheumatology, 525 Rhinitis, 469, 499, 525 Ribose, 459, 525 Ribosome, 525, 534 Rigidity, 517, 525 Risk factor, 3, 4, 333, 520, 525 Ristocetin, 525, 536 Rod, 466, 521, 525 Role-play, 290, 525 Rubber, 525, 530 S Saline, 366, 469, 525 Saliva, 288, 362, 364, 402, 525 Salivary, 322, 402, 440, 441, 442, 443, 478, 480, 486, 513, 525, 538 Salivary glands, 402, 440, 441, 442, 443, 478, 480, 486, 525 Salivation, 485, 525 Saponins, 526, 530 Sarcoidosis, 328, 399, 402, 526 Scans, 330, 333, 526 Schizoid, 526, 538 Schizophrenia, 526, 538 Schizotypal Personality Disorder, 526, 538 Scleroderma, 402, 526 Sclerosis, 429, 508, 526

Scoliosis, 330, 526 Scrotum, 526, 536 Secretin, 6, 382, 455, 526 Secretory, 4, 5, 123, 139, 347, 349, 356, 358, 361, 364, 379, 418, 508, 526 Seizures, 514, 526 Selenium, 292, 293, 310, 526 Self Care, 411, 527 Self-Help Groups, 390, 527 Semen, 466, 520, 527 Seminal vesicles, 527, 536 Semisynthetic, 471, 474, 527 Senile, 512, 527 Sensor, 409, 527 Sequence Analysis, 126, 527 Sequence Homology, 515, 527 Sequencing, 134, 139, 518, 527 Serine, 474, 483, 527, 534 Serotonin, 516, 527 Serous, 123, 397, 484, 527 Sex Characteristics, 460, 463, 511, 527 Sex Determination, 430, 527 Sexually Transmitted Diseases, 400, 527 Shock, 502, 527, 534 Short Bowel Syndrome, 386, 528 Side effect, 361, 362, 402, 413, 417, 460, 468, 528, 533 Sigma Factor, 528 Signs and Symptoms, 306, 377, 524, 528, 535 Sinusitis, 357, 407, 528 Skeletal, 309, 463, 508, 528 Skeleton, 459, 500, 528 Sludge, 386, 528 Small intestine, 467, 471, 473, 474, 478, 482, 483, 494, 496, 498, 500, 509, 528, 534 Smooth muscle, 386, 462, 470, 494, 495, 508, 528, 531 Soaps, 487, 528 Social Environment, 522, 528 Social Support, 528, 530 Social Work, 312, 528 Sodium Channels, 528 Soft tissue, 469, 474, 528 Solvent, 467, 491, 529 Soma, 529 Somatic, 6, 123, 460, 505, 507, 515, 529 Sound wave, 330, 477, 522, 529, 535 Soybean Oil, 297, 529 Spastic, 500, 529 Specialist, 330, 385, 390, 393, 444, 480, 529 Specificity, 460, 464, 483, 529

Index 553

Spectrum, 6, 367, 529 Sperm, 463, 473, 529 Spermatozoa, 466, 527, 529, 536 Sphenoid, 514, 529 Sphincter, 501, 523, 529 Spinal cord, 390, 472, 473, 484, 506, 510, 515, 529 Spinal Cord Injuries, 390, 529 Spinous, 485, 500, 529 Spirometry, 340, 529 Spleen, 462, 478, 504, 526, 529 Spontaneous Abortion, 389, 529 Sporadic, 524, 530 Sports Medicine, 400, 448, 530 Sprue, 399, 530 Sputa, 124, 129, 137, 294, 530 Staging, 526, 530 Standard therapy, 357, 530 Steatorrhea, 6, 340, 530 Steatosis, 303, 487, 530 Steel, 530, 535, 536 Sterility, 497, 530 Sterilization, 404, 530 Steroid, 275, 414, 467, 511, 526, 530 Stethoscopes, 530 Stimulants, 491, 530 Stimulus, 481, 482, 498, 499, 530, 532 Stool, 331, 456, 497, 500, 501, 530 Strand, 125, 346, 357, 369, 370, 518, 530 Stress, 6, 7, 287, 400, 454, 471, 500, 513, 519, 525, 530 Stress management, 287, 530 Stricture, 5, 531 Stroke, 343, 424, 531 Subacute, 497, 528, 531 Subclinical, 497, 526, 531 Subcutaneous, 341, 482, 502, 514, 531 Subspecies, 529, 531 Substance P, 485, 523, 525, 526, 531 Substrate, 7, 364, 495, 510, 531 Superinfection, 466, 531 Support group, 298, 440, 441, 442, 443, 444, 456, 457, 531 Suppression, 353, 531 Surfactant, 531 Survival Analysis, 531 Sweat Glands, 325, 347, 348, 349, 357, 367, 426, 440, 441, 442, 443, 531 Symphysis, 520, 531 Symptomatic, 374, 375, 514, 531 Symptomatic treatment, 375, 531 Synergistic, 138, 311, 531, 533

Systemic disease, 5, 402, 532 Systemic lupus erythematosus, 402, 532 Systolic, 495, 532 T Taurine, 274, 292, 293, 294, 308, 311, 348, 467, 472, 532 Telangiectasia, 430, 532 Terminator, 475, 532 Testicular, 400, 532 Testis, 511, 532 Thalamic, 465, 532 Thalamic Diseases, 465, 532 Therapeutics, 284, 288, 289, 296, 325, 329, 408, 417, 532 Thermal, 469, 480, 510, 518, 532 Thoracic, 279, 298, 403, 404, 532 Threonine, 515, 527, 532 Threshold, 495, 532 Thrombin, 518, 520, 532 Thrombomodulin, 520, 532 Thrombosis, 467, 521, 531, 532 Thyroid, 532, 535 Thyroxine, 516, 532 Tic, 332, 350, 359, 366, 371, 441, 533 Time Management, 530, 533 Tissue, 275, 330, 332, 366, 382, 398, 463, 464, 465, 467, 468, 469, 470, 472, 477, 481, 482, 483, 484, 485, 487, 488, 492, 493, 494, 495, 496, 498, 500, 501, 502, 503, 504, 505, 508, 509, 510, 512, 513, 514, 515, 517, 518, 523, 524, 528, 529, 531, 532, 533, 534 Tissue Culture, 533 Tobacco Mosaic Virus, 354, 533 Tobamovirus, 533 Tolerance, 6, 288, 378, 491, 533 Tomography, 533 Tonic, 485, 533 Tonicity, 493, 500, 533 Tooth Preparation, 459, 533 Topical, 386, 414, 495, 516, 528, 533 Toxic, v, 329, 378, 389, 465, 467, 472, 475, 479, 484, 486, 496, 526, 533, 536 Toxicity, 389, 481, 505, 525, 533 Toxicology, 426, 533 Toxins, 329, 463, 491, 497, 507, 533 Toxoplasmosis, 466, 533 Trace element, 5, 469, 474, 487, 510, 533 Trachea, 469, 501, 516, 532, 533, 534 Tracheoesophageal Fistula, 485, 534 Transcriptase, 525, 534 Transduction, 534

554 Cystic Fibrosis

Transfection, 468, 534 Transferases, 3, 492, 534 Translation, 353, 485, 534 Translational, 534 Translocation, 296, 474, 485, 534 Transmitter, 459, 481, 499, 511, 534, 537 Transplantation, 4, 5, 138, 279, 332, 387, 435, 440, 443, 474, 503, 504, 534 Trauma, 402, 466, 509, 514, 532, 534 Trees, 462, 525, 534 Tricuspid Atresia, 477, 534 Trypsin, 456, 461, 474, 484, 534, 538 Tuberculosis, 477, 503, 534 Tuberous Sclerosis, 430, 534 Tumor Necrosis Factor, 124, 366, 534 Tungsten, 471, 534 Tyrosine, 311, 481, 521, 535 U Ubiquitin, 378, 535 Ulcerative colitis, 386, 497, 535 Ultrasonography, 4, 535 Ultrasound test, 332, 535 Unconscious, 479, 496, 535 Unsaturated Fats, 487, 535 Uracil, 535 Uraemia, 514, 535 Urea, 531, 535 Uremia, 524, 535 Ureter, 502, 535 Urethra, 515, 520, 535 Uridine Triphosphate, 341, 535 Urinary, 136, 443, 474, 490, 497, 521, 535, 538 Urinary tract, 443, 521, 535 Urinary tract infection, 521, 535 Urine, 330, 331, 332, 364, 468, 481, 493, 497, 504, 513, 535 Urogenital, 490, 535 Ursodeoxycholic Acid, 5, 292, 331, 334, 536 Uterus, 472, 483, 487, 506, 512, 520, 524, 536 V Vaccination, 536 Vaccine, 127, 460, 521, 536 Vagina, 470, 472, 479, 506, 524, 536 Vaginal, 503, 536 Vaginitis, 470, 536 Valves, 330, 536 Vanadium, 363, 373, 536 Vancomycin, 134, 416, 536 Varices, 6, 536

Vas Deferens, 395, 536 Vascular, 484, 495, 497, 502, 506, 510, 536 Vasculitis, 514, 536 Vasoactive, 536 Vasoactive Intestinal Peptide, 536 Vasodilator, 469, 481, 494, 536 Vector, 138, 334, 336, 352, 405, 418, 514, 534, 536 Vein, 331, 332, 499, 511, 514, 536 Venous, 467, 479, 521, 534, 536 Ventilation, 7, 288, 339, 536 Ventilator, 505, 524, 536 Ventral, 398, 536 Ventricle, 465, 477, 521, 532, 534, 537 Ventricular, 477, 534, 537 Venules, 468, 470, 484, 506, 537 Vertebrae, 529, 537 Vesicular, 537 Veterinary Medicine, 425, 537 Vibrio, 398, 473, 537 Vibrio cholerae, 473, 537 Video Recording, 401, 537 Videodisc Recording, 537 Villous, 471, 537 Viral, 122, 353, 387, 388, 418, 490, 525, 534, 537 Viral Hepatitis, 387, 388, 537 Viral vector, 537 Virulence, 135, 354, 531, 533, 537 Virulent, 537 Virus, 124, 129, 138, 334, 353, 405, 466, 484, 490, 492, 534, 537 Viscera, 529, 537 Viscosity, 5, 136, 138, 356, 378, 380, 525, 537 Vital Capacity, 488, 537 Vitamin A, 5, 524, 537 Vitro, 126, 131, 295, 494, 538 Vivo, 538 Vocal cord, 285, 538 Voriconazole, 538 W Weight Gain, 8, 305, 334, 341, 342, 362, 487, 538 Weight Perception, 310, 538 White blood cell, 327, 459, 463, 501, 504, 507, 508, 510, 517, 538 Withdrawal, 400, 538 Womb, 524, 536, 538 Wounds, Gunshot, 529, 538 X Xanthine, 368, 538

Index 555

Xerostomia, 401, 402, 538 X-ray, 326, 330, 455, 456, 469, 471, 476, 483, 489, 511, 522, 526, 538

Y Yeasts, 470, 488, 516, 538 Z Zymogen, 474, 520, 538

556 Cystic Fibrosis

Index 557

558 Cystic Fibrosis