PULMONARY FIBROSIS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES
J AMES N. P ARKER , 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 2004 by ICON Group International, Inc. Copyright 2004 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., 1960Pulmonary 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: 0-597-84570-0 1. Pulmonary 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.
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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 pulmonary 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 PULMONARY FIBROSIS .............................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Pulmonary Fibrosis....................................................................... 6 E-Journals: PubMed Central ....................................................................................................... 61 The National Library of Medicine: PubMed ................................................................................ 63 CHAPTER 2. NUTRITION AND PULMONARY FIBROSIS .................................................................. 111 Overview.................................................................................................................................... 111 Finding Nutrition Studies on Pulmonary Fibrosis.................................................................... 111 Federal Resources on Nutrition ................................................................................................. 113 Additional Web Resources ......................................................................................................... 114 CHAPTER 3. DISSERTATIONS ON PULMONARY FIBROSIS .............................................................. 115 Overview.................................................................................................................................... 115 Dissertations on Pulmonary Fibrosis ........................................................................................ 115 Keeping Current ........................................................................................................................ 115 CHAPTER 4. CLINICAL TRIALS AND PULMONARY FIBROSIS ........................................................ 117 Overview.................................................................................................................................... 117 Recent Trials on Pulmonary Fibrosis......................................................................................... 117 Keeping Current on Clinical Trials ........................................................................................... 125 CHAPTER 5. PATENTS ON PULMONARY FIBROSIS ........................................................................ 127 Overview.................................................................................................................................... 127 Patents on Pulmonary Fibrosis.................................................................................................. 127 Patent Applications on Pulmonary Fibrosis .............................................................................. 138 Keeping Current ........................................................................................................................ 153 CHAPTER 6. BOOKS ON PULMONARY FIBROSIS ............................................................................ 155 Overview.................................................................................................................................... 155 Book Summaries: Online Booksellers......................................................................................... 155 Chapters on Pulmonary Fibrosis................................................................................................ 156 CHAPTER 7. PERIODICALS AND NEWS ON PULMONARY FIBROSIS .............................................. 157 Overview.................................................................................................................................... 157 News Services and Press Releases.............................................................................................. 157 Academic Periodicals covering Pulmonary Fibrosis .................................................................. 160 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 161 Overview.................................................................................................................................... 161 U.S. Pharmacopeia..................................................................................................................... 161 Commercial Databases ............................................................................................................... 162 Researching Orphan Drugs ....................................................................................................... 162 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 167 Overview.................................................................................................................................... 167 NIH Guidelines.......................................................................................................................... 167 NIH Databases........................................................................................................................... 169 Other Commercial Databases..................................................................................................... 171 The Genome Project and Pulmonary Fibrosis............................................................................ 171 APPENDIX B. PATIENT RESOURCES ............................................................................................... 175 Overview.................................................................................................................................... 175 Patient Guideline Sources.......................................................................................................... 175 Finding Associations.................................................................................................................. 183 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 185 Overview.................................................................................................................................... 185 Preparation................................................................................................................................. 185
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Finding a Local Medical Library................................................................................................ 185 Medical Libraries in the U.S. and Canada ................................................................................. 185 ONLINE GLOSSARIES................................................................................................................ 191 Online Dictionary Directories ................................................................................................... 191 PULMONARY FIBROSIS DICTIONARY ................................................................................ 193 INDEX .............................................................................................................................................. 271
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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 pulmonary 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 pulmonary 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 pulmonary 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 pulmonary 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 pulmonary 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 pulmonary 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 PULMONARY FIBROSIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on pulmonary 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 pulmonary 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 “pulmonary 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: •
Pulmonary Manifestations of Gastroesophageal Reflux Disease Source: Practical Gastroenterology. 24(4): 27, 30, 34, 42, 46, 49-50. April 2000. Contact: Available from Shugar Publishing. 12 Moniebogue Lane, Westhampton Beach, NY 11978. (516) 288-4404. Fax (516) 288-4435. Summary: Gastroesophageal reflux disease (GERD) is a spectrum of disease best defined as symptoms or signs of esophageal or adjacent organ injury secondary to the reflux of gastric contents (principally acid and pepsin) into the esophagus or beyond (into the oral cavity or lung). This article reviews the pulmonary (lung) manifestations of GERD. The most common presentations are heartburn, a burning sensation behind the breastbone just after meals or on bending over (relieved with antacids or an over the
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Pulmonary Fibrosis
counter (OTC) H2 receptor antagonist), or regurgitation (the spontaneous return of gastric contents into the esophagus). Careful study has shown that numerous pulmonary symptoms including asthma, chronic cough, and pulmonary fibrosis amongst others may be due to or exacerbated by GERD. The author focuses on prevalence, clinical presentation, and approach to the diagnosis and therapy of these patients. The patient with pulmonary presentations of GERD often presents a diagnostic challenge for clinicians because of the absence of heartburn or regurgitation. Treatment follows the general principals for management of patients with heartburn and includes use of lifestyle modifications, pharmacological therapy, and antireflux surgery. The author recommends beginning therapy with omeprazole 20 mg twice daily, lansoprazole 30 mg twice daily or rabeprazole 20 mg twice daily before breakfast and dinner for two to three months; this regimen results in 70 percent response rate. Referral for ambulatory pH monitoring to document the effectiveness of therapy and assessment of the presence of continued nocturnal (nighttime) exposure is indicated if patients are refractory to proton pump inhibitors. 1 figure. 1 table. 19 references. •
Extrahepatic Manifestations of Hepatitis C and the Association With Alcoholic Liver Disease Source: Seminars in Liver Disease. 15(1): 101-109. February 1995. Contact: Available from Thieme Medical Publishers, Inc. 381 Park Avenue South, New York, NY 10016. (800) 782-3488. Summary: In this article, the authors consider the extrahepatic manifestations of hepatitis C and the association with alcoholic liver disease. Topics include rheumatoid arthritis; pulmonary fibrosis; lichen planus; salivary gland lesions; porphyria cutanea tarda; Mooren corneal ulcer; aplastic anemia; vasculitis, and essential mixed cryoglobulinemia; glomerulonephritis; generalized vasculitis and miscellaneous vasculitides; and the association between hepatitis C and alcoholic liver disease. The authors conclude that data supporting a link between HCV infection and rheumatoid arthritis and pulmonary fibrosis are not convincing; an association between HCV and lichen planus, Sjogren's syndrome, porphyria cutanea tarda, and Mooren corneal ulceration are more intriguing but far from being established unequivocally. In contrast, data supporting a link between HCV and some vasculitis syndromes, those circumstantial, are convincing. Data also points toward a combination of HCV and alcohol in the pathogenesis of liver injury in patients with alcoholic liver disease. 1 table. 79 references.
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Hepatitis C Virus: What Recent Studies Can Tell Us Source: Postgraduate Medicine. 95(6): 121-122, 125-126, 128-130. May 1, 1994. Summary: In this article, the authors review the hepatitis C virus (HCV), presenting some recent developments in epidemiology and diagnosis, and examining the relationship of HCV infection to other disorders and the effectiveness of current drug therapy. Topics include transmission through blood products and hemodialysis; needlestick in health care workers; the infectivity of bodily secretions; the hepatitis C virus genome; diagnostic considerations; associated medical disorders, including hepatocellular cancer, chronic hepatitis, chronic liver disease, cryoglobulinemia, glomerulonephritis, porphyria cutanea tarda, and idiopathic pulmonary fibrosis; and treatment options, notably interferon alfa-2b and the use of oral ribavirin. 1 figure. 3 tables. 18 references. (AA-M).
Studies
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Respiratory Complications of Gastrointestinal Diseases Source: Gastroenterology Clinics of North America. 27(4): 721-746. December 1998. Contact: Available from W.B. Saunders. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452 or (407) 345-4000. Summary: The importance of acid reflux in the pathophysiology of disease of the respiratory tract is becoming increasingly well documented. This article describes the pathogenesis and clinical syndromes affecting the respiratory tract that are commonly encountered in clinical practice. For a substantial percentage of patients with respiratory disorders, gastroesophageal reflux (GER) is the sole cause of these symptoms. Respiratory disorders suspected of being related to GER include asthma, chronic cough, pulmonary fibrosis, pneumonia, and apnea in infants. For each of these disorders, the authors review the pathophysiology, the role of gastrointestinal motility, the interplay of medications, and treatment options. A separate section offers a review of diagnostic techniques in these complications, including radiography, endoscopy, esophageal manometry, and ambulatory pH monitoring. Most important, it has been shown that medical and surgical treatments are available for the effective management of these symptoms and related patient morbidity. 4 figures. 1 table. 115 references.
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New Treatments for Rheumatoid Arthritis Source: Postgraduate Medicine. 106(4): 82-85,88-90,92. October 1, 1999. Summary: This journal article provides health professionals with information on new slow acting antirheumatic drugs that are currently or soon to be available. During the past decade, perspectives on the nature and treatment of rheumatoid arthritis (RA) have changed. RA is now recognized as a serious systemic disorder. Methotrexate, a slow acting agent that inhibits dihydrofolate reductase, has become the gold standard of RA therapy. The result of its pharmacologic effects is impairment in the functioning of inflammatory cells that mediate the rheumatoid process. In addition to its medical effectiveness, methotrexate is well tolerated and relatively inexpensive. However, its potential toxic effects include bone marrow suppression, hepatotoxicity, interstitial pneumonitis, pulmonary fibrosis, increased susceptibility to infection, and pseudo sun sensitivity. Although the immunosuppressive agent cyclosporine has been used to treat RA in Europe for more than a decade, it is rarely used by American and Canadian rheumatologists. It is typically used in combination with methotrexate in patients who do not respond to methotrexate alone. Various cytotoxic drugs have been found to be helpful in the treatment of recalcitrant RA; however, their usefulness is limited by the severity of their toxic side effects. Newly emerging drugs for RA include leflunomide, tumor necrosis factor (TNF)-alpha inhibitors such as infliximab and etanercept, and interleukin-1 (IL-1) inhibitors. Leflunomide, the first antipyrimidine agent to be used to treat RA, inhibits the ability of dihydroorotate dehydrogenase to convert dihydroorotate to orotate. Efficacy studies have demonstrated the effectiveness of the agent. Infliximab contains monoclonal antibodies that bind circulating TNF-alpha, thereby inhibiting the proinflammatory effects of the circulating lymphokine. Although infliximab awaits final approval by the Food and Drug Administration, for use in RA, patients have shown definite clinical improvement after intravenous administration of the agent. However, adverse reactions are common. Etanercept is the first effective biologic antirheumatic therapeutic agent to become available for clinical use. This agent has been effective in relieving RA symptoms and improving function, and its reported adverse effects have been modest. However, its use is limited by the need to administer it parenterally and
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its excessive cost. The most effective IL-1 inhibitor is a human recombinant IL-1 receptor antagonist that is now under investigation. 1 table and 27 references.
Federally Funded Research on Pulmonary Fibrosis The U.S. Government supports a variety of research studies relating to pulmonary 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 pulmonary 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 pulmonary fibrosis. The following is typical of the type of information found when searching the CRISP database for pulmonary fibrosis: •
Project Title: RESPONSE
5-LIPOXYGENASE
PRODUCTS
IN
ASTHMATIC
IMMUNE
Principal Investigator & Institution: Henderson, William R.; Associate Professor; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2004 Summary: The 5-lipoxygenase (5-LO) products, the leukotriene (LT)s, are clearly important participants in the pulmonary inflammatory process in patients with asthma. We have developed a protocol for administration of ovalbumin (OVA_ as allergen to induce late-phase allergen-specific pulmonary disease in normal BAL:B/c and C57BL/6 mice. OVA-treated mice display a disease strikingly similar to allergen-induced human asthma. In our mouse model of asthma, we have found that leukotrienes are key mediators of the mucus release and eosinophil infiltration of the airways. With the availability of mutant mice deficient in 5-LO and both isoforms of cyclooxygenase (COX) (together wit specific inhibitors/antagonists of the lipid mediators), we will determine the contribution of the 5-LO pathway to the induction and resolution of allergic airway inflammation and AHR. These studies will be performed in both our standard protocol and a long-term model of allergen-induced lung fibrosis in mice. Our goal will be to define immune mechanisms by which leukotrienes influences the activation and effector functions of T cells and dendritic cells, key cells in the mediation of allergic airway inflammation. Our specifi aims are as follows: Specific Aim 1. To characterize further the role of the 5-LO pathway in allergic pulmonary inflammation and AHR. We will examine these questions: a) Will intrapulmonary 5-LO pathway blockade prevent AHR? b) Will 5-LO pathway blockade resolve ongoing allergic airway inflammation? and c) Wil 5-LO pathway blockade prevent allergen-induced lung fibrosis? Specific Aim 2. To determine the interrelationship of the 5-LO pathway with 2
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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COX-2 pathway and platelet activating factor (PAF) in the mediation of allergic airway inflammation and AHR. The following questions will be studied: a) Is COX-2 pathway activation important in development of allergic inflammation and AHR? and b) Will blockade of secretory phospholipase A2 (sPLA2) and PAF inhibit allergic lung inflammation and AHR? and Specific Aim 3. To determine the mechanisms by which leukotriene inhibition blocks allergic pulmonary inflammation and AHR in the murine model of asthma. We will study these questions: a) Will 5-LO pathway blockade prevent allergen-induced T cell proliferation and/or cytokine generation necessary for airway inflammation and AHR? and b) Is 5-LO pathway activation required for adoptive transfer of AHR b T cells? The more specific our knowledge of the biochemical and immunological changes becomes, the more likely it is that specific interventions producing more benefit than harm in reducing leukotriene-reduced inflammation, will be found. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: A FUNCTIONAL GENOMICS HEART & LUNG DEVELOP. PROGRAM Principal Investigator & Institution: Hoffman, Eric P.; Director, Research Center for Genetic Me; Children's Research Institute Washington, D.C., Dc 20010 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: Drs. Eric Hoffman and Dietrich Stephan (whose primary interests are focused on muscle disease and leukemia) are PI and Co-PI on the Program's Expression Array Core and have extensive experience with all aspects of array use and data analysis. They have established collaborations with Dr. Michael Bitmer, Dr. Yidony Chen and the entire NHGRI array community. As a post-doctoral fellow in the laboratory of Dr. Jeffery Trent (member of this Program's External Advisory Committee), and a pioneer in DNA microarray technology, Dr. Stephan developed several alternative approaches to label total RNA for efficient signal detection under varying circumstances which have become the standard protocol used at NHGRI and has become a quite robust and reliable system for detecting signals over several orders of magnitude. In addition to building and using 7K expression arrays, Dr. Stephan was the first at NHGRI to develop genomic DNA microarray systems. Dr. Hoffman's laboratory is particularly interested in systematic assessments of the sensitivity and specificity of the Affymetrix vs. cDNA array approaches, and shows preliminary data pointing out the importance of redundant measurements, and correlative studies. Indeed, the proposed systematic comparison of the Affymetrix and cDNA array experimental platforms should be the first of this type of quality control of expression array data, and should prove highly valuable to both Program investigations and the research community at large. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: A LINKAGE STUDY IN FAMILIAL PULMONARY FIBROSIS Principal Investigator & Institution: Schwartz, David A.; Professor of Medicine and Genetics; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 20-AUG-2000; Project End 31-JUL-2005 Summary: (Adapted from Investigator's Abstract) The overall goal of this project is to investigate inherited genetic factors that play a role in the development of pulmonary fibrosis. The overall hypothesis of this investigation is that inherited genetic factors predispose individuals to develop pulmonary fibrosis. The goal of this investigation is to identify a group of genetic loci that play a role in the development of familial
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pulmonary fibrosis. The overall hypothesis is supported by the following observations: familial pulmonary fibrosis is indistinguishable pathologically from idiopathic pulmonary fibrosis and appears to be inherited as an autosomal dominant trait with variable penetrance; pulmonary fibrosis is associated with pleiotropic genetic disorders, such as Hermansky-Pudlak syndrome, neuofibromatosis, tuberous sclerosis, NeimannPick disease, Gaucher's disease, and familial hypocalciuric hypercalcemia; pulmonary fibrosis is frequently observed in autoimmune disease, including rheumatoid arthritis and systemic sclerosis; variable susceptibility is evident among workers who are reported to be exposed occupationally to similar concentrations of fibrogenic dusts; and inbred strains of mice differ in their susceptibility to fibrogenic dust. In conjunction with the exponential growth of human molecular genetics, the investigators state that these clinical observations suggest that a well organized approach to define the genetic determinants of pulmonary fibrosis is scientifically feasible and justified. This project proposes to use standard genetic methodology (linkage analysis) to investigate the distribution of polymorphisms for anonymous genetic markers in families with familial pulmonary fibrosis. The investigators state that their comprehensive genome-wide study, using standard genetic markers, will allow them to identify loci which subsequently may prove to contain novel genes that play a role in the pathogenesis of pulmonary fibrosis. Once genetic loci are defined in familial pulmonary fibrosis, candidate genes can be identified on the basis of both positional and functional criteria. Moreover, they note that this approach will provide basic information on high priority loci that will be applicable to the rapidly evolving dense human transcript map for pulmonary fibrosis in families with two or more cases of pulmonary fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACID SPHINGOMYELINASE AND NIEMANN-PICK DISEASE Principal Investigator & Institution: Schuchman, Edward H.; Professor &Vice Chairman for Research; Human Genetics; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-FEB-1992; Project End 31-JAN-2007 Summary: (provided by applicant): Types A & B Niemann-Pick Disease (NPD) are lipid storage disorders resulting from the deficient activity of the lysosomal hydrolase, acid sphingomyelinase (ASM). Type A NPD is a severe neuro-degenerative disorder, which leads to death in early childhood, while patients with Type B NPD have little or no neurological abnormalities and often survive into adulthood. The overall goals of this research are to investigate the underlying causes of the distinct neurological & nonneurological forms of NPD, including the role of ASM in ceramide-mediated cell signaling & disease pathogenesis, and to develop effective treatments for these disorders. Previously, our laboratory: 1) Isolated the full-length cDNAs & genes encoding human & murine ASM, 2) Identified the first ASM mutations causing NPD & developed the first NPD molecular diagnostic program, 3) Constructed a knock-out mouse model for this disorder, 4) Stably over-expressed, purified & characterized recombinant human ASM from CHO cells, 5) Evaluated enzyme replacement, bone marrow transplantation & hematopoietic stem cell gene therapy in the NPD mouse model, and 6) Characterized ceramide-mediated signal transduction in the NPD mouse. In the upcoming funding period we are proposing four specific aims: 1) Investigate the pulmonary disease in NPD mice & develop lung-specific therapies for Type B NPD, 2) Investigate the neurological disease in NPD mice & develop CNS-specific therapies for Type A NPD, 3) Investigate the reproductive biology of NPD mice, including the development of approaches for the selection of normal vs. NPD gametes and
Studies
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preimplantation embryos, and 4) Continue to conduct world-wide ASM mutation analysis & structure/function studies. We believe that this research will provide fundamental insights into the underlying biology of NPD & ASM, and lead to the development of effective treatments for these disorders and/or methods to prevent or minimize NPD births. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACTIVATION OF LATENT TGFB BY THE INTEGRIN ALPHA VB6 Principal Investigator & Institution: Munger, John S.; Assistant Professor; Medicine; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2002; Project Start 07-FEB-2000; Project End 31-JAN-2004 Summary: Transforming growth factor-beta1 (TGFbeta1) is a widely-expressed cytokine that has major effects on most cell types. TGFbeta1 is anti- inflammatory, pro-fibrotic, and casually linked to fibrotic diseases, e.g. pulmonary fibrosis. TGFbeta1 is secreted in an inactive complex (FTGFbeta1) with its pro-peptide dimer, which is called latencyassociated (LAP). Activation of LTGFbeta1 is a key control point in TGFbeta1 biology, but is poorly understood. Only thrombospondin-1 (TSP1) has been shown previously to active PTGFbeta1 in normal animals. We found that LAP is a ligand for the epitheliumspecific integrin alphavbeta6, and that cells expressing alphavbeta6 bind and activate latent TGFbeta1. This mechanism can explain the heretofore puzzling phenotype of beta6 integrin knock-out mice: inflammation in lung and skin, and protection from bleomycin-induced pulmonary fibrosis. Our results provide the first evidence that dysregulated TGFbeta1 activation causes fibrosis. Our goals are to understand quantitatively the interactions between LTGFbeta and alphavbeta6 that lead to activation, and to develop an animal model an animal model and knowledge to explore fully the biological role of a of avbeta6-mediated LTGFbeta1 activation. In Aim 1 we will analyze the activation mechanism by focusing on alphavbeta6- LTGFbeta1 interactions. We will make TGFbeta1-mull alphavbeta6- expressing cells to which specifically engineered forms of LTGFbeta1 will be added (either by transfection or as recombinant protein). In this system we will then determine the relative activatability of two major forms of LTGFbeta1 (the so-called small and large latent complexes), the relative effects of LTGFbeta1 concentration and alphavbeta6 expression levels of activation, the activatability of soluble and matrix-bound latent TGFbeta1, and the integrin: LTGFbeta1 stoichiometry required for activation. Also, we will assess the influence of integrin/LTGFbeta1 binding affinity on activation. The results will be incorporated into an activation model and related to activation in vivo. In Aim 2, we will create a mouse expressing a mutant form of LTGFbeta1 that cannot be activated by integrins (the RGD integrin binding sites in LAP will be mutated to RGE). The phenotypes of these mice and beta6 integrin null mice will be compared to confirm that the beta6 null phenotype is due specifically to loss of TGFbeta1 activation. To interpret the phenotype will test the ability of other RGD-binding integrins to activate LTGFbeta1. Finally, we will cross RGE-TGFbeta1 mice with TSP1 null mice to assess the summed effects of the two currently known TGFbeta1 activation mechanisms, namely alphavbeta6 and TSP1. The results of these aims will lead to better understanding of alphavbeta6-mediated TGFbeta1 activation in disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ALTERED C/EBPB REGULATION IN IPF LUNG FIBROBLASTS Principal Investigator & Institution: Cruz-Gervis, Roberto A.; Internal Medicine; Meharry Medical College 1005-D B Todd Blvd Nashville, Tn 37208
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Pulmonary Fibrosis
Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-JUL-2005 Summary: (Adapted from applicant's abstract) Lung fibroblasts produce large amounts of inflammatory mediators and growth factors that appear to be associated with the development of IPF. The investigators have found that fibroblasts isolated from the lungs of patients with IPF (HF-IPF) produce more IL-6 than do fibroblasts isolated from normal human lungs(HF-NL). Since the IL-6 promoter is under the control of the transcription factors nuclear factor kB(NFkB) and CAAT/enhances binding protein-beta (C/EBPbeta) they measure activation of these proteins. NfkB activation was increased by IL-1beta, but not PGE2, and the response was similar in HF-IPF and HF-NL. In contrast, C/EBPbeta (a.k.a nuclear factor IL-6 [NF-IL6]) activity was increased by both PGE2 and IL-1beta. In addition, there was greater C/EBPbeta activation in HF- IPF compared to HF-NL, which correlated with IL-6 production. C/EBPbeta mRNA contains three inframe translation start sites and, therefore, three different C/EBPbeta isoforms may be produced. The two larger isoforms (p42C/EBPbeta) are transcription activators, while the smallest isoform (p20/EBP beta) lacks a transactivating domain and displays increased DNA affinity, and therefore, is a potent transcription repressor. Recent evidence suggests that C/EBPbeta may have a role in the process of fibrosis. C/EBPbeta has been shown, in liver cells, to stimulate the expression of insulin-like growth factor (IGF)- 1, hepatocyte growth factor (HGF) and collagen-alpha1 genes. Furthermore, transforming growth factor (TGF)-beta induces gene expression of procollagen I via C/EBPbeta. The investigators also have preliminary data showing that, when compared to HF-NL, HF-IPF fail to increase the p20C/EBPbeta:p42C/EBPbeta ratio when stimulated with IL-1beta and PGE2. They hypothesize that phenotypically altered fibroblasts perpetuate the inflammatory and fibrotic response because they have an exaggerated activation of C/EBPbeta, which may be due to a higher p42C/EBPbeta activity, decreased p20C/EBPbeta production, or both. The aim is to establish a relationship between increased C/EPbeta activity, with growth factor (IGF-1, PDGF) production, collagen synthesis and proliferation in primary lung fibroblasts. They will determine whether transfecting primary lung fibroblasts with a plasmid expression vector containing the gene encoding p42C/EBPbeta will result in increased gene expression and protein production of collagen I, and the growth factors TGF- beta, PDGF and IGF-1. In addition, they will determine whether transfecting primary lung fibroblasts with a plasmid expression vector containing the gene encoding p20C/EBPbeta will reduce the stimulated (IL-1beta and TGF-beta) protein production and gene expression of IGF-1, PDGF-1, PDGF and collagen I, as well as fibroblast proliferation. This work could provide a rationale for treatment of IPF with either the p20C/EBPbeta protein or the gene encoding this C/EBPbeta isoform. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ALVEOLAR EPITHELIUM IN PULMONARY FIBROSIS Principal Investigator & Institution: Mason, Robert J.; Professor; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Abstract) Type II cell hyperplasia is a hallmark of pulmonary fibrosis, but the role of the epithelium on the fibrotic process is unknown. Although there has been numerous studies on the mesenchymal epithelial interactions in the developing lung, there have been relatively few studies in the adult lung. The purpose of this project is to define the epithelial mesenchymal interactions in the adult lung especially as they relate to pulmonary fibrosis. Much of the focus of this proposal will be on the biologic antagonism between KGF and TGF-beta. KGF is an important growth
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factor for type H cells and induces differentiation in vitro, whereas TGF-b inhibits proliferation and antagonizes the effects of KGF on differentiation. Another major question that remains are differences between normal cells and hyperplastic type II cells and if hyperplastic type H cells produced by KGF are different from hyperplastic type H cells seen in fibrotic lung disease. In co-culture normal type II cells inhibit fibroblast growth, but the effect of hyperplastic type II cells from fibrotic lung on fibroblast proliferation is not known. The in vitro studies in this proposal rely on two new culture systems for rat type II cells to maintain differentiated function of type H cells. One has apical access and the other basolateral access. In this proposal we seek to determine (1) if alveolar type H cells can be stimulated to inhibit fibroblast proliferation, (2) the signaling pathways for KGF especially those that lead to differentiation, (3) mechanisms for KGF and TGF-b antagonism, and (4) effects of INFY on production of SP-A and SPD, growth factor receptor expression, and production of chemokines and profibrogenic growth factors. These studies are designed to define the interaction between alveolar epithelial cells and fibroblasts and mechanism of action of KGF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ALVEOLAR TYPE II CELL GROWTH IN INJURY Principal Investigator & Institution: Hastings, Randolph H.; Veterans Medical Research Fdn/San Diego Foundation of San Diego San Diego, Ca 92161 Timing: Fiscal Year 2002; Project Start 15-SEP-1999; Project End 31-AUG-2004 Summary: Silica causes lung injury and eventual pulmonary fibrosis. Alveolar type I epithelial cell damage and type II epithelial cell proliferation are prominent features of the injury. Our pilot studies show that type II cells undergo apoptosis afer silica injury also. It is widely believed that type II cell proliferation is an important repair process. However, the functional and structural impact of type II cell growth on recovery from silica induced injury has never been defined and the factors that regulate type II cell growth and death after silica exposure are unknown. Our studies suggest that amino terminal and mid-molecule portions of parathyroid regulate these cell after silicainduced lung injury. PTHrP is a pro- hormone that is processed after translation into different daughter peptides with distinct biologic activities. We have found that lung PTHrP expression falls after silica injury in rats, coincident with the onset of type II cell proliferation and apoptosis. Treating rats with exogenous PTHrP 1- 34, the aminoterminal fragment, reduces pneumocyte division (measured by BrdU uptake), while exogenous PTHrP 67-86, a mid-molecule fragment, decreases type II cell apoptosis (measured by TUNEL staining). We hypothesis that the decrease in amino-terminal and mid-proliferation and apoptosis. Furthermore, we believe that an increase in the type II cell population is beneficial in repairing the epithelium, restoring lung architecture and function, and reducing pulmonary fibrosis. Our specific aims are as follows: 1) We will define the structure-function relationships for the effects of PTHrP peptides on the number of type II cells and fibroblasts in the alveoli after silica injury. 3) We will examine the effect of changes in type II cell number on epithelial repair, progression of pulmonary fibrosis and pulmonary structure after silica-induced lung injury. This project will lead to an understanding of the importance of type II cell growth for epithelial repair after silica-induced lung injury and will assess the role of a novel family of growth factors in regulating pneumocyte growth and death. The project will evaluate the potential use of PTHrP-related therapeutic interventions that might speed or improve recovery following silica-induced lung injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Pulmonary Fibrosis
Project Title: ALVEOLIZATION IN FIBRILLIN-1 DEFECTIVE MICE Principal Investigator & Institution: Neptune, Enid R.; Assistant Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 13-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): Diseases of impaired gas exchange, such as emphysema and lung fibrosis, are prevalent, clinically burdensome ,and difficult to treat. Because lung transplantation remains the only definitive treatment option for these diseases, much interest has been focused upon understanding the cellular and molecular basis of alveolar formation. As the current knowledge of mammalian lung alveolization is quite limited, this grant is directed towards exploring the mechanism of impaired alveolar septation in mouse models in an effort to understand the requirements of normal septation. The PI has recently observed distal airspace enlargement in two strains of fibrillin-I deficient mice and has found that TGF-beta is a critical mediator of this defect. The first objective is to determine the natural history of impaired septation in three fibrillin-1 defective mouse models. This pursuit should establish whether septation defects may represent important risk factors for the development of emphysema and pulmonary fibrosis. The natural history of the alveolization defects in these models will be correlated with the evolution of aberrant TGF-beta signaling previously observed in two of the models. The second objective is to identify the pulmonary morphologic aberrations which precede the observed septation defects in an effort to reveal critical mediators of septation. Several approaches will be employed to establish whether abnormalities in pulmonary vascular development, matrix composition, or both underlie the disruptions in septation. The final objective is to use chip-based gene expression profiling of murine lung to identify novel and important mediators of septation. The PI of this project is an instructor in the Department of Medicine. She is committed to a career in academic medicine and plans to spend 80 percent of her time in research pursuits. She has had previous training in signal transduction and, more recently, the use of transgenic mouse models to probe human disease. She now wants to expand her research interests to investigating mammalian lung development. To achieve this, she will take sponsored courses on murine development and attend lectures in the developmental genetics department at Johns Hopkins School of Medicine. The environment at Johns Hopkins provides several esteemed scientists who can provide guidance in the use of mouse models to probe lung pathology and developmental aberrations. Their involvement as well as a formal education program in both the Division of Pulmonary Medicine and Institute of Genetic Medicine should facilitate the achievement of her stated research objectives as well as aid in her development into a fully independent investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ANGIOGENESIS IN HYPEROXIC LUNG FIBROSIS Principal Investigator & Institution: Douglas, Ivor S.; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): This 5-year training program proposes the development plan for a career as an independent biomedical researcher in the area of lung injury and angiogenesis. The principal investigator, has completed Pulmonary and Critical Care Fellowship training through the ABIM Research Pathway. With the sponsors and experienced collaborators he will expand on his scientific skills in preparation for career progression as an independent physician-scientist. The program
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will emphasize skills in molecular biology of angiogenesis and macrophage regulation of fibrosis using a murine hyperoxia model. To advance his knowledge in computational biology he will attend courses in applied statistics. Steven Greenberg M.D. a macrophage biologist, and Paul Rothman M.D., a renowned immunologist in the area of molecular regulation of cytokine signaling, will provide sponsorship. The program will benefit from collaborative expertise of Jan Kitajewski PhD, an expert in angiogenesis and Patty Lee, M.D. who will provide consultative support for the hyperoxia studies. Additionally, George Yancopoulos, a world renowned investigator, will collaborate and serve with the sponsors, Drs. Kitajewski and Lee on an advisory committee every 8 weeks. This committee will review progress and provide close scientific support and career advice. Prolonged hyperoxia results in lung fibrosis in humans and mice. The accompanying vascular remodeling contributes to pulmonary hypertension, right heart failure, and premature death. This program addresses the questions: Do macrophage-derived angiogenic regulatory factors, particularly angiopoietin-2 (Ang-2), contribute to vascular remodeling in response to prolonged sublethal hyperoxia. Do these vascular alterations contribute, independently, to the development of lung fibrosis? And does macrophage-derived Ang-2 directly inhibit endothelial cell survival in response to hyperoxia? The role of macrophage-derived mediators in hyperoxic lung injury remains unclear. We demonstrate in preliminary experiments, increased Ang-2 mRNA and protein in response to hyperoxic exposure in RAW 264.7 and in a mouse model of sublethal hyperoxic lung fibrosis. These mice develop macrophage-predominant cellular infiltration, collagen deposition and pulmonary vascular regression that recapitulates features of subacute lung fibrosis in humans. The following specific aims will be accomplished: 1) The characterization of fibrotic and vascular remodeling responses in hyperoxia-exposed mice by immunohistochemistry, Western and Northern blotting and ELISA to quantify changes in markers of lung fibrosis, angiogenesis and expression of angiogenic regulators and their receptors. The effects on pulmonary vasculature will be evaluated by confocal microscopy. 2) Functional changes in response to altered expression of macrophagederived angiogenic regulators by angiogenesis assays. Macrophage-depleted mice will be used to assess the contribution of lung macrophages. 3) Lung targeted overexpression of Ang-1 or 2 by adenovirus transfection or blocking antibodies prior to hyperoxia to determine the contribution of Ang-2 to pulmonary vascular remodeling and fibrosis during prolonged sublethal hyperoxia. 4) Determine if Ang-2 mediated endothelial survival inhibition is PI3K/Akt dependent. Columbia University has an established record of successful mentorship and training for K08 Career awardees in their preparation for careers as independent. 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 2002; 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
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Pulmonary Fibrosis
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 •
Project Title: APPLIED GENOMICS IN CARDIOPULMONARY DISEASE Principal Investigator & Institution: Scott, Alan L.; Physiology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: The overall goal of the Animal/Proteomic Component of the "Applied Genomic Program in Cardiopulmonary Disease" is to define and test the relevance of disease specific gene candidates that predict lung and cardiac remodeling in animal models of cardiopulmonary diseases utilizing gene profiling approaches. Identification of susceptibility genes for human disease is hampered by variability in clinical phenotype, genetic heterogeneity in human populations and the experimental difficulty in addressing the molecular mechanisms underlying complex pathological processes in humans. Thus our strategy is to take advantage of the experimental tractability of murine models of disease to provide high quality of candidate genes underlying remodeling processes in multiple cardiopulmonary disease. To achieve this goal, we have assembled an outstanding group of investigators with broad and overlapping expertise with animal models of cardiopulmonary diseases including asthma, pulmonary fibrosis, cardiac failure, emphysema, hyperoxia-induced lung injury and pulmonary hypertension. Our preliminary data suggest that these models are predictive of human disease and that the gene profiling approach can successfully be used to identify genes important in human disease. The specific aims of this component are l) to define a set of predictor genes for tissue remodeling using Affymetrix 5000 predictor oligonucleotide microarrays (Mu19K) in each of the six animal models of disease; 2) to refine the number of candidate genes and to establish the kinetics of gene expression by constructing custom cDNA arrays for 1000-5000 predictor genes in each model; and 3) to compare and contract gene expression profiles between models and human systems in order to prioritize candidates for further analysis by proteomic and single nucleotide polymorphism (SNPs) approaches; 4) to utilize proteomic approaches to study the consequences of changes in gene expression at the cell and tissue level; and 5) to being to determine the functional relevance of this focused set of genes to remodeling processes by utilizing transgenic and knockout technologies. The combined (mouse and human) approach of this program to the identification of disease specific genes for lung and cardiac remodeling should greatly facilitate future disease discovery. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BASIS OF VARIABILITY OF LUNG GPCR SIGNALING Principal Investigator & Institution: Liggett, Stephen B.; Professor; None; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008
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Summary: (provided by applicant): Many major signaling events in the lung are carried out by the superfamily of G-protein coupled receptors (GPCRs). These include bronchial smooth muscle relaxation and contraction, mucous secretion, ciliary beat frequency, inflammation, immune cell trafficking, pulmonary vascular tone and permeability, and alveolar fluid and electrolyte transport, as well as many yet to be defined functions. Approximately 75 GPCRs are estimated to be expressed in human lung. Within the next five years, the great majority of all therapeutic agents will target GPCRs. However, the physiologic, pathologic, and pharmacologic behavior of GPCR signaling displays substantial interindividual variability which is thought to be due to common variants (polymorphisms) of the genes encoding these receptors. Such polymorphisms have been estimated to account for as much as 50% of the variability in the response to therapeutic agonists and antagonists targeted to GPCRs. Indeed, with just one GPCR, the (2adrenergic receptor, we have shown that coding and promoter polymorphisms alter receptor expression, function, and regulation in vitro in cells, and in asthmatic patients, they are associated with clinical phenotypes and the response to beta-agonist therapy. The long-term goals of this proposal are to identify polymorphisms of up to 20 pulmonary GPCR genes, and by the use of recombinant expression techniques to delineate their biochemical and pharmacologic impact on cellular signaling relevant to lung homeostasis and pathobiology. In Aim 1, the polymorphisms of these 20 GPCR genes will be delineated in the promoter, 5' untranslated, coding, intron/exon junctions, and 3' untranslated regions from genomic DNA samples from a cohort of 60 ethnically diverse individuals. In Aim 2, the common combinations of polymorphisms (haplotypes) will be delineated in the population. In Aim 3, constructs will be developed and model cell systems utilized for recombinant expression of GPCR haplotypes to determine the biological effects of polymorphisms on receptor expression, signaling, or regulation. These studies will provide the basis for interindividual susceptibility and therapeutic responsiveness, the variability in pathobiology, and the potential for developing new treatment strategies, for a diverse range of lung diseases including asthma, pulmonary hypertension, pneumonia, pulmonary fibrosis, COPD, and pulmonary edema. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIODEGRADABLE SEALANT FOR BIOPSY TRACTS IN SOFT TISSUES Principal Investigator & Institution: Hronowski, Lucjan J J.; Biopsy Sciences, Llc 6340 N Pinnacle Ridge Dr Tucson, Az 85718 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 31-AUG-2003 Summary: (provided by applicant): Percutaneous fine needle biopsy is a common method of determining if a lung nodule is benign or malignant. Using imaging guidance (CT, fluoroscopy, ultrasound or bronchoscopy) a sharp needle is advanced into a suspicious area and cells are aspirated into the needle. These cells are then evaluated under a microscope and are characterized as benign, infectious or malignant. There are over 169,500 cases of lung cancer diagnosed in the U.S. and over 600,000 lung biopsies performed worldwide every year. The most common complication of this procedure is a lung collapse (pneumothorax), which occurs in 20-40% of cases. In greater than 10% of these lung collapses, the patient becomes symptomatic and requires chest tube placement and hospitalization. The development of a novel biopsy needle tract sealant that will reduce or eliminate pneumothorax would be most valuable. The focus of the current investigation is to evaluate the possibility of using an expansile polymer to seal these needle tracts. Further, in the investigation we plan on studying a deployment
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Pulmonary Fibrosis
system that plugs the tract but does not irritate the parietal pleura. Initial Investigation into the tissue compatibility will also be examined. There is presently no commercially available product in the U.S. to prevent or reduce the pneumothorax rate after lung Fine Needle Aspiration Biopsy (FNAB) Procedures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROTEINS
BIOGENESIS
AND
FUNCTION
OF
CONNECTIVE
TISSUE
Principal Investigator & Institution: Bornstein, Paul; Professor; Biochemistry; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-FEB-1975; Project End 31-JAN-2005 Summary: The transcriptional regulation of the genes encoding the two type I collagen chains, alpha1(I) and alpha2(I), is one of special interest because these genes are expressed at widely different levels that correlate with the tissue specificity of collagen synthesis, and with development and maturation of the organism. Furthermore, the genes for alpha1(I) and alpha2(I) are responsive to cues generated by injury and repair, and by a variety of cytokines, hormones, and pharmacological agents. Finally, the expression of type I collagen genes is disturbed in orders such as pulmonary fibrosis and cirrhosis, and in diseases such as scleroderma. Although post-transcriptional mechanisms undoubtedly play an important role in regulating collagen synthesis, there is good evidence that transcriptional control represents the major means by which this regulation is achieved. A major goal of this grant is to determine how this astonishingly intricate pattern of expression is established and maintained, and how it is altered during development, in response to injury, and in disease. Current studies of gene regulation generally involve the evaluation of mutations in chimeric regulatory/reporter genes in transfection and transgenic experiments. While these approaches represent necessary preliminary steps, it is our contention that definitive results can best be achieved by testing such mutations in the context of the endogenous gene. Gene targeting techniques will therefore be used to create mutations in putative regulatory regions of the Collal gene in mice, and mutant mice will be evaluated for expression of the altered allele and for phenotypic changes. In particular, the proposed experiments will test the hypothesis that modular elements in the Collal gene direct the synthesis of type I collagen selectively to tissues such as skin and bone. It is anticipated that some of the mutations created in mice will generate useful models for human disorders of these tissues, specifically some of the Ehlers-Danlos syndromes and osteoporosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOMARKERS IN SPUTUM IN COPD Principal Investigator & Institution: Broide, David H.; Associate Professor of Medicine; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 23-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): The overall goal of this proposal is to identify biomarkers in the sputum of patients with emphysema that associate with emphysema but not with either healthy controls, smokers without emphysema, or lung diseases associated with airway inflammation and fibrosis such as asthma or idiopathic pulmonary fibrosis. The approach we plan to use to identify sputum biomarkers in emphysema will use both hypothesis driven experiments to explore candidate sputum
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biomarkers of inflammation (LTB4, IL-8, TNF), fibrosis (TGF- beta, PGDF, FGF), metalloproteases (MMP-1, MMP-9, MMP-12, TIMP), elastin degradation (desmosine in urine) as well as an alternative approach using both proteomic analysis of sputum and bronchoalveolar lavage, and genomic studies of airway epithelium and alveolar macrophages to identify potential novel biomarkers of emphysema that correlate with CT scan evidence of emphysema. Levels of biomarkers will be measured over a two year period and be correlated with CT scan extent of emphysema. If such a non-invasive biomarker were identified this could either serve as a biomarker in studying the effects of intervention with anti-inflammatory medications or smoking cessation in subjects with emphysema, or alternatively serve to identify smokers at risk for the development of emphysema. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FORMATION
CHEMOKINE
RECEPTOR
DYNAMICS
IN
GRANULOMA
Principal Investigator & Institution: Chensue, Stephen W.; Pathology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 01-AUG-1998; Project End 31-MAR-2007 Summary: (provided by applicant): Hypersensitivity-type granulomas (GR) are T cellmediated chronic inflammatory lesions observed in a wide variety of infectious and noninfectious diseases often causing serious morbidity and mortality. Understanding the manner in which T cells participate and promote theses lesions will aid the development of interventions. These lesions can be classified as type-1 or type-2 based upon the relative participation of Th1 and Th2 associated cytokines. The current paradigm is that Th1 and Th2 CD4+ helper cells are recruited to inflammatory sites by chemokines (CK) and show selective migration by virtue of differential chemokine receptor expression. Using animal models of synchronized, type-1 and type-2 pulmonary GR formation elicited respectively by protein antigens of Mycobacteria tuberculosis and Schistosoma mansoni, we found indications of both shared and polarized CK receptor expression among type-1 and type-2 CD4+ memory helper cells as well as antigen stimulated regulation. However, the in vivo significance and contribution of these findings to GR formation is unknown. The present proposal will extend this work and test the hypothesis that effector Th1 and Th2 cells are recruited to inflammatory sites by way of innate phase chemokines through polarized postactivation chemokine receptors. The specific aims will employ state-of-the-art laser capture microdissection (LCM) and real time, gene sequence detection technologies to reveal the microenvironmental expression and function of Th cell CK receptors. Aim 1 will use LCM to define the temporal expression and tissue compartmental location of CK transcripts during synchronous Ag-bead and asychronous infectious type-1 and type-2 GR in order to allow correlation to T cell CK receptor expression. Aim 2 will determine the distribution of induced CK receptor transcripts among effector Th1 and Th2 cells generated in vivo. Aim 3 will reveal the potential biologic contribution Aginduced receptors such as CXCR3, CCR4 and CCR8 to selective Th migration using direct chemotaxis of antigen-activated CD4+ T cells. Aim 4 will define the temporal expression of CK receptor transcripts within the tissue microenvironments during synchronous Ag-bead and asychronous infectious type-1 and type-2 GR formation. Finally, Aim 5 will examine the migratory behavior of adoptively transferred CD4+ T cells with targeted CK receptor knockout and concomitant transgenic expression of green fluorescent protein (GFP). These studies will potentially provide novel and
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important information regarding the contribution of CK receptors to CD4+ T trafficking in chronic inflammatory responses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHEMOKINES IN LUNG TRANSPLANTATION Principal Investigator & Institution: Medoff, Benjamin D.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 04-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): With the proposed Mentored Clinical Scientist Development Award the applicant will continue his investigations into basic mechanisms of lung inflammation. After two productive years in this laboratory the applicant remains firmly committed to a career in academic pulmonary medicine. The proposed research will allow the applicant to master a broad range of laboratory techniques in immunology, cell, and molecular biology. The research experience will be supplemented by a program of study of immunology and medical science. The project focuses on the development of inflammation and fibrosis following lung transplantation and the role of chemokines in these processes. After a lung is transplanted there may be several types of injury to the graft, including ischemia-reperfusion injury, acute rejection, and chronic rejection. These immune mediated injuries contribute to the development of scarring of the airways, so called bronchiolitis obliterans (BO). Over 50% of all lung transplants will develop BO after transplantation, and this remains the major cause of morbidity and mortality after lung transplantation. Neutrophils have been shown to be a prominent component of ischemia-reperfusion injury while T lymphocytes are the primary mediators of both acute and chronic rejection. The proposed project will determine which chemokines are produced after transplantation and their contribution to the development of graft injury and subsequent BO. Further experiments will manipulate chemokine or chemokine receptor expression in animal models of lung transplantation to investigate their role in the development of graft injury and BO. The applicant specifically proposes to: (1) investigate the expression of chemokines and chemokine receptors in the lung following transplantation in patients with and without acute rejection and BO; (2) investigate the role of chemokines in the development of ischemia-reperfusion injury in the airways using the murine tracheal heterotopic model of lung transplantation; (3) investigate the role of chemokines in the development of acute airway rejection and the development of BO in the murine tracheal heterotopic model of lung transplantation; (4) develop a novel murine model of airway rejection and BO. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CHONDROPROTECTIVE EFFECTS OF SUPEROXIDE DISMUTASE Principal Investigator & Institution: Chu, Constance R.; Orthopaedic Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2004 Summary: (applicant's abstract): Destruction of articular cartilage through disease processes such as inflammatory arthritis and osteoarthritis causes significant pain and disability. The normal balance between anabolic and catabolic processes is altered so that chondrocyte synthesis of matrix components cannot compensate for the increased rates of degradation found in these conditions. The effects of superoxide dismutase on articular cartilage homeostasis has not been systematically studied. Exploratory studies using extracelluar superoxide dismutase (EC-SOD) knock-out and transgenic mice
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originally developed for evaluating the pathogenesis of pulmonary fibrosis to examine these relationships are proposed. The long term goal is to explore the potential chondroprotective effects of EC-SOD. The working hypothesis is that EC-SOD plays a central role in protecting against cartilage degradation in the arthritic joint. To test the hypothesis that EC-SOD plays a central role in protecting against articular cartilage loss in the arthritic joint by comparing the structural and metabolic responses of articular cartilage following zymosan induced gonarthritis between wild-type, EC-SOD knockout mice which cannot produce EC-SOD, and EC-SOD transgenic mice which produce excess EC-SOD. Studies in experimental models of arthritis have implicated nitric oxide (NO) as an important pathogenic factor. EC-SOD may prevent the reaction of NO with superoxide to form peroxynitrite, a potent oxidant which may account for some of the damaging effects of NO. Interleukin-l (IL-l) inhibition of proteoglycan synthesis has been linked to the presence of NO. To test the hypothesis that prevention of peroxynitrite formation is one mechanism by which EC-SOD protects against IL-1 inhibition of carnage repair, we plan to compare NO production, nitrotyrosine immunoreactivity, matrix metalloproteinases, and proteoglycan synthesis between wildtype, EC-SOD knockout and EC-SOD transgenic mice following intra articular injection of IL-1. IL-l has been associated with development of chondrocyte insensitivity to the anabolic actions of Insulin-like Growth Factor-I (IGF) in both in vitro and in vivo models of arthritis. In contrast to wild-type mice, iNOS knockout mice maintain their anabolic response to IGF-1 following intra articular injection of IL-1. This implicates NO and NO derivatives such as peroxynitrite as critical, factors in the development of chondrocyte insensitivity to IGF-1 in the arthritic joint. To test the hypothesis that peroxynitrite is the reactive species involved in IL-1 induced chondrocyte unresponsiveness to the anabolic effects of IGF-1, we plan to compare NO production, nitrotyrosine immunoreactivity, and proteoglycan synthesis in the presence of IGF-1 between wild-type EC-SOD knockout and EC-SOD transgenic mice following intra articular injection of IL-1. The proposed studies will advance the current knowledge base on the effects of EC-SOD in modulating cartilage degradation in the arthritic joint. These studies will also serve to improve understanding of the relative roles of NO and peroxynitrite on the pathophysiology of arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COLLAGEN TRANSCRIPTION AND LUNG FIBROSIS Principal Investigator & Institution: Smith, Barbara D.; Professor; Biochemistry; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2005 Summary: Certain lung injuries induce large increases in connective tissue content, particularly collagen, resulting in fibrosis. During injury, cells are exposed to molecules such as interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGFbeta), regulating production of matrix components. Clinical trials for interstitial pulmonary fibrosis (IPF) are ongoing. However, very little is understood concerning collagen repression by this mediator. This project focuses on establishing the mechanisms by which collagen transcription is repressed by IFN- gamma. We have recently described a regulatory factor for X-box (RFX) binding site at the collagen transcription start site. RFX1 represses collagen transcription. RFX1 interacts with and activates c-Abl, a non- receptor tyrosine kinase that can phosphorylate itself, RFX1 and the carboxyl domain of RNA polymerase II (CTD). C-Abl interacts with RFX1 at the collagen transcription start site. This proposal determines whether c-Abl participates in signal transduction pathways leading to decreased collagen synthesis. RFX5 forms a
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Pulmonary Fibrosis
complex at the collagen transcription start site when RFX1 is removed. IFN-gamma induces class II transcription activator (CIITA) which interacts with RFX5 forming a complex with two other proteins that activate major histocompatibility class II proteins (MHC-II). Since IFN-gamma represses collagen synthesis, we hypothesize that RFX proteins mediate collagen transcription repression during IFN-gamma treatment. Our overall hypothesis is that IFN-gamma repression occurs on the collagen promoter by cooperative interactions of RFX protein family members at the start site with other proteins binding to the proximal promoter. The specific aims are to; 1) Determine the function and interactions of RFX family before and after IFN-gamma treatment. 2) Examine the functional interactions of c-Abl with RFX proteins at the collagen transcription start site. 3) Examine the localization and kinase activity of c-Abl and RFX in lung fibroblasts under different treatments and in samples of human lung tissue. 4) Use transgenic animals with collagen-promoter-CAT constructs or animals deficient in c-Abl or RFX5 complex to investigate collagen transcriptional regulation during fibrosis and treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CTGF IN LUNG DEVELOPMENT AND BPD Principal Investigator & Institution: Rosenbloom, Joel; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Abstract) Although there is increasing evidence that failure of normal lung septation is a component of bronchopulmonary dysplasia (BPD) currently seen in small premature infants, a fibroproliferative response remains responsible for many of the untoward alterations in pulmonary function. While the pathogenic mechanisms underlying this response are complex, it is likely that many of the harmful aspects are mediated by the manifold effects of TGF-B as a final common pathway. Strong evidence suggests that many of the effects of TGF-B on fibroblast proliferation and extracelluar matrix production are mediated by connective tissue growth factor (CTGF). The preliminary data demonstrate that CTGF expression by cultured human fetal lung fibroblasts and airway smooth muscle cells is greatly stimulated by TGF-B1 and that CTGF is expressed in the developing lung. The investigators propose the following hypotheses: (1) A TGF-B superfamily member stimulates the expression of CTGF which acts as a downstream mediator in the regulation of branching and other morphologic events during normal lung development. (2) The signaling pathway by which TGF-B up-regulates CTGF expression involves cellular components in addition to the Smads. (3) CTGF is a major effector molecule in the pathogenesis of pulmonary fibrosis seen in BPD. To test these hypotheses, they will: (1) Determine the temporal and spatial expression of CTGF in the developing mouse and human lung and determine its potential role in lung development by conditional ablation. (2) Define the signaling pathway and mechanisms whereby TGF-B1 up-regulates the expression of CTGF and modulates expression of matrix proteins. (3) Develop strategies for inhibiting the fibrotic response mediated by TGF-B and CTGF. This work will be carried out in close collaboration with Projects 5 & 6, will interact significantly with Projects 1 and 4, will utilize the Tissue Culture Core for the implementation of the mouse lung bud model and will obtain human lung samples from the Clinical Core. Identification of the mechanisms of action of CTGF and the pathways regulating its expression are of considerable importance, since CTGF may play a key role in normal lung development and blocking its abnormal production may ameliorate the fibrotic response seen in BPD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DISRUPTION OF PDGF SIGNAL TRANSDUCTION IN LUNG FIBROSIS Principal Investigator & Institution: Lasky, Joseph A.; Associate Professor; Medicine; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2005 Summary: The formation of scars within the lungs (pulmonary fibrosis) frequently leads to shortness of breath, disability and even death. Occupational exposure to organic or inorganic dusts are well-known to cause pulmonary fibrosis. The etiology of many cases of lung fibrosis remains unknown, or idiopathic, but it is thought that occupational and environmental exposure to particulates may be responsible for upwards of 25% of these idiopathic cases. Unfortunately, current medical treatment is frequently ineffective in halting or reversing lung fibrosis. The overall purpose of this study is to better understand the basic mechanism of lung scarring so that physicians will some day be able to intervene in the pulmonary scarring process and thereby prevent suffering and postpone death. A common structural feature of lung fibrosis is an increase in the number of cells called fibroblasts. A scar is formed when fibroblasts move into a wound and proliferate. Fibroblast proliferation and chemotaxis are mediated by growth factors and cytokines. Platelet-derived growth factor (PDGF) is a potent fibroblast growth factor and chemoattractant, which binds to lung fibroblast surface receptors to generate secondary messengers that stimulate cell growth. Although PDGF expression is upregulated at the site of fibroproliferative lung lesions, it remains to be demonstrated whether or not PDGF is actually directing fibroproliferation during lung fibrogenesis. The hypothesis is that disruption of PDGF receptor signal transduction will significantly inhibit the development of lung fibrogenesis. To test this hypothesis, two strategies directed at disrupting PDGF receptor signal transduction in lung fibroblasts in vitro and in vivo will be employed. The first approach will utilize a newly-developed tyrosine kinase inhibitor that is selective for PDGF receptors, whereas the second approach will use dominant-negative PDGF receptor constructs to inhibit murine lung fibroblast proliferation. It is expected that the information derived from employing these two strategies will be complementary. In concert, these experiments will define for the first time the key role PDGF plays in the pathogenesis of pulmonary fibrosis and help answer whether future research should be directed toward blocking the activity of PDGF to treat lung fibrosis in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EFFECTS OF IPF AND ITS TREATMENT ON INNATE IMMUNITY Principal Investigator & Institution: Ganz, Tomas; Professor; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Abstract) Interferon-gamma (IFN-gamma), a promising agent for the treatment of IPF, is also the most potent known stimulant of host defense against bacterial, fungal and viral infections. We hypothesize that unlike the immunosuppressive drugs prednisone and azathiopnine, IFN-gamma reduces the infectious pulmonary complications of IPF and their adverse effects on the clinical course and respiratory performance. We propose to compare the effects of immunosuppressive regimens vs. IFN-gamma on innate mucosal host defenses and to identify specific mechanisms and molecular effectors that are modulated by the contrasting treatment modalities. We will: 1. Compare the effects of IFN-gamma vs. high dose prednisone on the composition and density of nasal and pharyngeal microbial
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flora. 2. Analyze the effects of IFN-gamma vs. high dose prednisone on known effector proteins of innate host defense in nasal epithelia 3. Analyze the effects of IFN-gamma vs. high dose prednisone on known effector proteins of innate host defense in the lower airways 4. Using proteomics, identify novel proteins (potential effectors and mediators) whose concentrations in nasal or lung fluids are induced or suppressed during treatment with IFN-gamma vs. high dose prednisone As a subsidiary objective, we will sample the azathiopnine-treated patients to test the hypothesis that like high dose prednisone, azathioprine will also have suppressive effects on mucosal host defense compared to IFN-gamma In the aggregate, this study will explore novel concepts of the modulation of mucosal host defenses by immunostimulatory vs. immunosuppressive agents. This is an exciting opportunity to study these mechanisms under well-controlled conditions in humans. The proposal also explores a novel alternative mechanism for the potentially beneficial effect of IFN-gamma in IPF-the avoidance or active prevention of secondary infections that exacerbate the clinical course of conventionally-treated patients with this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FIBROBLAST ABLATION AS TREATMENT FOR PULMONARY FIBROSIS Principal Investigator & Institution: Henke, Craig A.; Associate Professor of Medicine; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Pulmonary fibrosis is characterized by the progressive accumulation of fibroblasts within the alveolar wall and airspace with subsequent deposition of collagen in the distal airspace. This is manifested clinically by severe shunt physiology and often leads to respiratory failure and death. Unfortunately, therapeutic modalities for fibroproliferative lung diseases, which suppress inflammation, have had limited clinical benefit in terms of halting progressive fibrosis. This suggests therapy targeting fibroblasts is essential. It is well documented that some patients with extensive alveolar fibrosis are capable of full recovery. Experimental evidence indicates that removal of unwanted fibroblasts occurs by apoptosis at a critical timepoint during tissue repair allowing restoration of normal anatomic patterns. Therefore, we hypothesize that selective removal of fibroblasts actively participating in the fibrotic process at a critical time period after lung injury will be beneficial in attenuating pulmonary fibrosis and promoting lung repair. In a proof of principle study we plan to utilize transgenic mice we have developed expressing HSV-TK from the mouse alpha 2 type I [alpha2(I)] collagen promoter to test our hypothesis. To selectively target fibroblasts, an alpha2(I) collagen promoter that has selective expression by fibroblasts will be used. To achieve fibroblast ablation, we will employ the thymidine kinase gene of the herpes simplex virus (HSV-TK). Those fibroblasts actively participating in the fibrotic process (e.g., those actively synthesizing large amounts of type I collagen) will express transgene derived HSV-TK and metabolize the antiviral agent ganciclovir (GCV) to toxic nucleotide analogs which disturb nucleic acid synthesis and induce cell death. To create pulmonary fibrosis, the murine model of bleomycin-induced pulmonary fibrosis will be utilized. In this model of pulmonary fibrosis alpha2(I) collagen gene expression by fibroblasts is markedly increased. Therefore fibroblast ablation will be regulated both regionally by the use of the alpha2(I) collagen promoter to target lung fibroblasts actively synthesizing type I collagen and temporally by when GCV is administered. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FIBRONECTIN DEPOSITION AND PULMONARY FIBROSIS Principal Investigator & Institution: Hocking, Denise C.; Assistant Professor; Pharmacology-Physiology; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2004 Summary: (Applicant's abstract): Pulmonary fibrosis is a potentially lethal lung disorder characterized by fibroblast proliferation and excessive accumulation of extracellular matrix proteins, including fibronectin and types I and III collagen. As a consequence of matrix deposition, thickening of the alveolar septum and loss of functional alveolar capillaries can lead to impaired pulmonary function. The development of pulmonary fibrosis is a common response to acute injury and inflammation in the lung. Current therapies, however, have little effect on the progression of the disease. Fibronectin expression and deposition are markedly increased in tissues following injury, where it functions as a chemoattractant and adhesive molecule for migrating cells. Excess or inappropriate deposition of fibronectin into the extracellula matrix during the reparative phase of injury has been associated with fibrotic changes. Evidence suggests that polymerized fibronectin may serve as a templat for subsequent collagen deposition. However, the precise relationship between fibronectin polymerization and collagen synthesis and deposition during pulmonary fibrosis is not known. The goal of these studies is to elucidate the role of multimeric fibronectin in regulating cell migration, collagen synthesi and collagen deposition. Recombinant fibronectin fragments, which inhibit fibronectin polymerization in vitro, will be used to determine the relationshi between fibronectin polymerization and collagen deposition, in vitro and in vivo, using an animal model of fibrosis. These studies will provide informatio crucial to understanding the role of extracellular matrix fibronectin in regulating cell activities which contribute to the development of fibrosis. Elucidating the effect of fibronectin matrix assembly on cell behavior is central to designing methods of intervention during abnormal or altered fibronectin deposition, as occurs during fibrosis. As such, the overall aim of this proposal is to identify mechanisms which control and modulate fibronectin deposition in order to define strategies aimed at limiting the excess deposition of extracellular matrix during pulmonary fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FUNCTIONAL ASSESSMENT OF PULMONARY TOXICITY WITH MRM Principal Investigator & Institution: Johnson, G. Allen.; Professor; Radiology; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 30-SEP-1996; Project End 31-AUG-2006 Summary: (Provided by Applicant): We propose continuation of studies of the environmental impact of particulate matter on lung structure and function using in vivo magnetic resonance microscopy. We will expand our previous work with hyperpolarized 3He to support localized three-dimensional structural imaging at 1 x 104 mm3. We will extend our physiologic support system and spiral encoding techniques to quantitative flow measurements and functional imaging at 1 x 10-2 mm3. We will study the impact of particulates in three specific models: 1) elastase-induced injury, a model of emphysema; 2) inflammation and remodeling in the endotoxin sensitive C3H/HeBFeJ mouse, a model of organic dust induced asthma; and 3) inflammation and remodeling in the vanadium pentoxide model of asthma, which is characterized by
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extensive bronchiolar fibrosis. The proposal will refine methods that will be applicable to a much wider range of basic pulmonary studies while obtaining detailed assessment of structural and functional changes in three important models of human disease. By extending the methodologies to the mouse, we will build a critical bridge between man and mouse models of pulmonary disease that will be essential to understanding the pathophysiology of pulmonary disease and the validation of new therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENE REGULATION DURING INTERMITTENT HYPOXIA Principal Investigator & Institution: Prabhakar, Nanduri R.; Professor; Physiology and Biophysics; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2004 Summary: Episodic or intermittent hypoxia (IH) is associated with many pathophysiological situations, including sleep apneas and lung diseases such as chronic obstructive pulmonary disease (COPD), asthma, or pulmonary fibrosis. Experimental studies on humans, as well as animals, have documented that IH has long term effects on the cardio-respiratory systems leading to pathophysical conditions such as hypertension. Despite its clinical significance little is known about the molecular mechanisms underlying IH. The investigators have devised a technique that exposes cells to alternating cycles of low oxygen simulating IH seen in intact animals. Using this technique, they discovered two features that distinguish IH from SH. First, for a given duration and severity of hypoxia, IH is more potent in activating gene expression. Second, increases in gene expression persisted for hours after terminating IH, a phenomenon resembling long-term facilitation (LTF). The overall goal of the current proposal is to identify the mechanisms underlying activation of gene expression by IH. The application specifically will test the hypothesis that gene activation by IH depends on the duration of oxygenation intervening the hypoxic episodes, and reactive oxygen species (ROS) play a crucial role. The investigators will use an integrated approach to test this hypothesis using both cell culture systems and in vivo experiments on wild type and mutant mice. The current proposal focuses on the regulation of c-fos and tyrosine hydrosylase (TH) genes. The Specific Aims are: 1) To assess the importance of episodic re- oxygenation on gene induction by IH and to determine whether IH-induced elevations in mRNAs are due to increased transcription, stability or both; 2) To determine the role of reactive oxygen species (ROS) and HNE signaling pathways to gene induction by IH; 3) To examine the contribution of Ca2- dependent an HNE signaling pathways to gene expression by IH; 4) To correlate cellular effects of IH on gene expression with chronic systemic responses to IH in intact animals using c-fos knockout mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENETIC TUBERCULOSIS
CONTROL
OF
PULMONARY
CAVITIES
IN
Principal Investigator & Institution: Hunter, Robert L.; Professor and Chairman; Pathology and Lab Medicine; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 10-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) Since it has no animal or environmental reservoir, M. tuberculosis (MTB) must be aerosolized by diseased individuals in order to propagate. The organism accomplishes this most effectively by forming pulmonary cavities. One of
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us (PMS) has recently observed genetic deficiencies in MTB strains with reduced capacity to cause pulmonary cavities in humans. Another of us (RH) has developed a mouse model that suggests the toxicity of cord factor (trehalose 6,6" dimycolate (TDM)) contributes to the formation of cavities. Together, we now propose to identify and characterize MTB genes that control the formation of pulmonary cavities. We will use: 1) two different DNA microarrays to determine, on a genome wide scale, the presence and expression profile of all MTB genes; 2) a new mouse model that manifests the type of caseating granuloma that gives rise to cavities; and 3) conventional genetic approaches for gene knock-outs and complementation. We will build a matrix database of well characterized clinical isolates that records clinical cavity formation, results of assays of toxic lipids and whole genome DNA microarray identification of gene deletion and expression. Analysis of this database will generate specific hypotheses as to which mycobacterial genes are associated with the production of toxic lipids and/or are responsible for pulmonary cavities. These hypotheses will be tested using conventional genetic approaches and by further application of our mouse model. Specifically, we will use three existing NIH funded collections to identify 30 mycobacterial clones that do and 30 that do not cause cavitation. We will grow these isolates as pellicles and assay the amount, distribution, structure and toxicity of TDM. Next, we will use a Bayesian statistical approach to identify genes whose presence or expression is associated with loss of cavity production in humans and/or with the production of toxic TDM. In parallel, we will validate the relevance of our animal model using strains that do or do not produce cavities in humans. Finally, we will use conventional genetic approaches to knock out or insert genes associated with cavity formation and will test the capacity of these modified strains to produce TDM (or other relevant parameters) and induce cavities in our mouse model. If successful, new insights into the pathogenesis of pulmonary cavities may lead to specific interventions to prevent this highly infectious disease manifestation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC SUSCEPTIBILITY TO CHRONIC BERYLLIUM DISEASE Principal Investigator & Institution: Gordon, Terry; Associate Professor; Physiology and Neuroscience; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2003; Project Start 10-APR-2003; Project End 31-JAN-2007 Summary: (provided by applicant): This research proposal will examine the role of host genetic factors in the adverse pulmonary effects of inhaled beryllium. Investigators have clearly demonstrated that only a portion of exposed workers develop chronic beryllium disease (CBD). The reason for the variability in response to inhaled beryllium is not known, but strong evidence suggests that inter-individual differences in the molecular coding for immune system proteins play a major role. Using a gene-by-gene research approach, investigators have shown that one or more nucleotide polymorphisms in HLA are significantly associated with the development of CBD. These molecular epidemiology studies have focused on genetic differences in the major histocompatiblity complex, thus ignoring the potential role of other genes to explain the variability in response to beryllium-induced CBD. Moreover, in addition to modifying genes, environmental factors such as dose and speciation of beryllium are believed to play significant roles in the induction of CBD. Thus, an understanding of the gene environment interaction is critical in clarifying the mechanism(s) of host response to beryllium exposure. A predictive genetic animal model of inter-individual variation for CBD will permit the dissection of the factors of genes and environment in CBD.
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Although genetic studies in mice and guinea pigs have previously suggested inter-strain variability in the response to beryllium, a systematic and complete genome wide search for susceptibility genes for CBD has not been conducted. We will directly address this research gap by examining the response of genetically homogeneous, inbred strains of mice exposed to beryllium using a murine model of beryllium-induced lung granulomas. The primary objectives of this project are: 1) to test the hypothesis that there is a genetic basis for the induction of CBD in response to inhalation of beryllium aerosols; 2) to quantify the contribution of genetic versus environmental factors; and 3) to identify candidate genes that play a critical role in the molecular pathways leading to CBD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC VS ENVIRONMENT IN SCLERODERMA OUTCOMES STUDY Principal Investigator & Institution: Reveille, John D.; Professor; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: The hypothesis to be tested in this proposal is that systemic sclerosis (SSC) is a more aggressive disease in non-Caucasians who manifest a higher occurrence of critical organ involvement and a worse prognosis, and that reasons for this may include both genetic factor factors as well as sociodemographic or behavioral determinants. To ascertain this we have established a multi-ethic cohort of 175 patients with SSC of relatively recent onset (
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leukocytes) at one point early in disease course predict disease progression (using the outcomes stated above). 7) To examine the relative contributions and interactions of genetic, demographic, socioeconomic, cultural, family history and initial and followup clinical and laboratory features on the course and outcome of early SSc through time dependent statistical analytic approaches including proportional hazard Cox-regression models and longitudinal analysis methods. By elucidating the sociodemographic, behavioral and genetic contributions to morbidity and mortality in SSC, interventions would be possible that could improve the course and outcome of this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETICS OF HOST RESISTANCE & SUSCEPTIBILITY TO TB Principal Investigator & Institution: Kramnik, Igor; Assistant Professor of Immunology & Infe; None; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 30-SEP-1997; Project End 31-JUL-2007 Summary: (provided by applicant): A significant variation in susceptibility to tuberculosis among immunocompetent individuals is partially explained by genetic heterogeneity within the host population. However, precise mechanisms of the genetic control of anti-tuberculosis immunity are unknown. We employ a mouse experimental model of tuberculosis for the genetic analysis of the naturally occurring variation in tuberculosis resistance among immunocompetent inbred mouse strains to identify and isolate genes important for determining susceptibility to this infection. We have previously mapped the sstl locus, which controls progression of pulmonary tuberculosis early after infection. Using the sst1-resistant congenic mice we mapped six new quantitative trait loci (QTL) that control variation in tuberculosis resistance among the sstl-resistant hosts. Functional expression of some of those loci is sstl-dependent. We will study the new loci and characterize their possible interactions using genotypeassisted breeding and advanced backcross-intercross progeny testing in order to narrow candidate intervals and establish conditions for their further genetic dissection. We will generate a set of congenic strains by transferring new candidate QTLs on a C3H background and dissect those loci into smaller chromosomal segments to facilitate positional cloning. Using new congenic strains we will study cells that form lung granulomas in resistant and susceptible animals. Identify correlates of tuberculosis resistance and susceptibility at molecular level and establish proxy phenotypes for each locus that can be used as surrogate biomarkers for predicting genetic susceptibility in segregating populations. Identification of molecules encoded in QTLs will help explain critical functional differences conferred by the genetic polymorphisms on mechanisms of host resistance to tuberculosis at both systemic and lung-specific levels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENOMIC & METABOLIC PROFILING OF ORPHAN NUCLEAR RECEPTORS Principal Investigator & Institution: Evans, Ronald M.; Senior Member; Salk Institute for Biological Studies 10010 N Torrey Pines Rd La Jolla, Ca 920371099 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2007 Summary: A significant number of diseases whose effects are felt most acutely in the aging population-atherosclerosis, hypertension, pulmonary fibrosis, and a variety of ocular pathologies-have their roots in the loss of control over metabolic and physiological processes in earlier stages of life. In many cases, orphan nuclear receptors
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(ONRs) through their participation in the regulation of key tissue-specific target gene networks, are critical components these pathways. This project will focus on the role of ONRs in lipid homeostasis especially as it relates to signal by PPARalpha, gamma, and delta, as well as the steroid xenobiotic receptor SCR and its murine homologue PXR. In order to establish a systematic approach to dissect the functions of these and other orphan nuclear receptors, the PPARs SXR will be studied in a systematic fashion by guidelines developed by the Receptor Atlas Group (RAG). This includes construction of a standardized mouse tissue RNA array for quantitative PCR analysis. In this manner, receptor expression patterns, we well as target genes identified by a universal microarray platform, will be collected to build a relational database of orphan nuclear receptor metabolic function. Additionally, the RAG will utilizes a consistent methodology to analyze the function of orphan nuclear receptors in response to dietary manipulation pharmacologic treatments, and diurnal variations in gene expression in both wild type and transgenic knock-out knock-in mouse lines. The data collected in this manner will be contained within a shared Bioinformatics Resource where RAG and other laboratories can compare nuclear receptor function through a common scientific platform. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GLUTATHIONE TRANSPORT, OXIDATIVE STRESS AND LUNG INJURY Principal Investigator & Institution: Day, Brian J.; Associate Professor; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2004; Project Start 15-DEC-2003; Project End 30-NOV-2007 Summary: (provided by applicant): The overall goal of this application is to understand the role of glutathione (GSH) transport in the subcellular mechanisms of oxidative lung damage. (CF) is a genetic disorder that results in persistent lung inflammation and chronic infection that is implicated in progressive lung injury. Exciting preliminary studies indicate that the genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) produces an antioxidant imbalance by decreasing GSH transport into the pulmonary epithelial lining fluid (ELF) and possibly altering GSH transport into the mitochondria. Modulation of GSH transport by the CFTR gene may render the CF patient vulnerable both exogenous and endogenous oxidative stress and thus contribute to the CF pulmonary phenotype. Although evidence exists supporting the role of oxidative stress in the lungs of CF patients, the etiologic and pathogenic relationship between the CFTR gene deficits to oxidative stress has yet to be established. Proposed experiments will delineate the relationship between altered GSH transport and oxidative stress in pulmonary injury associated with CF. The CFTR KO mouse provides a unique way to study pathophysiological mechanisms by which defective GSH transport contributes to antioxidant imbalance and oxidative stress responses in the lung. The CFTR KO recapitulates pulmonary GSH imbalance and oxidative stress of CF patients. It is hypothesized that altered lung GSH transport and metabolism contributes to exaggerated pulmonary oxidative injury and altered host defense. The hypothesis is addressed by the AIMS: (1) To characterize the altered GSH transport, metabolism, utilization, and associated oxidative stress in the lungs of the CFTR KO; (2) Determine whether modulation of GSH transporters can correct the GSH imbalance, oxidative stress, and host defense responses in the CFTR KO; (3) Determine if CFTR KO mice with altered GSH transport are more sensitive to acute lung injury. To accomplish the above aims, the steady-state levels of GSH, GSSG, and GSNO and associated enzyme activities are determined in the lungs of CFTR KO and wild type mice. In addition, markers of
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oxidative damage to protein, lipid, and DNA are quantitated. GSH transport through ABC cassette proteins will be characterized, modulated, and correlated with changes in oxidative stress and host defense. Lung injury models of infection and oxidative stress are utilized to assess the role of altered GSH transport in lung injury responses. Catalytic antioxidant metalloporphyrins and inhaled GSH are employed to reduce oxidant burden and correct the exaggerated pulmonary oxidative injury response in CF. These studies may emphasize the potential adverse effects of oxidative stress from oxidant air pollutants in sensitive populations with pre-existing lung disease, since a large number of pulmonary diseases (including COPD, ARDS, asthma and pulmonary fibrosis) also have deficits pulmonary ELF GSH Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GROWTH FACTORS AND SIGNALING PATHWAYS IN PF Principal Investigator & Institution: Worthen, G Scott.; Associate Professor and Senior Faculty m; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2003; Project Start 19-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): Pulmonary fibrosis is an idiopathic interstitial lung disease with high mortality. The illness is characterized by abnormal intraparenchymal deposition of collagen, with focal accumulations of fibroblasts, myofibroblasts and young connective tissue that are found in unique locations within the affected lung. We propose that aberrant responses of fibroblasts to growth factor and cytokine signaling underlie the progression of disease, and may represent appropriate targets for therapy and markers of response. Using a combination of broadbased techniques, the gene expression patterns of lungs and fibroblasts from patients with pulmonary fibrosis and controls will be discerned using novel algorithms allowing analysis of many thousands of genes per sample. Expression not only of relevant gene products but also signals reflecting response to growth factors and cytokines will be measured in tissue microarrays, where a single protein will be examined in hundreds of tissue samples. The activation state of distinct lung cellular compartments, defined in a fashion not previously feasible in tissue samples from human disease, will be mapped in patients and controls. The secretion of distinct proteins that reflect fibroblast origin and response to stimulation will be pursued both in vitro, but also using bronchoalveolar lavage as a window on secretion by lung cells. New proteomic techniques to enhance throughput and reduce variation will allow elucidation of BAL-derived proteins that reflect disease behavior. The result will be a set of targets plausibly involved in excessive fibroblastic response to signals, and in vitro evidence as to the potential success of intervention strategies. New biomarkers reflecting prognosis, nosology, and response to therapy will be discerned, potentially improving the yield of new trials. The data should advance our ability to treat and monitor pulmonary fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GROWTH FACTORS IN ASBESTOS INDUCED PULMONARY FIBROSIS Principal Investigator & Institution: Brody, Arnold R.; Professor and Vice Chairman; Pathology and Laboratory Medicine; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2002; Project Start 11-APR-1994; Project End 31-AUG-2004 Summary: The molecular mechanisms though which inhaled inorganic particles cause interstitial pulmonary fibrosis (IPF) are being investigated. Since there are numerous
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potential mediators that will be expressed during disease development, it is essential that studies focus on selected molecules that could be key. We have shown that tumor necrosis factor alpha receptor knock out (TNF-alphaRKO) mice are protected from the fibrogenic effects of inhaled asbestos fibers. These animals exhibit reduced expression of other cytokines such as platelet-derived growth factor, transforming growth factor alpha (TGF-alpha) and TGF-beta1, even though TNF-alpha expression remains up-regulated. Thus, we have focused this proposal on the hypothesis that TNF-alpha mediates the development of interstitial pulmonary fibrosis through regulation of TGF- beta production. Four Specific Aims will directly test this postulate: 1) To demonstrate reduced TGF-beta expression in the lungs of asbestos- exposed TNF-alpha receptor knockout (TNF-alphaRKO) mice by in situ hybridization (ISH) and immunohistochemistry (IHC). Our preliminary data show that these mice lack expression of TGF-beta1 after asbestos exposure. If this proves to be true in the final analysis, an important step in testing the postulate will be accomplished. 2) a. To establish whether or not latent or active TGF-beta transduced by adenovirus vector into the lungs of the TNF-alphaRKO mice induces fibroproliferative lung disease in the fibrogenic-resistant mice. b. To expose the virally-transduced animals to asbestos and establish TGF-beta expression as a mediator of fibrogenesis. If TGF-beta1 transduced by an adenovirus vector restores susceptibility to developing fibrogenesis, further evidence of a central role of this growth factor will be in hand. 3) To maintain, in culture, alveolar epithelial and mesenchymal cells from TNF-alphaRKO and TGF-betaKO mice to determine if TNF-alpha receptor signaling is necessary to up-regulate TGF-beta and collagen gene expression in vitro after asbestos exposure. The influence of TNF-alpha on expression of TGF-beta1 and pro alpha1(I) collagen (as postulated) is completely unknown in primary pulmonary cells fro normal and knockout through treatment of mesenchymal cells with antisense vectors directed at expression of the TNF-alpha and TGF-beta genes, As a potential therapeutic approach, we show that an anti-sense TGFbeta1 gene vector blocks expression of TGF-beta1 as well as pro alpha1(I) collagen after treatment with TNF-alpha. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNOBIOLOGY OF LUNG FIBROSIS Principal Investigator & Institution: Mora, Ana L.; Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 04-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a progressive, lethal form of interstitial lung disease. The pathogenesis of IPF is not well understood but a common paradigm postulates an initial alveolar injury, which triggers an inflammatory response and fibrosis. Certain subsets of T lymphocytes have been implicated in promoting lung fibrogenesis. Specifically, a predominantly T helper type 2 lymphocyte (Th2) response with the characteristic cytokine profile consisting of IL-4, IL5, IL-10 and IL-13 production (as opposed to a Th1 response) predisposes towards a fibrotic response rather than repair. In addition, Th2 cytokines stimulate the production of TGF-beta, a critical fibrogenic factor. In this project, we propose to clarify the roles of T cell isotypes and their characteristic cytokines on lung fibrosis in animals. We will conduct parallel studies in the rodent bleomycin model and in a new murine gamma herpesvirus model that we believe relevant to the human disease. Therefore, we propose the following hypotheses: 1. Murine gamma herpesvirus (MHV68) infection of the lungs of susceptible mice will cause a predominantly Th2 lymphocyte response and will cause persistent and progressive pulmonary fibrosis. 2. Defective Th1 effector function
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and/or a predominance of Th2 responses predisposes to the development of lung fibrosis caused by either bleomycin or gamma herpesvirus infection. 3. The IL-4 receptor (IL-4Ralpha) signaling pathway in lung cells mediates increased TGF-beta production and lung fibrosis. To test these hypotheses, we propose the following specific aims: 1. In B cell deficient mice, to determine effects of bleomycin or infection of the lungs with MHV68 on lung function, histopathotogy, lung collagen content, Th1 and Th2 lymphocyte responses and cytokine ILL-4, IL-5, IL-13, IFNgamma, TGFbeta) production by whole lung and lung-derived T lymphocytes. 2. To determine effects of specific depletion of CD4+ and CD8+ T cell subsets on pulmonary responses to bleomycin or MHV68 infection. 3. Using adoptive transfer of in vitro polarized Th1 and Th2 cells and genetically engineered mice biased toward Th1 or Th2 responses, to clarify relationships between the T-lymphocyte responses and responses of the lungs to bleomycin or MHV68 infection. 4. Using IL-4 receptor deficient mice with and without adoptive transfer of normal Th2 cells, to determine whether IL-4 signaling in cells other than T lymphocytes is important to the lung fibrogenic response to MHV68 or bleomycin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IN VIVO FUNCTION OF PULMONARY INTERGRINS Principal Investigator & Institution: Sheppard, Dean C.; Professor; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-APR-1995; Project End 31-MAR-2004 Summary: (Adapted from the Applicant's): This is a competitive renewal application to study the mechanisms whereby the epithelial integrin avb6 regulates pulmonary inflammation and fibrosis as well as airway remodeling. The investigators have shown that a homozygous null mutation of the b6 subunit gene leads to an accumulation of activated macrophages and lymphocytes in the lungs and airways of affected mice and to induction of the macrophage metalloelastase (MME) gene, yet the mice are protected from bleomycin-induced pulmonary fibrosis. Having shown that avb6 binds to a specific sequence within the latency-associated protein (LAP) of TGFb1, the investigators propose to use the b6 subunit knockout mouse (b6-/-) model to study the in vivo role of avb6 in lung inflammation and fibrosis. There are 3 specific aims. The first aim is to determine the role of TGFb1 activation in the induction of lung inflammation and protection from pulmonary fibrosis in beta6-/- mice. For this, transgenic mice expressing full-length and mutant forms of the b6 subunit will be used to determine whether TGFb1 activation or other effects of avb6 can prevent lung inflammation or induce pulmonary fibrosis. Also, they will evaluate whether avb6 acts upstream or downstream of TGFb1 activation, by infecting wild type and b6-/- mice with adenoviruses expressing either active or latent TGFb1 or transgenes that are considered to induce pulmonary fibrosis by acting upstream of TGFb. The second aim is to determine the significance of MME induction in the beta-/- phenotype. For this purpose, they will examine macrophage phenotypic features of double knockout (MME-/- b6-/-) mice generated by cross breeding of MME-/- and b-/- mice. The third aim is to determine the role of avb6 induction in airway remodeling. This will be accomplished by cross breeding b6-/- mice with transgenic mice that develop sub-epithelial fibrosis due to overexpression of IL-6, IL-11 or IL-13. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Pulmonary Fibrosis
Project Title: INTERFERON-G REGULATION OF BLEOMYCIN PULMONARY TOXICITY Principal Investigator & Institution: Chen, Edward S.; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 04-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): The genetic and immunologic basis of pulmonary fibrosis is poorly understood. In rodents, intratracheal bleomycin induces rapidly progressive inflammation similar to human organizing diffuse alveolar damage (DAD), with sub-acute lung injury characterized by exudative events involving cellular infiltration, increased lung permeability, and fibrin deposition. In bleomycin-susceptible mouse strains, pro-inflammatory cytokines play a key role in initiating inflammation and lung injury, and likely mediate subsequent granulation tissue formation and associated acute collagen synthesis. By addressing mechanisms that mediate exudative events that follow inflammation and lung injury, we may develop a critical understanding of factors that promote the transition from granulation tissue to chronic fibrosis that may bear relevance to the progression of human interstitial lung disease, such as idiopathic pulmonary fibrosis (IPF). Our published data demonstrate that interferon-gamma (IFN-gamma) plays an important role in the inflammatory and fibrotic processes in the murine bleomycin model. We found that IFN-gamma protein in bronchoalveolar lavage (BAL) fluid was significantly higher 12 to 24 h following bleomycin administration in bleomycin-sensitive but not in resistant mouse strains, and that the inflammatory and fibrotic response to bleomycin in IFN-gamma knockout mice was significantly reduced compared to sensitive wild-type controls, strongly supporting a role for IFN-gamma in mediating Neomycin-induced pulmonary toxicity. Since these studies stand in contrast to well-known direct anti-fibrotic effects of IFN-gamma, we suggest that differential effects of IFN-gamma on inflammation and fibrosis in response to bleomycin may be dependent on the timing and regulation of endogenous IFNgamma expression, or on the dosing schedule and route of administration of exogenous IFN-gamma. Furthermore, we hypothesize that IFN-gamma-mediated bleomycin pulmonary toxicity is enhanced by up-regulation of IL-12 and IL-18, inducers of IFNgamma, and is effected, in part, through the induction of iNOS with enhanced lung injury. The specific aims of this proposal are: (1) to determine the role of post-exposure IFN-gamma administration on the inflammatory and fibrotic response to Neomycin, (2) to determine if IFN-gamma regulatory cytokines IL-12 and IL-18 mediate bleomycininduced pulmonary toxicity through enhanced IFN-gamma production, and (3) to determine if IFN-gamma potentiates bleomycin-induced pulmonary toxicity through direct up-regulation of iNOS expression. Understanding the mechanisms involved in IFN-gamma mediated pulmonary inflammation and fibrosis in the murine model of bleomycin pulmonary toxicity may provide insight into mechanisms involved in pulmonary fibrosis associated with human DAD, Th1 mediated interstitial lung diseases such as sarcoidosis, hypersensitivity pneumonitis, silicosis, and possibly, IPF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FIBROSIS
INTERFERON-GAMMA
IN
EXPERIMENTAL
PULMONARY
Principal Investigator & Institution: Enelow, Richard I.; Associate Professor and Chief; Internal Medicine; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-JUL-2003
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Summary: (provided by applicant): Chronic fibrotic lung disease occurs in a variety of clinical settings, including the idiopathic interstitial pneumonias, as well as in many of the rheumatic diseases. We previously developed a model of acute T cell-mediated pulmonary injury, which results in severe alveolar injury, leading to significant respiratory impairment and death within a few days. This model involves the adoptive transfer of activated CD8+ T cells into recipient animals expressing the specific antigen on alveolar epithelial cells. In contrast with the acute lung injury occurring after transfer of wild-type CD8+ T cells, we have recently found that chronic inflammation and fibrosis may result from the CD8+ T cell recognition of alveolar antigen in the absence of IFN-gamma exclusively in the antigen-specific cell population, and have found that these T cells induce a totally different pattern of lung injury, including a more chronic pattern of inflammation and, importantly, interstitial and intraluminal fibrosis. This was accomplished by using IFN-gamma-deficient CD8+ T cell clones for adoptive transfer, which results in inflammation and fibrosis that evolves over a period of 2-4 weeks after administration. This very exciting result represents the first animal model of pulmonary fibrosis that does not involve an exogenous toxin, and which evolves entirely from a single, well-defined molecular interaction, the T cell receptor recognition of antigen on alveolar epithelial cells. In order to understand the mechanisms which underly the resolution of acute pulmonary inflammation which results directly from expression of IFN-gamma by the antigen-specific CD8+ T cell, and the factors which may lead to chronic inflammation and fibrosis in its absence, we propose the following Specific Aims:1. To characterize the impact of IFN-gamma expressed by CD8+ T cells on input and host T lymphocyte activities in vivo.2. To characterize the specific effects of IFNgamma expressed by CD8+ T cells on host macrophages and the impact on progression to chronic pulmonary inflammation.3. To characterize the specific effects of CD8+ T cell recognition in the absence of IFN-gamma on antigen-presenting epithelial cells and the impact on progression to chronic pulmonary inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INTERFERON-GAMMA TO TREAT CHRONIC HCV INFECTION Principal Investigator & Institution: Muir, Andrew J.; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 21-SEP-2001; Project End 31-AUG-2004 Summary: (adapted from the application) Current treatment options for chronic hepatitis C infection remain limited and unsatisfactory. Treatment with interferon-alpha and ribavirin leads to a sustained response in the minority of patients, and many patients may not be eligible for treatment due to side effects associated with these medications. Other treatment options are clearly necessary for chronic hepatitis C infection. A major complication of chronic hepatitis C infection is fibrogenesis, ultimately leading to development of cirrhosis. Animal models have demonstrated that interferon-gamma reduces fibrogenesis through its effect on stellate cells. A recent report in patients with idiopathic pulmonary fibrosis found that interferon-gamma was well-tolerated and led to improved pulmonary function, ostensibly due to a reduction in fibrogenesis. Given these data, we postulate not only that interferon-gamma will be effective for treatment of hepatitis C mediated fibrogenesis, but also that it will be safe. We have therefore proposed a phase I study to assess the effectiveness of interferongamma in twenty patients with chronic hepatitis C infection. The patients will include those who have failed previous therapy with interferon-alpha or are not candidates for interferon-alpha therapy. Men or women 18 years of age or older are eligible. Other inclusion criteria are serum positive for hepatitis C virus by PCR; liver biopsy consistent
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Pulmonary Fibrosis
with chronic hepatitis and with a fibrosis score of at least one on the Knodell scale; compensated liver disease; and informed, written consent obtained prior to entry. All patients will receive 200 micrograms of interferon-gamma three times a week for twelve months. Patients will undergo liver biopsy prior to treatment and at the end of treatment. Safety and tolerance will be evaluated at weeks 1, 2, 4, 8 and then every 4 weeks during treatment and at weeks 4 and 12 following the completion of therapy. Serum HCV-RNA will be evaluated prior to initiating therapy and at the end of therapy. The primary endpoint of this study will be the histological response of patients with chronic hepatitis C infection to treatment with interferon-gamma. Secondary endpoints include the biochemical response, inflammatory and regulatory cytokine levels, and quality of life during treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LOCAL ANGIOTENSIN SYSTEM IN LUNG FIBROGENESIS Principal Investigator & Institution: Maier, Lisa A.; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 04-SEP-1998; Project End 31-AUG-2003 Summary: (Adapted from applicant's abstract) Chronic beryllium disease (CBD) is a granulomatous lung disease that occurs after exposure to beryllium in the workplace. Beryllium stimulates an exuberant cellular immune response resulting in granuloma formation which eventually may progress to pulmonary fibrosis. The mechanism of fibrosis in the setting of T-cell mediated hypersensitivity is not well understood. Preliminary studies in CBD have found mast cells as the source of basic fibroblast growth factor (bFGF) in the formation of the fibrosis that surrounds granulomas. It is a potent activator of fibroblast and smooth muscle cell proliferation, contributing to fibrogenesis. Basic FGF is one of the key growth factors stimulated by angiotensin II. Angiotensin-converting enzyme (ACE) and its enzymatic product angiotensin II (ATII) promote fibrosis in cardiovascular disease, by an unknown mechanism. ACE activity is high in CBD. Thus, the investigators hypothesize that the local angiotensin system responds to beryllium-induced lung injury by promoting fibrosis through the production of bFGF. Furthermore, they hypothesize that this fibrotic response is counterbalanced by a cell mediated immune response to beryllium in which there is marked interferon gamma (IFN-y) production. They will conduct experiments to determine whether beryllium can increase ACE activity and ATII production in CBD bronchoalveolar lavage (BAL) cells. By examining biopsy tissues after beryllium skin patch testing, they will assess the role of beryllium in stimulating ACE, ATII, and mRNA expression for ACE and ATII receptors during granuloma formation. The investigators will link the ATII production from beryllium stimulated macrophages to fibrosis by measuring ATII stimulation of the fibrotic growth factor, bFGF, from mast cells using a human mast cell line. They will define the mechanism of bFGF upregulation by ATII. Finally, to demonstrate that the beryllium-mediated immune response inhibits this fibrotic response, they will assess the role of IFN-y in downregulating the ATII stimulated bFGF production. These studies will help establish a role for the angiotensin system in granulomatous lung disease and the path to fibrogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: LUNG FIBROSIS: TREATMENT AND MYOFIBROBLAST CONTROL Principal Investigator & Institution: Schwarz, Marvin I.; Professor of Medicine; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206
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Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Abstract) In Project 5 we propose to define the role of the fibroblastic foci and myofibroblast presence in IPF/UIP pathogenesis, to test an antiproliferative therapy for this disorder, and develop surrogate markers which predict outcome. Because of its antiproliferative properties and antagonism of transforming growth factor-beta-1 (TGF-b1) functions in vitro, as well as TGFb-1 driven myofibroblast generation, we propose to study the efficacy of interferon gamma (IFN) (subcutaneous and inhaled) in idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP). In the recently initiated phase III trial, we will define surrogate markers of outcome; to include dyspnea scores, physiologic tests, quantitative image analysis of the high resolution computed tomographic images, and fibroproliferative biomarkers. Recently, we were instrumental in organizing an NHLBI workshop which proposed systematic evaluation of several available novel therapeutic agents that could abrogate the fibroproliferative response. Myofibroblast apoptosis, proliferation, clonality and structure of fibroblastic foci will be compared to bronchiolitis obliterans organizing pneumonia (BOOP), a disease whose positive outcome exceeds IPF/UIP. Gene expression patterns of whole IPF[UIP lung will be analyzed by microarray and compared to normals and BOOP to determine differences and characteristic patterns. Microdissection of fibroblastic foci in IPF1UIP and Masson's bodies of BOOP will be performed. Based on this and utilizing laser capture microdissection BOOP will be performed to determine diagnostic patterns. The goal is to determine gene expression patterns of IPF/UIP and BOOP, which predict clinical behavior and are typical for that particular disease. We will also determine within the IPFIUIP group which genes reflect a bad vs. improved prognosis and the differential gene expression pattern between Fibroblastic foci (IPF/IJIP) and Masson's bodies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LUNG PHOSPHOLIPID APPEARANCE AND STABILITY Principal Investigator & Institution: Jobe, Alan H.; Professor of Pediatrics; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2002; Project Start 30-SEP-1977; Project End 31-MAR-2003 Summary: The overall goal is to understand how the lung regulates surfactant pools in health and disease. The hypothesis is that alveolar surfactant is regulated by cytokines/growth factors/hormones and that studies of surfactant metabolism and function in transgenic mice with abnormalities in these systems will provide insights into surfactant homeostasis. Although there is considerable information about the overall kinetics of metabolism of the major surfactant components - saturated phosphatidylcholine (Sat PC) and the surfactant associated SP-A, SP-B and SP-C, the relative contributions of type II cells, Clara cells, and macrophages to alveolar metabolism is not known. The contributions of these cell types to the metabolism will be evaluated in normal mice. Transgenic mice with alveolar proteinosis (GM-CSF-I-,IL-4 overexpression) and pulmonary fibrosis (TGFalpha overexpression) will be used to identify the metabolic pathway(s) and/or cell types responsible for the abnormalities in surfactant homeostasis. Measurements will be made of precursor incorporation into Sat PC and the surfactant proteins, secretion and alveolar and lung clearances of these surfactant components. Surfactants of abnormal composition resulting from transgenic constructs that lack SP-A or SP-D, overexpress SP-A, and overexpress SP-A and SP-B will be evaluated for in vitro biophysical properties and function to learn the ranges of surfactant function consistent with relatively normal lung function. Because the abnormalities in surfactant in these transgenic mice are similar to those encountered in
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Pulmonary Fibrosis
patients with alveolar proteinosis, pulmonary fibrosis, other lung injuries and bronchopulmonary dysplasia, the results will provide a framework to understand surfactant metabolic abnormalities in human lung diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LUNG RADIATION PROTECTION BY MNSOD TRANSGENE THERAPY Principal Investigator & Institution: Greenberger, Joel S.; Professor and Chairman; Radiation Oncology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-DEC-1998; Project End 31-JAN-2006 Summary: (provided by applicant): Thoracic radiotherapy (RT) is often limited by lung toxicity (pulmonary fibrosis). Pulmonary fibrosis ensues after an unexplained latent period which follows the acute reaction and is characterized by reduction in pulmonary vital capacity and exertional dyspnea. Elevation of fibrogenic cytokines, most notably, TGF-B1 and B2 (TGF-B1-B2), and fibroblast proliferation that extends from irradiated to adjacent lung, are features at the molecular and cellular levels. The principal investigator recently demonstrated that intratracheal (IT) injection of manganese superoxide dismutase-plasmid/liposomes (MnSOD-PL) protects the murine lung from irradiation-induced organizing alveolitis/fibrosis induced by single dose or fractionated irradiation. The proposed research will use validated, genetically modified animal models along with quantitative molecular methods to elucidate the cellular mechanism of irradiation lung fibrosis and the level(s) at which epitope-hemagglutinin (HA)-tagged MnSOD transgene therapy protects. The first specific aim tests the hypothesis that organizing alveolitis/fibrosis is initiated by accumulation of macrophage attractant, VCAM-1 in endothelial cells at 80-100 days after irradiation. The second specific aim tests the hypothesis that TGF-B1-B2 production by bone marrow-derived bronchoalveolar macrophages (BAMs) mediates fibroblast recruitment and proliferation. The third specific aim tests the hypothesis that circulating fibroblast progenitor cells, also of bone marrow origin, home to, and proliferate in irradiated lung to produce organizing alveolitis/fibrosis. Methods include BrdU in situ labelling, histopathology, green fluorescent protein-positive (GFP+) male hematopoietic stem cell (macrophage progenitor) engraftment to GFP- female mice and transplantation of GFP+ purified bone marrow stromal cells (BMSCs), continuous anti-TGF-B antibody or soluble TGF-B receptor (TGF-B-R) delivery, injection of HA-MnSOD-PL, fractionated irradiation, and in situ assays of DNA damage. These experiments will provide substantial, new insight into the basic pathogenesis of the pulmonary irradiation response. A comprehensive understanding of the underlying mechanisms is critical for identifying novel targets for intervention. This project may facilitate development of specific strategies to minimize pulmonary irradiation toxicity, thereby making RT safer and more effective. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISMS IN THE REMODELING OF LUNG STRUCTURE Principal Investigator & Institution: Senior, Robert M.; Professor; Barnes-Jewish Hospital Ms 90-94-212 St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 01-SEP-1983; Project End 31-AUG-2003 Summary: This multidisciplinary program will utilize concepts and techniques of cell and molecular biology to investigate lung development, lung structure, alterations in
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lung structure due to inflammation, mechanisms of alveolar repair, and alveolar surface proteins. Our overall hypothesis is that extracellular matrix has a fundamental role in lung development and the preservation of normal lung architecture and function, and that disturbances in extracellular matrix are pivotal in emphysema, the acute respiratory disease syndrome, pulmonary fibrosis, chronic pulmonary hypertension, and other disorders in which lung structure is altered. In this program we will study: (1) alveolar basement membranes in lung development and disease; (2) alveolar surface proteins as factors in host defense; (3) matrix metalloproteinase expression by alveolar epithelium; (4) macrophage elastase in emphysema; and (5) pulmonary vascular development and remodeling. A number of molecules will receive emphasis, including laminin alpha chains, surfactant proteins A and D (SP-A and SP- D), cytokines (TNF-alpha, IL-1, IL-6), LPS binding protein, matrilysin, macrophage elastase, tropoelastin, fibrillin-2, microfibril-associated glycoprotein (MAGP), and latent TGF-beta/1-binding protein-2 (LTBP-2). The proposed studies will encompass lung cells in culture, embryonic lungs in culture, transgenic mice, rodent models of alveolar injury induced by hyperoxia, bleomycin, N-nitroso-N-methylurethane, and tobacco smoke, and interactions between SP-D, microorganisms, and macrophages. Human lung tissue and lung cells will be analyzed in some studies. A Morphology Core organized into Histology, Immunology, and Molecular Biology components will assist with tissue processing and diverse morphologic procedures, including 'in situ' hybridization and immunostaining, and will assist in the development of immunologic reagents. The Morphology Core will provide a center for correlative interactions among the investigators in their independent, yet complementary, studies of lung biology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISMS OF CYTOPROTECTION IN ACUTE LUNG INJURY Principal Investigator & Institution: Choi, Augustine M.; Professor; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-MAY-2008 Summary: (provided by applicant): The lung is a major target organ for oxidant injury. Damaging effects of reactive oxygen species (ROS) including superoxide and hydroxyl radicals, and hydrogen peroxide, are generated by the incomplete reduction of oxygen. These toxic ROS can damage cellular constituents such as nucleic acids, proteins, and lipids and play a vital role in both acute and chronic inflammatory diseases of the lung such as adult respiratory distress syndrome (ARDS), pulmonary fibrosis, asthma and emphysema. It is now apparent that the expression of a variety of genes are regulated following oxidant lung injury, and some of these gene products such as the gaseous molecules carbon monoxide (CO), nitric oxide (NO), and the growth factor keratinocyte growth factor (KGF), and the antioxidant enzyme extracellular superoxide dismutase (ECSOD) are cytoprotective against oxidant lung injury. It is a unifying hypothesis of this program project that these various cytoprotective molecules mediate their effector protective functions via distinct and overlapping signal transduction pathways. We will test this hypothesis by addressing these aims: 1) We will examine the mechanism by which CO mediates cytoprotection against hyperoxia, in particular the role of p38 MAPK in mediating CO-induced cytoprotection. 2) We will focus on the mechanism by which KGF-induced activation provides survival signaling in response to oxidant lung injury. 3) We will focus on the anti-apoptotic effects of iNOS derived NO in limiting injury to the pulmonary endothelium of intact mice exposed to 100% oxygen and the mechanism by which NO inhibits LPS-induced apoptosis in cultured mouse lung endothelium (MLEC). 4) We will examine the mechanism by which EC-SOD in the lung
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Pulmonary Fibrosis
defend against oxidant-induced lung injury. These proposed studies will provide novel insight into oxidative and signaling mechanisms that contribute to acute lung injury and point to potential new therapeutic targets. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISMS ALLOGRAFTS
OF
MAST
CELL
APOPTOSIS
IN
LUNG
Principal Investigator & Institution: Fang, Kenneth C.; Cardiovascular Research Institute; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2004 Summary: Mast cells and their mediators play critical roles in homeostatic wound healing pathways. Therefore, the premature demise of the mast cell population via programmed cell death or apoptosis may permit uncontrolled tissue remodeling which progresses to fibrosis. Metalloproteinases and their inhibitors exert diverse influences on cellular functions by processing matrix proteins and by regulating the dynamic display of membrane- anchored receptors, adhesion molecules and growth factors at the cell surface. The overall hypothesis of this proposal is that metalloproteinase-dependent mechanisms regulate mast cell apoptosis during fibrinogenesis. Binding of c-kit ligand (stem cell factor) to kit receptor tyrosine kinase regulates mast cell proliferation and apoptosis, and also induces receptor down-regulation via an uncharacterized metalloproteinase-dependent cleavage of Kit's extracellular domain. The experimental design employs complementary approaches using a rat model of lung transplantassociated airway fibrosis to study the role of metalloproteinases in mast cell apoptosis in vivo, and cultured mast cells to investigate the role of metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs) in molecular mechanisms which regulate proteolytic shedding of the Kit ectodomain. Consistent features of mast cells in fibrotic lung disorders, including transplant-associated obliterative bronchiolitis are fluctuations in the size of their population and persistent degranulation of stored mediators. To address the overall hypothesis, the proposed studies will investigate metalloproteinasedependent induction of mast cell apoptosis and the role of mast cell mediators in regulating proteolytic processing of Kt receptor. Aim 1 will identify the role of metalloproteinases and mast cell apoptosis during the development of obliterative bronchiolitis in a rat lung allograft model. Aim 2 will clarify the metalloproteinasedependent Kit receptor shedding mechanism by investigating mast cell expression of metalloproteinases such as tumor necrosis. Factor-alpha converting enzyme (TACE), and by identifying the proteases and peptide sites cleaved in Kit ectodomain processing. Aim 3 will determine the role of mast cell proteases and oxygen radicals in proteolytic and non-proteolytic processing of TIMPs which not only inhibit metalloproteolytic sheddases, but also regulate apoptosis. These studies should provide valuable insights into the role of mast cells in the pathogenesis of fibrotic lung disorders and also clarify mechanisms responsible for the development of obliterative bronchiolitis, the major obstacle to improved outcome and survival in lung transplant patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISMS OF MYOFIBROBLAST SURVIVAL IN FIBROSIS Principal Investigator & Institution: Riches, David W.; Professor and Division Head; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003
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Summary: (Applicant's Abstract) Idiopathic pulmonary fibrosis/usual interstitial pneumonitis (IPF/UIP) is a fatal parenchymal lung disease characterized by interstitial and alveolar fibroproliferation and the appearance of myofibroblasts. Little is known about the mechanisms of myofibroblast accumulation in IPF/UIP or why they fail to be eliminated as occurs during normal wound repair. Previous studies from this and other laboratories have shown that survival factors, especially IGF-I, are abundantly expressed by macrophages and alveolar epithelial cells in IPF/UIP. In this proposal, we will test the hypothesis that the presence of survival factors, including IGF-I, in the parenchyma and airspaces of patients with IPF/UIP protect myofibroblasts from apoptosis. Under these conditions, myofibroblasts are proposed to accumulate in numbers and can thus contribute to parenchymal fibrosis for extended periods of time. The major goals of this proposal are three-fold: (i) to investigate the conditions and mechanisms that mediate myofibroblast apoptosis under conditions of growth factor and stretch withdrawal; (ii) to determine how IGF-I serves to protect myofibroblasts from undergoing apoptosis; and (iii) to investigate the mechanism of dysregulation of myofibroblast apoptosis in IPF/UIP. These goals will be addressed by four specific aims. Specific aim one will address the role of growth factors, physical forces and IGF-I in myofibroblast differentiation, reversion to a fibroblast phenotype and apoptosis. These studies will form a basis for determining the mechanisms that promote myofibroblast apoptosis with a focus on the mechanisms of caspase activation (specific aim two). The objective of specific aim three is to uncover the mechanisms through which IGF-I prevents the initiation of the death program. The focus of these studies will include the mechanism of inactivation of the effector capsases (3, 6 and 7) and the potential role of anti-apoptotic proteins. Lastly, in specific aim four, we propose to apply what has been learned from this studies conducted in this proposal to address the mechanisms that promote protection from apoptosis in the lungs of patients with IPF/UIP. The findings from this work are expected to provide new insights into the mechanism of myofibroblast apoptosis and how this process becomes dysregulated in IPF/UIP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISMS OF PAI1 REGULATION BY LUNG MATRIX MOLECULES Principal Investigator & Institution: Olman, Mitchell A.; Associate Professor; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: Pulmonary fibrosis is a frequent and devastating complication of acute or indolent lung injury for which current therapy is effective in only 1/3 of cases. The fibroproliferative response after lung injury is characterized by matrix fibrin deposition and collagen accumulation. Several recent in vivo studies indicate that the serine protease inhibitor, plasminogen activator inhibitor (PAI-1) contributes to the fibrotic response. For example, in bleomycin-injured mice, PAI-1 is up- regulated in fibroproliferative lesional fibroblasts, and genetic deletion of PAI-1 confers protection from lung injury-induced fibrin and collagen deposition. These in vivo data provide strong evidence of a fibrogenic role for PAI-1, however, the regulatory pathways involved in fibroblast PAI-1 expression have yet to be elucidated. Furthermore, the proposed mechanism of PAI-1's in vivo effect through inhibition of alveolar fibrin clearance remains unproven. Our goal is to understand the mechanism of regulation of PAI-1 expression, and its role in the molecular events that result in pulmonary fibrosis. We have recently shown that fibroblasts up-regulate their expression of PAI-1 in
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Pulmonary Fibrosis
response to fibrin D dimer, a plasmin-generated proteolytic fragment of fibrin that is abundant in fibroproliferative lesions. The work proposed herein will advance the field by defining the mechanism(s) by which D dimer increases PAI-1 expression in fibroblasts, and by determining the effect of in vivo manipulation of alveolar fibrinolysis on PAI-1 expression and on the fibrotic process. In the first two specific aims, we will determine the relative importance of changes in PAI-1 transcription rates and mRNA half-fife, and identify the critical cis and trans acting factors in basal and D dimerstimulated PAI-1 transcription in fibroblasts. In specific aim 3, we will study effect of experimentally-induced alveolar fibrinolysis, with its attendant generation of D dimer, on lung PAI-1 expression and on the fibrotic response to bleomycin lung injury. We hope the knowledge of the molecular events in pulmonary fibrosis will lead to novel identifiable targets for therapeutic modalities aimed at reducing the fibroproliferative response to lung injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: KNOCKOUT
METALLOELASTASE
INDUCTION
FOLLOWING
INTEGRIN
Principal Investigator & Institution: Morris, David G.; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 08-FEB-2001; Project End 31-JAN-2006 Summary: (Adapted from applicant?s abstract) Dr. David Morris is a pulmonary and critical care physician with a strong commitment to an academic career as an independent investigator in respiratory cellular and molecular biology. His particular interest is lung remodeling. Through work in the Lung Biology Center at UCSF/SFGH he has identified a novel animal model of bronchitis and emphysema resulting from inactivation of an epithelial integrin (alpha2- beta6). He is proposing a program of advanced research training consisting of independent experimental studies mentored by an expert in integrin biology (Dr. Dean Sheppard); a research advisory committee including experts on matrix metalloproteinases (Dr. Zena Werb), protease biology (Dr. Caughey), and pulmonary immunology (Dr. Erle); and a formal didactic program including courses in biochemistry, cell biology, and immunology. His research program will address the hypothesis that the integrin alpha2-beta6 on the surface of respiratory epithelial cells modulates alveolar macrophage expression of Macrophage Metalloelastase (MME, MMP-12) thereby regulating airway inflammation, and matrix degradation. He will address this hypothesis through three specific aims. First, he will determine which regions of the beta6 integrin subunit are critical to prevent persistent MMP-12 (MME) overexpression by alveolar macrophages and avert the development of emphysema in beta6 -/- mice using novel transgenic lines. Second, he will determine the role of MMP-12 (MME) upregulation in the recruitment and activation of macrophages and lymphocytes in beta6 -/- mice using double knockout mice. Finally, he will determine the role of Transforming Growth Factor Beta1, and of alpha2-beta6 mediated activation of latent TGFbeta1 in the regulation of airway inflammation and MMP-12 (MME) expression in vivo using both adenovector gene transfer and transgenic approaches. This work promises to yield important insights into the fundamental biology underlying both chronic airway inflammation and emphysema. Dr. Morris will complete this work in the Lung Biology Center (LBC), internationally recognized research center with an outstanding record of training independent academic pulmonary scientists. The Department of Medicine and LBC are fully committed to Dr. Morris? career development and to making all necessary resources available to facilitate successful completion of this work.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR MECHANISTIC BASIS FOR RADIATION INDUCED PULMONARY LATE EFFECTS Principal Investigator & Institution: Finkelstein, Jacob N.; Professor; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JUL-2003 Summary: (Applicant?s Description)The general goal of this program is directed at gaining a deeper understanding of the molecular mechanisms which are the basis for the normal tissue late effects which are observed in the lung following radiation. Previous CERRIS programs have led to the paradigm of radiation late effects being dependent upon the "conversation" which takes place between a number of injured cells, rather than the classic concept of a single target cell. In pursuit of this goal, they mean to further define the conversation, which they have hypothesized as a "cytokine cascade", in terms of the spatial and temporal release of proinflammatory and profibrotic cytokines and growth factors, and their genetic context. Expansion of this paradigm has led them to postulate the role of the immune system in the development of late tissue effects and this will be explored in more detail. Modulation of the cytokine cascade(s) and/or the immune system will be investigated as a means of both elucidating the roles of specific cytokines, as well as suggesting routes of amelioration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MULTIDISCIPLINARY TRAINING IN PULMONARY RESEARCH Principal Investigator & Institution: Frampton, Mark W.; Associate Professor; Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-AUG-2006 Summary: Applicant's Abstract This Institutional National Research Service Award is designed to develop skilled investigators who will pursue research-oriented careers directed at solving basic and clinical problems related to lung diseases. Training spans a variety of disciplines, including molecular and cell biology, immunology, microbiology, toxicology, biochemistry, pulmonary and critical care medicine, and neonatology. Predoctoral students who have demonstrated an interest in lung research will be accepted for training through Graduate Education in Biomedical Sciences (GEBS) Clusters, after they have passed their preliminary examinations. Support will begin after the second year of graduate training, and will continue for approximately three years, leading to a thesis and Ph.D. degree related to lung diseases. Post-doctoral M.D. training candidates will be accepted after completion of their subspecialty clinical training, based on a high likelihood of pursuing a research oriented career. Post-doctoral M.D.s come from residency programs in adult and pediatric pulmonology, neonatology, immunology, and infectious diseases. Post-doctoral students with the Ph.D. degree who have developed skills applicable to lung research are also candidates for training. Didactic courses, seminars, and conferences, including instruction in research ethics, will supplement the major commitment to direct research experie'nce. Trainees will develop research protocols with close supervision by their sponsors, and a committee from the interdisciplinary faculty with expertise in appropriately related fields. Training will-take place in laboratories in the clinical and basic science departments and institutes at the University of Rochester School of Medicine and Dentistry. Faculty have laboratories studying a wide range of topics suitable for training. Major research themes include lung immunology and inflammation, the molecular basis of lung injury, effects of
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Pulmonary Fibrosis
gaseous and particulate air pollution, and airway production of nitric oxide, and mechanisms leading to pulmonary fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEW MOLECULAR TARGETS IN PULMONARY FIBROSIS Principal Investigator & Institution: Kaminski, Naftali; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): Idiopathic Pulmonary Fibrosis (IPF) is a progressive and largely untreatable group of disorders that affects up to 100,000 people in the United States Current proven therapies are only effective in a minority of affected individuals Despite the significant progress in understanding the general mechanisms that lead to pulmonary fibrosis in murine lungs, little is known about the molecular mechanisms and networks that determine the fibrotic pulmonary phenotype in IPF The research proposed is based on the hypothesis that the unique phenotypic aspects of IPF, temporal heterogeneity, lack of significant inflammation and abundance of myofibroblast foci, represent molecular mechanisms that are specific to IPF. Therefore, understanding the molecular networks that underlie these characteristics will lead to identification of novel rational molecular targets for intervention in IPF. This hypothesis will be tested by addressing the following specific aims: 1. To create a comprehensive expression profile of human pulmonary fibrosis. This will be achieved by identifying gene expression patterns that distinguish IPF from normal lung tissue and from other interstitial lung diseases, by identifying regional and temporal changes in gene expression and by identifying cell specific gene expression patterns in IPF lungs. 2. To identify "target" pathways and regulatory molecules that are candidates for therapeutic interventions using advanced computational methods This computational aimi includes: Determination of clinically relevant patterns of expression, identification of transcriptional regulation of observed expression patterns and generation of advanced computational methods that characterize gene expression "modules" and reconstruct "missing" key events in disease progression from gene expression data. 3. To verify protein expression levels of candidate molecules. This will be achieved by generating tissue arrays in which all interstitial lung diseases are represented. These arrays will be used for validation, frequency determination and cellular localization of abnormalities in protein expression of candidate molecules. 4. To identify the candidate molecules that affect "fibrosis related" cellular phenotypes using high throughout cell based assays. This will be done by assessing the effect of in-vitro inhibiting or inducing the expression of validated candidate molecules on ECM production and cytokine and growth factor secretion. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEW PATHWAYS IN IL7 MEDIATED ANTIFIBROTIC RESPONSES Principal Investigator & Institution: Dubinett, Steven M.; Professor of Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Abstract) Idiopathic pulmonary fibrosis (IPF) is a devastating disease with less than a 50% five-year survival. Thus novel therapeutic strategies are cleariv needed. A developing paradigm views pulmonary fibrosis as an "IFNgamma deficiency disorder" the therapeutic replacement of IFNgamma has shown promise in
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preliminary clinical trials. In the current study we will investigate the capacity of the potent type 1 cytokine interleukin 7 (IL-7) to limit pulmonary fibrosis by both IFNgamma-dependent and independent pathways. In marked contrast to the current forms of therapy for IPF, IL-7 potently enhances cell-mediated immunity. In addition to its capacity to induce IFNgamma, IL-7 downregulates both TGF-beta production and TGF-P signaling in pulmonary fibroblasts. In this 1 proposal we hypothesize that IL-7 can augment antifibrotic responses by: 1) stimulating IFNgamma production, 2) downregulating fibroblast TGF-beta synthesis and TGF-beta signaling and. 3) promoting epithelial survival by induction of cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) production. Our preliminarv studies indicate that IL-7 potently upregulates IFNgamma, downregulates both TGF-beta production and signaling and significantly inhibits bleomycin-induced pulmonary fibrosis in vivo. The specific alms are: 1) To assess the determinants of the IL-7-mediated anti-fibrotic response in in vivo models of pulmonary fibrosis. 2) To assess the efficacy and mechanisms of IL-7mediated inhibition of human fibroblast TGF-beta production and signaling. 3) The longitudinal variation of expression of COX-2 and PGE2 in IPF patients will be correlated with clinical parameters of therapeutic response during IFNgamma therapy. Although IL7 shares several biological effects with IFNgamma, its capacity to induce endogenous IFNgamma production in vivo contrasts with the effect of administration of recombinant IFNgamma. These activities, together with the capacity to promote epithelial cell survival, make IL-7 a compelling cytokine for investigation in IPF. The development of pathogenesis-based. biological therapy for IPF offers an entirely new avenue for translational investigation that will lead to new therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OXIDANTS DIFFERENTIATION
AND
TGF-BETA
IN
MYOFIBROBLAST
Principal Investigator & Institution: Thannickal, Victor J.; Assistant Professor; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2005 Summary: The pathology of fibrotic lung diseases is characterized by fibroblastic foci in areas of active fibrosis. These fibroblastic foci contain fibroblasts with an activated, "myofibroblast" phenotype. Myofibroblasts are key effector cells in the pathogenesis of pulmonary fibrosis due to their high protein synthetic capacity [extracellular matrix (ECM) proteins, integrins, growth factors, growth factor receptors], resistance to apoptosis, enhanced proliferative responses to mitogens and ability to generate extracellular oxidants. The pro-fibrotic cytokine, TGF- beta1, is a potent induces of myofibroblast both in-vivo and in-vitro. However, this differentiation signal induced by TGF-beta1 is dependent on cell adhesive events that have yet to be fully characterized. Myofibroblast differentiation is associated with the assembly/activation of a submembranous, adhesive, cytoskeletal complex that results in the generation of extracellular H2O2. We hypothesize that myofibroblast-derived H2O2mediates oxidative cross-linking of ECM proteins that alters the substratum for fibroblasts, promoting further myofibroblast differentiation and, thereby, resulting in a selfperpetuating, positive feedback loop, leading to an unrelenting fibrotic process. Our specific aims are to: (1) Define signaling pathways that regulate myofibroblast differentiation: requirement for combinatorial signal integration of TGF-beta1 and cell adhesive signaling, (2) Characterize the H2O2-generating oxidase in myofibroblasts: association with focal adhesion and actin cytoskeleton, and (3) Examine
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Pulmonary Fibrosis
physiologic/pathophysiologic effects of the myofibroblast- derived oxidants: role in oxidative cross-linking of ECM proteins. It is anticipated that completion of these studies will provide a better understanding of myofibroblast biology that will aid in the development of novel, targeted therapies for fibrotic diseases in which myofibroblasts play an active role including idiopathic pulmonary fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PATHOLOGICAL CONSEQUENCES OF THE PLASMINOGEN SYSTEM Principal Investigator & Institution: Ploplis, Victoria A.; Research Professor; Chemistry and Biochemistry; University of Notre Dame 511 Main Bldg Notre Dame, in 46556 Timing: Fiscal Year 2002; Project Start 01-MAR-1999; Project End 31-MAR-2004 Summary: The long-term goal of this proposal is to test hypothesized functions of the plasminogen system in defined physiological and pathological processes utilizing gene knock-out mice and to identify previously unrecognized functions of this system. The contribution of the plasminogen system in hemostasis, through plasmin's ability to directly degrade fibrin, has been extensively analyzed and is well accepted. The identification of receptors for components of the plasminogen system on a number of cell surfaces implicates plasmin in playing a role in cell migratory events such as the inflammatory response. Paramount to this response and other cell migratory events is the degradation of extracellular matrix. Plasmin is believed to play a major role in this process either directly or through activation of other matrix degrading proteins, i.e., metalloproteases. The inflammatory response is associated with the early stages of a number of pathologies, such as pulmonary fibrosis and atheroscelerosis and regulation of these early events may dictate the clinical outcome of these diseases. The availability of gene knock-out mice to all components of the plasminogen system offers an unique opportunity to analyze, in vivo, in a mechanistic fashion its function in these pathologies. In this study mice deficient for components of the plasminogen system will be challenged utilizing two models of inflammatory diseases, pulmonary fibrosis and atherosclerosis. The effect components of the plasminogen system has on events associated with both early inflammatory response and later stages of these diseases will be investigated. Utilizing these gene knock-out mice, this proposal will specifically: (1) study bleomycin induced pulmonary fibrosis by assessing early inflammatory events; alterations in the integrity of the capillary/alveolar wall integrity; lesion development; and metalloprotease involvement. (2) study copper cuff induced atherosclerosis by determine qualitative and quantitative changes in the vessel wall and lumen utilizing a battery of histological and immunohistological techniques. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: RECEPTORS
PILOT--CHEMICAL
PROFILING
OF
ORPHAN
NUCLEAR
Principal Investigator & Institution: Downes, Michael; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2007 Summary: A solid clinical rationale exists for the discovery of novel orphan nuclear receptor (ONR) therapeutic ligands. The intimate associate, for example, between PPARgamma and carbohydrate and lipid metabolism, for example, finds clear expression in a variety of metabolic and aging disorders from atherosclerosis and lipid metabolism, for example, finds clear expression in a variety of metabolic and aging
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disorders, from atherosclerosis and diabetes, to Alzheimer's disease, decreased skin elasticity, male erectile dysfunction, pulmonary fibrosis, and atherosclerosis, and ocular diseases such as diabetic retinopathy, glaucoma, cataract formation, and age-related macular degeneration (AMD). This proposal will focus on the discovery of novel chemical tools for the purpose of advancing ONR research. A technology platform will be assembled that will facilitate the screening of chemical compound libraries for molecules able to modulate ONR-mediated transcription. Chemical screens that will be established to achieve this objective will consist of both in vivo and in vitro bas assays developed specifically for a high throughput (HTS) 384 well format. The assays developed exploit the agonist induced association of receptor ligand binding domains (LBDs) with nuclear receptor co-regulators and their derivative peptides. Currently we have diverse 18000 chemical compound library of mostly synthetic compounds that we have demonstrated to be viable for screening against ONRs. A pilot a screen of these compounds against FXR and identified novel compounds that robustly activate transcription of this ONR. The major goal of this project is to identify potent, specific compounds and make them freely available to the academic community to contribute high quality and unrestricted research on ONR function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PKCEPSILON-RELATED PROTEINS IN LUNG FIBROSIS Principal Investigator & Institution: Hoffman, Stanley R.; Associate Professor of Medicine and Cell; Medicine; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): This RFA asks investigators to identify novel targets that play a role in fibrogenesis, then to validate that altering the expression or function of targets does indeed inhibit pulmonary fibrosis. We already have identified a set of interconnected novel targets and have partially validated one target. Our central target is the e isoform of protein kinase C (PKC-epsilon). Cells cultured from the fibrotic lung tissue of scleroderma patients have altered PKC-epsilon signaling. The extracellular matrix protein tenascin is overexpressed in scleroderma lung fibroblasts due to altered PKC-epsilon signaling. Altered PKC-epsilon signaling is also revealed by the facts that: 1) Curcumin, from the Indian spice turmeric, inhibits collagen expression in scleroderma lung fibroblasts then causes the cells to undergo apoptosis while normal lung fibroblasts are unaffected by curcumin; and 2) Scleroderma lung fibroblasts can be made curcuminresistant by PKC-epsilon overexpression while PKC-epsilon depletion makes normal cells sensitive to curcumin. Moreover, three "binding partners" for PKC-epsilon (calponin, caveolin- 1, and RACK2) have altered levels of expression and subcellular localizations in scleroderma lung fibroblasts. The overexpression of tenascin and calponin in vivo has been confirmed in sections of lung tissue from scleroderma patients. Based on these observations, we will test the hypothesis that altering the expression or function of PKC-epsilon, of tenascin, or of binding partners for PKCepsilon will inhibit pulmonary fibrosis. Experiments will be performed using: 1) Cultured lung fibroblasts from scleroderma patients and matched normal subjects and 2) Mice in which lung fibrosis in induced using bleomycin. Specifically we will: 1) Optimize the delivery of potential treatments via lentivirus into the lungs of mice. 2) Perturb PKC-epsilon expression and function using curcumin, using virus that enhance or inhibit PKC-epsilon expression, and using a peptide that blocks PKC-epsilon translocation and function. These experiments will include a determination of why scleroderma fibroblasts are particularly sensitive to curcumin. 3) Perturb the expression
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Pulmonary Fibrosis
of PKC-epsilon binding partners using virus. 4) Inhibit tenascin expression using virus and test the idea that tenascin is a downstream mediator of the effects observed when PKC-epsilon expression is manipulated. The effects of these perturbations will be read out in terms of collagen expression and curcumin-induced apoptosis in cell cultures and in terms of survival, lung tissue morphology, and collagen levels in bleomycin-treated mice. These approaches will allow us to validate the role in lung fibrosis of the several target proteins that we have already identified. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PLASMIN, FIBRIN, AND METALLOPROTEINASES IN LUNG FIBROSIS Principal Investigator & Institution: Sisson, Thomas H.; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 20-AUG-2000; Project End 31-JUL-2005 Summary: The outlined proposal is designed as a training program that builds on prior experiences and ultimately leads to a career of independent research. Included in this program for the applicant is the introduction of new experimental techniques, investigation of a new area of basic science, and interaction with a new mentor. The research project will investigate an important aspect of the development of pulmonary fibrosis. Pulmonary fibrosis has been shown to occur in conjunction with depressed alveolar plasminogen activator activity. This impaired activity occurs from an imbalance between urokinase-type plasminogen activator (uPA) and its major inhibitor, plasminogen activator inhibitor-1 (PAI-1). Enhancing alveolar plasminogen activator activity through various means including targeted deletion of the PAI-1 gene or adenoviral-mediated gene transfer of the uPA cDNA results in decreased collagen accumulation following a fibrogenic insult. The mechanism by which enhanced alveolar plaminogen activator activity mitigates fibrosis is unknown. Insights into this mechanism may lead to new treatments. Of several possibilities, two mechanisms are most likely. The hypothesis of this proposal is that enhanced alveolar plasminogen activator activity may reduce fibrosis by removing the provisional fibrin matrix or by increased levels of matrix metalloproteinases (MMPs). To test this hypothesis, 3 models of enhanced alveolar plasminogen activator activity will be employed. These models include a PAI-1 deficient transgenic mouse, adenoviral-mediated gene transfer of the uPA cDNA to the alveolar space, and an inducible lung-specific uPA expressing transgenic mouse. In addition, to investigate the importance of fibrin in lung scarring, a fibrinogen deficient transgenic mouse will be employed. With these models, differences in fibrin accumulation and MMP activation in mice protected from fibrosis will be compared to susceptible controls. The opportunities provided by the training program will provide the foundation for career advancement and hopefully lead to new therapies for fibrotic lung diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PROTEOGLYCANS IN LUNG INFLAMMATION AND FIBROSIS Principal Investigator & Institution: Park, Pyong; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): Pulmonary fibrosis (PF) is an interstitial lung disease associated with high mortality. PF pathogenesis is a complex process where dysregulated inflammatory responses are thought to lead to the fibrotic phenotype. The
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molecular details of this dysregulated host response are not fully understood. Many potential mediators of PF pathogenesis have been identified during the last several decades. However, the mechanism as to how their activities are integrated and regulated during PF pathogenesis is poorly understood. Available data indicate that heparan sulfate proteoglycans (HSPGs) can regulate the activity of many key mediators of PF. Syndecan- 1 is the major cell surface HSPG of epithelia, including airway and alveolar epithelia. Activation of syndecan-1 shedding is one of the general host responses to tissue injury and inflammation, and shedding is activated in mice instilled with bleomycin, a potent inducer of lung inflammation and PF in humans and animals. Syndecan-1 is shed by metalloproteinases, such as matrix metalloproteinase (MMP)-7. The long-term objective of this research is to delineate how cell surface HSPGs regulate, in part, the highly complex mechanisms of PF pathogenesis. This proposal focuses on syndecan-1, and the goal is to define how syndecan-1 and its shedding function in lung inflammation and fibrosis. Four inter-related hypotheses will be tested in four Specific Aims: 1. Activation of syndecan-1 shedding by MMP-7 leads to the development of lung inflammation and fibrosis will be assessed by defining the molecular details of the syndecan-1-MMP-7 interactions; 2. Syndecan-1 ectodomains regulate lung inflammation and fibrosis by modulating chemokines will be evaluated by determining how syndecan-1 binds to the CXC chemokine KC and affects it's functions; 3. PF will be attenuated in the absence of syndecan-1, but exacerbated in the excess of syndecan-1 will be probed by determining how syndecan-1 null and overexpressing mice respond to bleomycin; and 4. Syndecan-1 shedding is activated in human PF will be assessed by measuring levels of shed syndecan-1 in bronchoalveolar lavage fluids and serum of patients with PF and other lung diseases. These studies, which will delineate how cell surface HSPGs such as syndecan-1 function during the pathogenesis of lung inflammation and fibrosis, should provide a foundation for the development of novel therapeutic agents and screening methods to combat PF and other lung diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PULMONARY HYPERTENSION FOLLOWING INTERMITTENT HYPOXIA Principal Investigator & Institution: Fagan, Karen A.; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Pulmonary hypertension (PHTN) is common in diseases characterized by chronic hypoxia (CH) (i.e. COPD, IPF) and occurs in 15-40% of patients with sleep apnea. Intermittent hypoxia (IH) mimicking the hypoxiareoxygenation cycles of sleep apnea causes systemic hypertension and altered regulation of systemic vascular tone. However, the effect of intermittent hypoxia on the pulmonary circulation is unknown. Recently, patients with sleep apnea-induced PHTN were found to have exaggerated hypoxic pulmonary vasoconstriction. Unlike in chronic hypoxia, hypoxia in sleep apnea is not continuous, thus the mechanisms causing sleep apneainduced PHTN are likely different from chronic hypoxia-induced PHTN. We therefore hypothesize that intermittent hypoxia leads to pulmonary hypertension by differential expression of genes important in regulating pulmonary vascular tone. Specifically, we hypothesize that oxidant stress in IH increases NOS and decreases SOD leading to PHTN through increased formation of peroxynitrite thus decreasing NO available for cellular effects such as attenuating vasoconstriction and mediating vasodilation. We further hypothesize that IH activates redox sensitive transcription factors leading to differential lung gone expression compared to CH. We will present data showing IH-
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Pulmonary Fibrosis
induced PHTN in both rats and mice. We also will present data showing differential expression of NOS (nitric oxide synthase) and SOD (superoxide dismutase) in the lung following IH compared to CH, which may contribute to IH-induced PHTN through increased oxidant stress and decreased NO activity. This proposal will address the questions: 1) does repetitive hypoxia-reoxygenation causes pulmonary hypertension, 2) that despite increased NOS, NO appears to be insufficient to prevent IH-induced PHTN, 3) decreased SOD may contribute to IH-induced PHTN by increasing oxidant stress and formation of peroxynitrite, and 4) does IH leads to differential gene expression through activation of specific signaling pathways compared to CH. We will correlate physiologic measures of PHTN and pulmonary vascular tone with expression and activity of NOS and SOD, measurements of oxidant stress and NO, and activation of specific signaling pathways leading to altered gone expression in IH. This proposal, for the first time, will identify the consequences of IH in the pulmonary circulation. Understanding mechanisms contributing to the development of PHTN in IH may lead improved cardiovascular morbidity and mortality in this common disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: QUANTATIVE PATHOGENESIS
IMAGE
ANALYSIS
MODELS
OF
IPF
Principal Investigator & Institution: Goldin, Jonathan G.; Acting Section Chief; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Abstract) Recently, imbalance in angiogenesis, dysregulation of the extra cellular matrix and fibroproliferation rather than inflammation has been postulated to perpetuate lung fibrosis in IPF. Detection of alveolitis may therefore have little prognostic or pathogenic relevance in the assessment of these cases. The heterogeneous pathology of UIP results in BAL and trans-bronchial biopsy (TBBx) to be subject to sampling errors compounding attempts to elucidate pathogenic pathways. A noninvasive mechanism to provide a "morphometric" assessment of the whole lung on a global and regional basis would be ideal. Quantitative Image Analysis (QIA) of HRCT data has shown a correlation with inflammation, angiogenesis and fibrosis and can identify these independent manifestations of IPF on a global and regional basis not possible with bronchoscopy or visual inspection of HRCT. The hypothesis is: CT-QIA can better detect the presence, extent and progression of inflammation, angiogenesis and fibrosis in patients with ILD and so can be used to distinguish patients with UIP, DIP, NSIP or NSIP with fibrosis not possible with conventional clinical, radiographic and physiologic assessment or with sampling limited BAL and TBBx. The specific aims are to 1) develop a CT-QIA model of pulmonary fibrosis in a murine model capable of assessing the development and progression of pulmonary fibrosis 2) develop a CT-QIA model of IPF capable of distinguishing inflammation, angiogenesis and fibrosis to better characterize patients with clinically diagnosed ILD with respect to pathologically defined UIP, DIP, NSIP and NSIP with fibrosis and 3) to determine the relative progression of inflammation, angiogenesis and fibrosis in patients with clinically assessed IPF treated with Prednisone alone, or IFN-gamma and low-dose prednisone or azathioprine plus prednisone. The main objective of this project is to distinguish between angiogenesis, inflammation and fibrosis in the pathogenesis of IPF in order to better characterize their relationship to the pathogenesis of IPF and to distinguish patients with UIP, DIP, NSIP or NSIP with fibrosis not possible with conventional techniques.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RADIATION PROTECTION CANCER THERAPY WITH AN SOD MIMETIC Principal Investigator & Institution: Gammans, Richard E.; Incara Pharmaceuticals Corporation Box 14287, 79 Tw Alexander Dr Research Triangle Park, Nc 27709 Timing: Fiscal Year 2003; Project Start 14-AUG-2003; Project End 31-JAN-2004 Summary: (provided by applicant): Phase I. In the treatment of cancer, radiation therapy has been limited by the tolerance of the surrounding normal tissues, such as lung or mucosa. Until now, there have been no compounds available that protect the normal tissues without reducing the tumor response to radiation therapy. The overall goal of this project is to develop a new approach to radiation therapy for cancer, based on the recently discovered radioprotective effects of novel synthetic catalytic SOD mimetic compounds. These compounds may also independently inhibit tumor growth under certain conditions. In Phase 1 of this SBIR application specific SOD mimetics will have demonstrated effectiveness in animal models of radiation therapy of human cancers. The proposed study will specifically research a selected compound in preparation for human studies directed at enhancing the efficacy of radiation therapy. The goal is to both increase tolerance of normal tissues to radiation therapy and retain or increase the net anti-tumor effects. Well-established functional, radiographic and histopathologic end-points will be used to assess possible mechanisms behind this compound's radioprotective effect in rat and hamster models of radiation-induced injury. Models of both radiation-induced mucositis and radiation-induced lung fibrosis will be studied. The antitumor effect of the selected SOD mimetic given alone or in combination with radiation therapy will be evaluated by using standard tumor growth delay assays. This new strategy of utilizing a single compound with both anti-tumor and radioprotective properties in combination with radiotherapy could result in an improvement in patient survival with a concomitant reduction in the risk of complications. The potential of independent tumor growth inhibition by the SOD mimetics would be an additional benefit. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: RARE LUNG DISEASE CLINICAL RESEARCH NETWORK Principal Investigator & Institution: Trapnell, Bruce C.; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): We seek to a establish a research network that will facilitate clinical research in rare lung diseases by 1) promoting collaboration among centers already focused to clinical research on rare lung diseases, 2) attracting & training highly qualified investigators, 3) collecting clinical data from geographically distributed patients into a large, centralized database, and 4) making the accumulated clinical data available to those affected or possibly affected by a rare lung disease, their clinicians, clinical and basic investigators and the general public. Disorders chosen for the initial focus of this network include: alpha-1 antitrypsin deficiency (AATD), lymphangioleiomyomatosis (LAM), pulmonary alveolar proteinosis (PAP) and hereditary idiopathic pulmonary fibrosis (hIPF). The network consists of clinical centers in Ohio (the coordinating center), Colorado, Florida, Maryland, Massachusetts, Oregon, South Carolina and Texas, as well as in Japan and Australia. Centers are required to have and maintain an exemplary record of active clinical research and an adequate rare
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Pulmonary Fibrosis
lung disease patient base. Participating patient support groups include the Alpha-1 Foundation, LAM Foundation and the Pulmonary Fibrosis Foundation. Many of these centers already work together closely. These centers and Foundations are also already closely integrated. For example, the Scientific Directors of all three participating foundations are active clinical investigators at clinical sites within the network. Furthermore, clinical sites were chosen from three currently active networks of collaborating clinical centers that include over 50 sites in 24 states distributed throughout the United States. All participating domestic clinical sites are associated with an active, NIH-supported general clinical research center (GCRC). Each center provides components required of the proposed network including ongoing longitudinal clinical studies, an excellent clinical training program, an active clinical research trials program designed to test novel therapies, develop diagnostic tests or evaluate outcome measures for rare lung diseases. Each of the Foundations provide education for patients, the lay public and the medical community. Importantly, one consequence of preparing this application has been the formation of the "Rare Lung Disease Foundation Consortium," which permits patient support groups with greater infrastructure to "nurture" the growth of less well-developed groups. It also provides support for individuals affected by a rare lung disease for which there is currently no foundation. Ongoing clinical, basic and translational studies at the centers chosen have already yielded critical insights into molecular mechanisms underlying lung function and defense in health and disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF COLLAGEN FORMATION IN PULMONARY FIBROSIS Principal Investigator & Institution: Goldstein, Ronald H.; Professor; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2006 Summary: The activation of myofibroblast is a central feature of interstitial pulmonary fibrosis. The objective of this proposal is to examine the regulation of the lung myofibroblast phenotype with an emphasis on the signal transduction pathways utilized by these cells to increase matrix deposition. Following lung injury in vivo, fibroblasts in the interstitial wall display a myofibroblast phenotype with increased expression of alpha-smooth muscle actin and alpha1(I) collagen mRNA. We have shown that prostaglandin E2 (PGE2) down-regulated steady state levels for alpha1(I) collagen, connective tissue growth factor and alpha- smooth muscle actin mRNA. PGE2 also stimulated Ca2+ activated K+ channels that decrease cell volume, and sensitized the cells to death receptor mediated apoptosis. These results indicate that PGE2 inhibits expression of the myofibroblast phenotype and has significant anti-fibrogenic properties. Preliminary data indicate that treatment of fibroblasts with PGE2 causes decreases in phosphatidylinositiol 3-kinase (PI-3K) as assessed by levels of phosphorylated protein kinase B/Akt. Employing inhibitors to PI-3K and mutant Akt constructs, we find that the activity of the PI-3K system regulates the stability of the alpha1(I) collagen mRNA. We hypothesize that fibroblast activation and the development of the myofibroblast phenotype involves an up- regulation in the activity of the PI-3K signal transduction pathways which in turn up-regulates alpha1(I) collagen and alpha- smooth muscle actin mRNA expression. PGE2 down-regulates these processes by affecting PI-3K activity and decreasing cell hydration. We plan to use cellular and molecular approaches to test our hypothesis in vitro and in vivo. Our studies will provide new insights into the regulation of the myofibroblast and suggest new therapeutic options for the treatment of pulmonary fibrosis.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF HOST RESPONSE GENES IN PATHOGENESIS OF TB Principal Investigator & Institution: Roman, Jesse R.; Division Director; Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 10-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death worldwide. Our inability to control the spread of this disease and the absence of new effective chemotherapeutic agents are due in part to the limited knowledge about host genes that control granuloma formation and other aspects of the host's response to this pathogen in lung. One host response considered important in tuberculosis is that of tissue remodeling which is characterized by alterations in extracellular matrix expression and degradation. Tissue remodeling is responsible for the development of Mtb- mediated fibrosis, bronchiectasis, and cavitation. Although these processes are often considered late manifestations of pulmonary tuberculosis, mounting evidence suggests that the genes involved in the control of tissue remodeling (TR genes) are expressed very early in lung after Mtb infection, and are involved in other key processes including leukocyte recruitment and granuloma formation. Consistent with this, we have demonstrated that: 1) Mtb Erdman bacilli and isolated cell wall components of Mtb induce the expression of TR genes encoding for extracellular matrices, matrix-degrading proteases, and pro-fibrotic growth factors in vitro (i.e., human monocyte/macrophages) and in vivo (C57BL/6 mice). In mice, the induction of TR genes correlated both spatially and temporally with the inflammatory response. 2) The induction of TR genes in monocyte/macrophages by Mtb occurs via receptormediated protein kinase pathways and requires the induction of specific transcription factors (e.g., AP-1). 3) The injection of trehalose-6,6'-dimycolate (previously called mycobacterial cord factor) or live Mtb Erdman strain into mice with knockout mutations in a TR gene (Matrix Metalloproteinase-9) resulted in increased inflammation and granuloma formation. Together, this information suggests that the interaction between Mtb and host cells triggers TR gene expression; in turn, the products of TR genes play important roles in the host response to Mtb. The overall goal of this application is to identify the TR genes that are differentially expressed in pulmonary tuberculosis and study their function. This will be accomplished in 3 specific aims designed to: 1) Identify host TR genes differentially expressed in vitro in human monocyte/macrophages after infection with Mtb using High Density Oligonucleotide Array or HDOA. 2) Identify the TR genes differentially expressed in the lungs of infected mice and in the lungs of humans with pulmonary tuberculosis using HDOA. 3) Determine the function of specific TR genes identified in Specific Aims I and II by infection of mice with gene knockout mutations. We propose to study the function of 3 (at the most 4) TR genes. We will begin exploring the function of 2 TR genes encoding for matrix metalloproteinases which we have demonstrated to be differentially expressed in Mtb-infected lungs and for which knockout animals are already available in our laboratory. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATION OF INTEGRIN FUNCTION Principal Investigator & Institution: Chapman, Harold A.; Professor; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-JAN-1991; Project End 31-DEC-2004
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Summary: Integrin function is intimately linked to many facets of lung biology including morphogenesis, inflammation, remodeling in the setting of injury, and tumor progression. Although the expression pattern and ligand specificity Of integrin heterodimers is well defined, regulation Of integrin function is much less well understood. Recent studies indicate that the function of a set of beta 1 and 2 integrins is regulated by the urokinase receptor (uPAR), a glycolipid-anchored non-integrin membrane protein. These studies reveal that uPAR, integrins, and a third membrane protein caveolin form a tri-partite complex which regulates integrin signaling. The recent identification of a uPAR binding site on the o' chain of the 132 integrin Mac-I (cDI lb1CDI8) verifies the direct association of uPAR with integrins and provides new insight into how integrins partn,er with other membrane proteins. On the basis of these recent studies it is proposed that BAR and caveolin promote 13land 132 integrin function by coordinately regulating Src family kinase activation during ligand engagement by these adhesion receptors Experiments are proposed to define further the interaction site between uPAR and Mac-I and use this information to loca1ize a binding site on 131 integrins. A goal of this line of experiments is to identify peptide-based reagents which disrupt uPARIintegrin/caveolin complexes. Caveolindeficient epithelial cells with defective 131 integrin signaling will be transfected with caveolin mutants and isotypes to elucidate mechanisms underlying caveolin's role in integrin regulation. The capacity of uPAR to regulate tyrosine kinases and phosphatases surrounding integrins will be tested in these cells and in macrophages. Reagents disrupting integrin/caveolin complexes will be used in murine models of neutrophil, monocyte, and eosinophil pulmonary inflammatory responses in vivo. The goals of the application are to understand the basic mechanisms through which uPAR and caveolin interact with and modify the signaling capacity of integrins and to determine whether agents which inhibit these interactions have the potential to regulate integrin function in vivo. Results of these experiments could provide a novel approach to regulation of integrin function in the setting of disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF PULMONARY ELASTIN PRODUCTION BY RETINOIDS Principal Investigator & Institution: Mcgowan, Stephen E.; Associate Professor; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2000; Project Start 01-SEP-1997; Project End 31-AUG-2004 Summary: Destructive inflammatory lung diseases lung diseases such as emphysema and bronchiectasis can irreversibly alter the elastic properties of the lung by degradation of the structural protein elastin. Since virtually all of the elastin in the normal lung is produced during early like, studying the factors which regulate elastin synthesis and deposition, and to ultimately repair the elastin network that is damaged in disease. Hypothesis: The perinatal lung contains a supply of retinoids, that it may use during the period of maximal alveolar septal elastin synthesis. Retinoids, and in particular retinoic acid (RA), may promote elastin synthesis by interstitial lung fibroblasts (LIF) and modulate the increase in elastin synthesis that is required for normal alveolar septal formation. Preliminary studies show that the quantities of RA and retinoic acid receptorgamma mRNA and protein in neonatal rat lung fibroblasts change in a temporal pattern that suggests they could help initiate an increase in elastin synthesis by these cells. Additional studies show that RA increases elastin production by cultured neonatal LIF and acts at the level of transcription. The major goal of the proposed research is to examine the molecular mechanisms by which RA may influence elastin synthesis during
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normal alveolar development. The acquisition and metabolism of retinoids by lung tissue and isolated LIF will be examined to assess the utilization of endogenous pulmonary stores. The basal and RA- induced expression of the various retinoic acid receptor (RAR) and retinoid-X receptor (RXR) genes will be studied in cultured rat LIF and in LIF isolated from RAR-gamma null mice. RAR and RXR mRNA and protein will be quantitated using ribonuclease protection assays and immunoblotting, respectively. The effects of a dominant negative RAR mutation of elastin expression will be examined in cultured cells. Elastin mRNA, insoluble elastin accumulation, and alveolar growth will be studied in mice bearing gene deletions for RAR-gamma and/or RXR-alpha. The molecular details of the effects of RA on the elastin gene will be elucidated by deletional analysis and mutagenesis of two potential RA response elements (RARE) within the 5' flanking region of the rat elastin gene. Electrophorectic mobility shift assays will be used to demonstrate RA-responsive increases in the binding of nuclear proteins to these elements, in cultured LIF and in the developing lung. A ligation-mediated polymerase chain reaction will be used to evaluate binding of proteins to these putative RARE in the elastin gene in vivo during lung development, and in response to exogenous RA. Elucidation of mechanisms whereby elastin synthesis is initiated in the alveoli would provide novel information that may also be applicable to idiopathic pulmonary fibrosis and bronchopulmonary dysplasia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF SILICA INDUCED ICAM1 EXPRESSION IN MICE Principal Investigator & Institution: Hubbard, Andrea K.; Associate Professor; Pharmaceutical Sciences; University of Connecticut Storrs Unit 1133 Storrs-Mansfield, Ct 06269 Timing: Fiscal Year 1999; Project Start 01-SEP-1999; Project End 31-AUG-2004 Summary: (Adapted from the Investigator's Abstract) In a mouse model of silica induced pulmonary inflammation and fibrosis developed in this laboratory, silica exposure increases expression of ICAM-1 on lung (alveolar~interstitial) macrophages and type II epithelial cells. By understanding the role and regulation of silica induced ICAM-1 expression in lung macrophages, it may be possible to modulate its expression, alter leukocyte trafficking and suppress lung injury. Using murine macrophages in vitro, this proposal will test the following hypothesis: Silica induced ICAM-1 expression in lung macrophages participates as a signal transduction molecule and is regulated, in part, by cytokines (TNFalpha, Il-1beta, IFNgamma) released in response to silica exposure. Specific Aim I:. To test the hypothesis that silica induced ICAM-1 expression participates in the ability of silica exposed murine macrophages to generate critical inflammatory mediators involved in particle induced pulmonary inflammation. Mouse macrophages (primary culture, a cell line) will be stimulated in vitro with silica particles to increase ICAM 1 expression. ICAM-1 -mediated signal transduction will then be activated either by the addition of rat anti-mouse ICAM antibody and a cross linking antibody or by co-culture with MAC-1 positive peritoneal PMNS. Products of this activation [cytokine (TNFalpha, IL-1beta, IFNgamma) release, reactive oxygen species and nitric oxide, ICAM-1 protein expression, transcription factor (NFkB, AP-1) activation] will be measured. Specific Aim 2: To test the hypothesis that TNFalpha, IL1beta, IFNgamma) participate in silica induced ICAM-1 expression. Mouse macrophages (primary culture, cell line) will be activated in vitro with silica particles and ICAM-1 protein expression, mRNA levels and promoter activation will be measured in the presence or absence of specific anti-cytokine antibodies. Mouse
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macrophages will also be exposed to these cytokines (individually or in combination) in the absence of silica to determine if these mediators will elicit ICAM-1 expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHROMIUM
REGULATION
OF
TRANSCRIPTIONAL
COMPETENCE
BY
Principal Investigator & Institution: Barchowsky, Aaron; Associate Professor; Pharmacology and Toxicology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2003 Summary: Hexavalent chromium (Cr(VI)) is in the top 20 compounds of the ATSDR/EPA priority list since it promotes interstitial lung fibrosis, induces asthma, and is recognized as a probable human lung carcinogen. Despite the epidemiological evidence for both occupationally and environmentally-derived pulmonary disease following inhalation of Cr(VI), there are few studies that define the cellular and molecular basis for pathologic changes in the Cr(VI)-exposed lung. Overall Objective: The overall objective of the proposed studies is to define the molecular signaling mechanisms through which non-cytotoxic concentrations of Cr(VI) alter inducible cytokine and profibrotic gene expression in airway and alveolar epithelial cells. We have recently defined a novel pathway through which Cr(VI) inhibits the transcriptional competence of the transcription factor NF-kappaB by promoting recruitment of the essential co-activator CREB-binding protein (CBP) to c-Jun. We hypothesize that Cr(VI)induced alteration of co-activator recruitment changes the profile of inducible gene expression and potentiates Fas-induced apoptosis. These effects of Cr(VI) favor development of pulmonary fibrosis. Specific Objectives: Aim 1 of the grant will use human lung cells in culture to define cellular signaling pathways that regulate Cr(VI)induced recruitment of CBP to specific transcription factors (e.g. c-Jun). Aim 2 will use these models to demonstrate that competition for CBP is the rate limiting step in Cr(VI)induced loss of NF-kappaB transactivation. The consequence of a switch in CBPdependent transcription factor competence on FAS- induced apoptosis and gene expression will be examined. The final Aim will use normal and unique transgenic mouse models to examine Cr(VI)-induced regulation of transcription factor activity and of inducible pro-apoptotic and pro-fibrotic phenotypic changes in vivo. Significance: The studies will define fundamental epigenetic mechanisms for altered inducible gene expression and increased susceptibility of airway and alveolar epithelial cells to apoptosis following exposure to Cr(VI). Apoptosis of the airway is now recognized as an underlying non-inflammatory mechanism for lung fibrosis. Thus, these studies will translate observations in cell culture into in vivo models of exposure to greatly improve the basic understanding of how Cr(VI) promotes pulmonary diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REMODELING OF HUMAN AIRWAYS IN DISEASE Principal Investigator & Institution: Pare, Peter D.; University of British Columbia 2075 Wesbrook Pl Vancouver, Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: The structural changes that occur in the airways of patients who have obstructive lung disease are the result of the host response to tissue injury. This complex process is influenced by both the genetic makeup of the host and the environmental insults which incite the injury. There is marked inter-individual variation in the
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response to these insults and those who have an exaggerated repair reaction develop more airway obstruction due to fibrosis and scaring. The investigators will take advantage of a large clinical and tissue registry of more than 1400 patients which has been collected over the past 20 years. In addition recent technical advances in the precision of High Resolution Computed Tomography (HRCT) will be used to quantify airway dimensions in life in patients who have Asthma and COPD. The differences in the composition of the connective tissue, and smooth muscle proteins which accumulate in the airway walls of patients with these disorders will be measured using immunohistochemistry, western analysis and measurement of mRNA. The hypotheses that will be tested include: 1) that the airway wall thickening in obstructive airway disease can be measured accurately using HRCT, 2) that abnormal scaring of the airway is related to alterations in the ratios of Platelet Derived Growth Factor (PDGF) and Transforming Growth Factor beta (TGFbeta), and of the relative abundance of the three TGFbeta isoforms TGFbeta1, TGFbeta2, TGFbeta3, 3) that increased airway smooth muscle force generation in airway disease is due to increased expression of contractile proteins by the muscle and increased formation of a compliant extracellular matrix, and 4) that specific gene polymorphisms in key matrix proteins is at the basis of individual susceptibility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF CELL AND DEBRIS REMOVAL IN FIBROSIS Principal Investigator & Institution: Henson, Peter M.; Professor; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Abstract) Tissue damage and inflammation have long been associated with fibrotic changes during wound healing and in pulmonary fibrosis. Resolution of inflammatory lesions involves removal of apoptopic inflammatory cells by uptake into macrophages and surrounding tissue cells, such as epithelial cells and fibroblasts. We suggest that the engulfment of apoptotic cells is driven by a variety of adhesion ligands acting in conjunction with a critical receptor for phosphatidylserine (the PS receptor or PSR) that actually mediates the signaling for phagocytosis. Ingestion via this receptor also initiates the production of active TGF. This mediator then has important effects in limiting further generation of inflammatory mediators, as well as the potential to initiate fibroblast to myofibroblast phenotypic conversion and the process of fibrosis. It is further suggested that cell debris and membrane fragments are removed by similar mechanisms with similar consequences. To explore these suggestions, the PSR will be examined 1) for its potential ability to initiate myofibroblast conversion via a reciprocal feedback induction of TGF; 2) for its upregulation in cells adjacent to an area of damage with resultant ingestion of the damaged cells and fragments as well as local generation of TGF; and 3) for its potential role in mediating resolution of inflammation and progression to fibrosis. Because of the ability of PSR ligation to initiate TGF synthesis and secretion from a variety of cell types in vitro and in vivo, this proposal will also examine the mechanisms of this induction by determining the points in TGF synthesis, secretion and activation that are affected and to begin to examine the signaling pathways involved. Experiments will be performed in epithelial cells, fibroblasts and macrophages since each of these express the PSR, ingest apoptotic cells and respond by induction of TGF, although with different consequences. The in vivo studies will be carried out in murine models of inflammation and fibrosis and will make use of a number of valuable knockout strains. The overall objective is to examine
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in detail one potentially important mechanism for inducing the generation of myofibroblasts in the lung. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF SP-C IN FAMILIAL INTERSTITIAL LUNG DISEASE Principal Investigator & Institution: Glasser, Stephan W.; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2004; Project Start 01-JAN-1994; Project End 31-MAR-2008 Summary: (provided by applicant): The experimental aims of this grant are based upon the central hypothesis that insufficient levels of pulmonary surfactant protein C (SP-C) results in an inherited interstitial lung disease (ILD). Examples of familial ILD have been linked to either the absence of SP-C or expression of mutated forms of SP-C. The pathologic features of familial ILD are complex and variable. Identification of early events initiating the injury has been complicated by the diagnosis of ILD usually occurring after the disease is well established. We have used gene targeting to develop SP-C deficient (-/-) mice that develop a progressive injury similar to the complex human ILD/pulmonary fibrosis. The SP-C-/- mice are a novel model to investigate SP-C related familial ILD and will be used to determine requirements for early intervention to prevent or arrest disease progression (Aims 1 and 2) and to identify changes in gene expression and associated molecular pathways that occur at the onset of disease process (Aim 3). In Aim 1, the timing, levels, and cell specific requirements for SP-C replacement to alter ILD will be determined. Genetic restoration of SP-C in type II cells of SP-C-/mice at discrete ages will be accomplished using inducible transgene technology. The SP-C-/- mice develop early indications of pulmonary inflammation and lipid imbalance, which includes lipid-filled macrophages and interstitial cells. SP-C stimulates surfactant lipid reutilization. Aim 2 will deliver exogenous SP-C preparations to lungs of very young SP-C-/- mice to determine if alveolar SP-C reverses the progressive lipidosis. Lipid pool sizes, cell infiltrates will be quantitated and cellular changes within the alveolar interstitium determined by electronmicroscopy. Inflammatory changes are detected in the lungs of young SP-C-/- mice. Experiments in Aim 3 will test the hypothesis that SP-C reduces LPS stimulation of alveolar cells to prevent inflammation. Final experiments will identify changes in type II cell gene expression associated with the loss of SP-C. The aims of this application focus on correction of early stages of developing ILD, and to identifying early cellular changes and changes in gene expression that could be targets for therapeutic intervention. The SP-C-/- mice provide a novel model of human interstitial disease where the inductive sequences of events remain undefined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SCOR IN PATHOLOGY OF FIBROTIC LUNG DISEASE Principal Investigator & Institution: Strieter, Robert M.; Professor and Chief; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 05-SEP-2001; Project End 31-JUL-2006 Summary: (Applicant's Abstract) The objective of this SCOR proposal is to further understand the pathogenesis of pulmonary fibrosis as it relates to IPF. The central hypothesis of this proposal is that the pathogenesis of pulmonary fibrosis is due to "multiple hits" that perpetuates an imbalance of over-expression of specific proinflammatory/proangiogenic/pro-fibrogenic mediators and impaired innate immunity,
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as compared to anti -inflammatory/anti angiogenic/anti-fibrogenic factors and normal host defense. This paradigm predicts that perpetuation of inflammation, angiogenesis, fibrosis, and susceptibility to recurrent infections beyond what one would expect from immunosuppression alone; ultimately results in impaired innate immunity, susceptibility to infectious disease, and perpetuation of a pro-fibrogenic environment in EPF. This predisposes the IPF patient to more multiple hits" leading to a vicious cycle of impaired pulmonary function and eventual death. The recognition of these relationships, and to what extent these responses are altered by increased susceptibility to microbes, may yield important clues to more effective prevention and treatment of this process in humans. The SCOR will utilize a multidisciplinary approach to test this central hypothesis. This expertise consists of investigators trained in Pulmonary Diseases, Radiology, Pathology, Cell and Molecular Biology, and Biostatistics. The strengths of this proposal are the investigators, who have productive and collaborative interests in mechanisms related to pulmonary fibrosis. The exceptional institutional resources for biomedical research, the proven commitment to collaborative interaction by both clinicians and basic scientists, and the access to a large population of IPF patients will assure that the studies designed in this proposal will come to fruition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STRUCTURE/FUNCTION OF CONNECTIVE TISSUE GROWTH FACTOR Principal Investigator & Institution: Grotendorst, Gary R.; Professor; Cell Biology and Anatomy; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-AUG-2005 Summary: Fibrotic disorders represent the largest segment of human disease for the populations of North America, Europe and Japan. These disorders are characterized by an overproduction of connective tissue (primarily collagen) and are widely recognized to be initiated in response to some type of injury which leads to the chronic inflammation and subsequent overproduction of growth factors that encourage the formation of connective tissue. There are no current therapies short of transplant or grafts which are effective to control the progression of any fibrotic disorder. Intensive studies over the last 25 years now suggest that a common mechanism may underlie many of these disorders. Thus, an advancement in our understanding of the cellular and molecular control mechanisms which regulate this process could have a significant impact on a wide range of human diseases, including atherosclerosis, pulmonary fibrosis, glomerulosclerosis, arthritis, glaucoma, diabetic retinopathy and others. One common growth factor which has been demonstrated to be overproduced in all fibrotic disorders examined to date is TGFb, which is believed to be an initiator of the connective tissue formation in these disorders. During the course of our studies on mechanisms whereby TGFb stimulates connective tissue formation, we discovered another growth factor, Connective Tissue Growth Factor (CTG F). CTGF synthesis selectively induced in mesenchymal cells by TGFb. We have found that agents which block CTGF synthesis or action are effective inhibitors of TGFb induced fibroblastic cell proliferation and collagen synthesis. This suggests that CTGF may be an important therapeutic target for the control of connective tissue formation in fibrotic disorders. Recently, we have determined that the individual domains of CTGF are responsible for signaling either the mitogenic activity (C-terminal domain of CTGF) or matrigenic activity (N-terminal domain). Our data also indicate that CTGF has an absolute requirement for the presence of EGF for mitogenic and IGF-2 for matrigenic activity. The current project will determine in a more detailed manner the role of the CTGF, CTG F,
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lGF and EGF receptors and the roles of EGF and IGF factor for signaling the mitogenic and matrigenic actions induced by TGFb in fibroblastic cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SURVIVIN REGULATION OF PULMONARY FIBROSIS Principal Investigator & Institution: Noble, Paul Wesley.; Chief, Pulmonary Critical Care; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): Idiopathic Pulmonary Fibrosis (IPF) is a progressive and usually fatal lung disease characterized by fibroblast proliferation and extracellular matrix deposition causing irreversible distortion of lung architecture. The pathogenic mechanisms are largely unknown, but a recently identified hallmark of the pathology in fatal IPF are isolates foci of fibroblasts that acquire smooth muscle-like properties, termed myofibroblasts located at the leading edge of dense collagen interspersed with areas of preserved lung architecture. Progressive fibrosis despite anti-inflammatory therapies have challenged the concept that fibrosis occurs solely as a consequence of unremitting inflammation and has led to the development of new paradigms in pathogenesis. Identification of fibroblastic foci has led to the concept that IPF is a result of an abnormal wound healing response to an exogenous injury. Furthermore, the biology of IPF has been suggested to have parallels with cancer biology including increased angiogenesis, excessive growth factor production and a failure of myofibroblasts to undergo apoptosis. Survivin is a recently identified bifunctional protein that suppresses apoptosis and regulates cell division. It is expressed by most tumors but not in most normal tissues. Survivin expression is cell cycle dependent and requires phosphorylation by Cdc2 kinase to function as an inhibitor of apoptosis. It is upregulated by certain growth factors including VEGF and IGF- 1. Recent studies have suggested that survivin may be an important target in cancer therapy. Our preliminary studies suggest that survivin is exprssed in fibroblastic foci in both IPF and experimental lung fibrosis. This has led us to hypothesize that survivin may regulate the recruitment and maintenance of fibroblastic foci and could be a novel target for therapy of pulmonary fibrosis. We will investigate this hypothesis in the following Specific Aims: 1. Characterize survivin expression in Idiopathic Interstitial Pneumonis. 2. Determine the role of survivin in vivo in the initiation and progression of experimental pulmonary fibrosis. 3. Determine the role of survivin in regulating the IPF fibroblast phenotype in vitro. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: T CELL AND EOSINOPHIL RECRUITMENT IN LUNG FIBROSIS Principal Investigator & Institution: Tager, Andrew M.; Assistant in Medicine; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 04-AUG-1999; Project End 31-JUL-2004 Summary: With the proposed Mentored Clinical Scientist Development Award, the applicant will build upon his prior experiences investigating the biology of inflammation in the lung. Based on very positive experiences in the laboratory to date, the applicant is firmly committed to a career in academic pulmonary and critical care medicine. The laboratory of Dr. Andrew D. Luster at the Massachusetts General Hospital will provide a rich intellectual environment to foster the candidate's scientific development toward his goal of independent investigation. The present proposal
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provides the applicant the opportunity to master a broad range of current laboratory techniques in molecular and cellular biology, supplemented by a program of didactic study of immunology. The research project proposed focuses on pathogenic mechanisms of pulmonary fibrosis. Pulmonary fibrotic disorders appear to be initiated by inflammation of the lower respiratory tract, which causes activation and proliferation of mesenchymal cells, and results in increased extracellular matrix deposition. Data both from patients and animal models indicate T cells and eosinophils participate in the inflammation of the lower respiratory tract, which causes activation and proliferation of mesenchymal cells, and results in increased extracellular matrix deposition. Data both from patients and animal models indicate T cells and eosinophils participate in the inflammation initiating at least some of these disorders. The research proposed is based on the hypotheses that the recruitment of T cells, their polarization toward the Th2 phenotype, and the consequent recruitment of eosinophils contribute to the pathogenesis of pulmonary fibrotic disorders The applicant specifically proposes to: (1) Investigate the role of the T cell chemoattractant IP-10 (interferon-induced protein of 10 kd) in T cell recruitment in BLM-induced fibrosis; (2) investigate the balance of Th1 versus Th2 responses in BLM-induced fibrosis, and the role of cytokines and costimulatory molecules in determining this balance; and (3) investigate the role of Th2 cytokines, and the eosinophil chemoattractants eotaxin and LTB4 (leukotriene B4), in eosinophil recruitment in BLM- induced fibrosis. The last area of the research proposed will include the generation of mice genetically deficient for the recently described murine LTB4 receptor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TGFB AND GENE THERAPY IN SILICA INDUCED LUNG FIBROSIS Principal Investigator & Institution: Sime, Patricia J.; Assistant Professor of Medicine; Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: Inhalation of silica in mining, sandblasting and quarrying occupations results in serious, potentially life threatening, pulmonary inflammatory and fibrotic pathologies including acute and chronic (nodular pulmonary fibrosis) silicosis. Thus the first objective of this proposal is to determine the mechanisms underlying silica-induced pulmonary inflammation and fibrosis, particularly the role of the cytokine transforming growth factor beta 1(TGfb1). TGFb is strongly implicated in pulmonary fibrosis induced by silica and other agents. The second objective is to develop novel gene-based therapeutic strategies for treatment of these fibrotic pathologies. The hypothesis will be tested that activated TGFb is a key mediator of crystalline silica-mediated fibrosis, and if inhibited a fibrotic outcome can be prevented. Two different anti-TGFb strategies will be utilized. The first will involve adenoviral vector mediated overexpression of the core protein of the proteoglycan decorin in mouse lung. Decorin is a physiological inhibitor of active TGFb. The second strategy will exploit the inhibitory nature of the preproportion of the TGFb molecule itself, termed the LAP. Transgenic mice overexpressing LAP under control of the lung specific SP- C promoter will be used, and should produce prolonged inhibition of active TGFb. Unlike crystalline silica, amorphous silica induces inflammation, but not fibrogenesis. It is hypothesized that this is related to failure of amorphous silica to upregulate active TGFb. The concept will be tested that over-expression of low levels of active TGFb, in the context of ongoing amorphous silica-induced injury and inflammation, will drive silica-mediated inflammation to fibrogenesis. Assessment will also be made of the ability this inflammatory milieu itself to activate latent TGFb. Finally, to further address the
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mechanisms of inflammation and fibrogenesis induced by different silicas, their potential to activate fibroblasts in vitro will be examined. The PI of this project has just been recruited as faculty to the Depts. of Medicine and Environmental Medicine. She is committed to an academic career, and will spend 80% of her time in research studies. She has had previous training in inflammation, fibrogenesis and gene transfer, and now plans to expand her studies to investigate environmental and occupational lung disease. To achieve this she wishes to obtain additional training in environmental toxicology, and the role of the immune system in fibroblast activation. The environment in Rochester has a critical mass of international experts in these areas, whose interests are aligned with those of the PI. They will collaborate with the PI, and form her advisory committee. In conjunction with a formal education program me this should allow her to successfully develop as an independent investigator, while yielding new insights into the pathogenesis and treatment of fibrotic pathologies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TH2 CYTOKINES AND CC CHEMOKINES IN PULMONARY FIBROSIS Principal Investigator & Institution: Keane, Michael P.; Assistant Professor; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Abstract) The pathogenesis of idiopathic pulmonary fibrosis is charactenized by an intense inflammatory response with accompanying fibroproliferation and deposition of extracellular matrix. The initial stimulus for inflammatory cell recruitment and the mechanisms responsible for the perpetuation and evolution of chronic inflammation, granulation tissue formation, and fibrosis have not been fully elucidated. While IL-13, a Th2 cytokine, has been shown to have direct effects on fibroblasts that supports fibroproliferation it is also a potent inducer of a novel CC chemokine, CIO, which is chemotactic for mononuclear phagocytes. The macrophage/mononuclear phagocyte has been shown to have a pivotal role in the pathogenesis of pulmonary fibrosis, serving as an important source of growth factors that regulate extracellular matrix synthesis. We hypothesize that the cytokine pathway of IL-13 to C1O promotes pulmonary fibrosis via a mechanism that is independent of the direct effect of IL-13 on fibroblasts. The expression of IL-13 and its receptor leads to the induction of C10, which promotes recruitment of a specific population of pro-fibrotic macrophages. The specific aims are as follows: 1)A. To characterize the expression and regulation of C1O during the pathogenesis of bleomycin-induced pulmonary fibrosis. B. To determine the relative and specific contributions of IL-13 and CIO to the development of pulmonary fibrosis. 2) To compare and contrast the disparity between ligand/receptor expression of IL-4/IL4R and IL-13/IL-13R as they relate to the induction of CIO, and the subsequent development of pulmonary fibrosis. 3) To assess IL-13/IL-13R signal transduction pathways that lead to the induction of CIO, and the subsequent development of pulmonary fibrosis. 4) To establish that CIO recruits a distinct population of macrophages that induce pulmonary fibrosis. 5) To study the effect of administration of exogenous interferon-gamma to patients with IPF on the balance of Th1/Th2 cytokines and the expression of MIP-18 (human homologue of C1O), and to correlate these findings with clinical, radiological and physiological parameters of disease activity. In this project both the bleomycin and FITC models of pulmonary fibrosis will be used. Techniques to be employed include a variety of molecular, immunological and cellular bioassays. Successful completion of these specific
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aims will provide insight into a novel pathway for macrophage recruitment that may lead to new therapeutic interventions in IPF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THERAPEUTIC TARGETING OF RANTES/CCL5 IN FUNGAL ASTHMA. Principal Investigator & Institution: Hogaboam, Cory M.; Associate Professor; Pathology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Profound airway inflammation and airway remodeling accompanies responses to the fungus Aspergillus fumigatus, complicating asthma and cystic fibrosis. The introduction of A. fumigatus conidia into the airways of mice previously sensitized to A. fumigatus leads a fungal asthma-like disease characterized by elevated IgE and IgG1, and pulmonary expression of chemokines and Th2 cytokines. These events are also associated with a marked peribronchial accumulation of CD4+ T cells and eosinophils concomitant with marked airway hyperresponsiveness, goblet cell hyperplasia and peribronchial fibrosis. Previously, we have shown that the immunoneutralization of monocyte chemo-attractant protein-1 (MCP-1/CCL2) in A. fumigatus-sensitized mice challenged with conidia leads to aggressive fungal colonization due to a major compromise in the innate immune response. In contrast, we have observed that the immunoneutralization of regulated on T-cell activation, normal T cell expressed and secreted (RANTES/CCL5) does not impair the elimination of A. fumigatus and inhibits the development of chronic fungal asthma. Using this model, we will address the hypothesis that the selective targeting of RANTES/CCL5-responsive cells in the lung abolishes allergic effector and remodeling features of this model without compromising the necessary innate immune responses. This hypothesis will be addressed through the following three Specific Aims: 1) To determine the roles of RANTES/CCL5 in the pulmonary innate immune response against live A. fumigatus conidia. 2) To determine the mechanism through which iRANTES/CCL5 modulates the allergic effector responses mediated by T cells and eosinophils. 3) To determine the mechanism through which RANTES/CCL5 contributes to the persistent airway remodeling features such as goblet cell hyperplasia and peribronchial fibrosis that characterize chronic fungal asthma. These detailed studies are now possible because of the availability of novel chimeric protein that selectively targets RANTES/CCL5-responsive cells in the lung. 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
3 4
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.
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unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “pulmonary 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 pulmonary fibrosis in the PubMed Central database: •
A new direction in the pathogenesis of idiopathic pulmonary fibrosis? by Gauldie J, Kolb M, Sime PJ.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64807
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Altered prostanoid production by fibroblasts cultured from the lungs of human subjects with idiopathic pulmonary fibrosis. by Cruz-Gervis R, Stecenko AA, Dworski R, Lane KB, Loyd JE, Pierson R, King G, Brigham KL.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107846
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Analysis of IL-12 p40 subunit gene and IFN-[gamma] G5644A polymorphisms in Idiopathic Pulmonary Fibrosis. by Latsi P, Pantelidis P, Vassilakis D, Sato H, Welsh KI, du Bois RM.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=185252
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Bone marrow --derived progenitor cells in pulmonary fibrosis. by Hashimoto N, Jin H, Liu T, Chensue SW, Phan SH.; 2004 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=310750
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Coronary artery revascularization followed by single-lung transplantation in a patient with combined end-stage idiopathic pulmonary fibrosis and left main coronary artery stenosis. by La Francesca S, Shennib H.; 1995; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325241
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Expression of Monocyte Chemoattractant Protein 1 mRNA in Human Idiopathic Pulmonary Fibrosis. by Antoniades HN, Neville-Golden J, Galanopoulos T, Kradin RL, Valente AJ, Graves DT.; 1992 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49293
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Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. by Zuo F, Kaminski N, Eugui E, Allard J, Yakhini Z, Ben-Dor A, Lollini L, Morris D, Kim Y, DeLustro B, Sheppard D, Pardo A, Selman M, Heller RA.; 2002 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122942
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Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis. by Kaminski N, Allard JD, Pittet JF, Zuo F, Griffiths MJ, Morris D, Huang X, Sheppard D, Heller RA.; 2000 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26512
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Growth factors in idiopathic pulmonary fibrosis: relative roles. by Allen JT, Spiteri MA.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64811
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Herpesvirus DNA Is Consistently Detected in Lungs of Patients with Idiopathic Pulmonary Fibrosis. by Tang YW, Johnson JE, Browning PJ, Cruz-Gervis RA, Davis A, Graham BS, Brigham KL, Oates Jr. JA, Loyd JE, Stecenko AA.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156536
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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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Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder. by Selman M, Pardo A.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64814
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IL-7 inhibits fibroblast TGF-[beta] production and signaling in pulmonary fibrosis. by Huang M, Sharma S, Zhu LX, Keane MP, Luo J, Zhang L, Burdick MD, Lin YQ, Dohadwala M, Gardner B, Batra RK, Strieter RM, Dubinett SM.; 2002 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150933
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The bone marrow leaves its scar: new concepts in pulmonary fibrosis. by Dunsmore SE, Shapiro SD.; 2004 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=311440
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Transforming Growth Factor [beta]1 is Present at Sites of Extracellular Matrix Gene Expression in Human Pulmonary Fibrosis. by Broekelmann TJ, Limper AH, Colby TV, McDonald JA.; 1991 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52144
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 pulmonary fibrosis, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “pulmonary fibrosis” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for pulmonary fibrosis (hyperlinks lead to article summaries): •
A case of syphilitic interstitial pulmonary fibrosis. Author(s): Jankovic S, Mise K, Alujevic A, Tocilj J, Marasovic D, Andjelinovic S. Source: Croatian Medical Journal. 1998 December; 39(4): 453-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9841951
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A clinical study of idiopathic pulmonary fibrosis based on autopsy studies in elderly patients. Author(s): Araki T, Katsura H, Sawabe M, Kida K. Source: Intern Med. 2003 June; 42(6): 483-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12857045
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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 dark side of interferon-gamma in the treatment of idiopathic pulmonary fibrosis? Author(s): Selman M. Source: American Journal of Respiratory and Critical Care Medicine. 2003 April 1; 167(7): 945-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12663333
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A matrix for new ideas in pulmonary fibrosis. Author(s): Cook DN, Brass DM, Schwartz DA. Source: American Journal of Respiratory Cell and Molecular Biology. 2002 August; 27(2): 122-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12151302
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A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. Author(s): Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE Jr; Idiopathic Pulmonary Fibrosis Study Group. Source: The New England Journal of Medicine. 2004 January 8; 350(2): 125-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14711911
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A rearranged form of Epstein-Barr virus DNA is associated with idiopathic pulmonary fibrosis. Author(s): Kelly BG, Lok SS, Hasleton PS, Egan JJ, Stewart JP. Source: American Journal of Respiratory and Critical Care Medicine. 2002 August 15; 166(4): 510-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12186829
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A study of the cough reflex in idiopathic pulmonary fibrosis. Author(s): Hope-Gill BD, Hilldrup S, Davies C, Newton RP, Harrison NK. Source: American Journal of Respiratory and Critical Care Medicine. 2003 October 15; 168(8): 995-1002. Epub 2003 August 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12917229
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Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis. Author(s): Chilosi M, Poletti V, Zamo A, Lestani M, Montagna L, Piccoli P, Pedron S, Bertaso M, Scarpa A, Murer B, Cancellieri A, Maestro R, Semenzato G, Doglioni C. Source: American Journal of Pathology. 2003 May; 162(5): 1495-502. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12707032
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Abnormal re-epithelialization and lung remodeling in idiopathic pulmonary fibrosis: the role of deltaN-p63. Author(s): Chilosi M, Poletti V, Murer B, Lestani M, Cancellieri A, Montagna L, Piccoli P, Cangi G, Semenzato G, Doglioni C. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 2002 October; 82(10): 1335-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12379768
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Acute exacerbation of idiopathic pulmonary fibrosis: report of a series. Author(s): Ambrosini V, Cancellieri A, Chilosi M, Zompatori M, Trisolini R, Saragoni L, Poletti V. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 November; 22(5): 821-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14621091
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Acute respiratory failure after interferon-gamma therapy of end-stage pulmonary fibrosis. Author(s): Honore I, Nunes H, Groussard O, Kambouchner M, Chambellan A, Aubier M, Valeyre D, Crestani B. Source: American Journal of Respiratory and Critical Care Medicine. 2003 April 1; 167(7): 953-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12663336
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Acute respiratory failure and pulmonary fibrosis secondary to administration of mycophenolate mofetil. Author(s): Gross DC, Sasaki TM, Buick MK, Light JA. Source: Transplantation. 1997 December 15; 64(11): 1607-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9415567
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Allelic imbalance demonstrated by microsatellite analysis of lung samples from patients with familial pulmonary fibrosis. Author(s): Thomas AQ, Carneal J, Markin C, Lane KB, Phillips JA 3rd, Loyd JE. Source: Chest. 2002 March; 121(3 Suppl): 25S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11893660
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Amiodarone induced pulmonary fibrosis in infancy. Author(s): Bowers PN, Fields J, Schwartz D, Rosenfeld LE, Nehgme R. Source: Pacing and Clinical Electrophysiology : Pace. 1998 August; 21(8): 1665-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9725167
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An 80-year-old man with idiopathic pulmonary fibrosis and new bilateral lung densities. Author(s): Jover J, Aranda C. Source: Chest. 1998 October; 114(4): 1210-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9792598
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Analysis of an IL-10 polymorphism in idiopathic pulmonary fibrosis. Author(s): Whittington HA, Freeburn RW, Godinho SI, Egan J, Haider Y, Millar AB. Source: Genes and Immunity. 2003 June; 4(4): 258-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12761561
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Anti-PL 12 and pulmonary fibrosis in a patient ten years after silica/silicate dust exposure. Author(s): Osterode W, Rudiger H, Graninger W, Petzl DH, Rappersberger K, Dekan G, Weihs A, Graninger W. Source: Clin Exp Rheumatol. 1998 September-October; 16(5): 622. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9779317
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Anti-transfer RNA antibodies in two patients with pulmonary fibrosis, Raynaud's phenomenon and polyarthritis. Author(s): Ohosone Y, Matsumura M, Chiba J, Nagaoka S, Matsuoka Y, Irimajiri S, Mimori T. Source: Clinical Rheumatology. 1998; 17(2): 144-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9641513
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Asbestosis and idiopathic pulmonary fibrosis: comparison of thin-section CT features. Author(s): Copley SJ, Wells AU, Sivakumaran P, Rubens MB, Lee YC, Desai SR, MacDonald SL, Thompson RI, Colby TV, Nicholson AG, du Bois RM, Musk AW, Hansell DM. Source: Radiology. 2003 December; 229(3): 731-6. Epub 2003 October 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14576443
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Association between pulmonary fibrosis and coronary artery disease. Author(s): Kizer JR, Zisman DA, Blumenthal NP, Kotloff RM, Kimmel SE, Strieter RM, Arcasoy SM, Ferrari VA, Hansen-Flaschen J. Source: Archives of Internal Medicine. 2004 March 8; 164(5): 551-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15006833
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B7-1, B7-2 and class II MHC molecules in idiopathic pulmonary fibrosis and bronchiolitis obliterans-organizing pneumonia. Author(s): Kaneko Y, Kuwano K, Kunitake R, Kawasaki M, Hagimoto N, Hara N. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2000 January; 15(1): 49-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10678620
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BALF N-acetylglucosaminidase and beta-galactosidase activities in idiopathic pulmonary fibrosis. Author(s): Gessner C, Wirtz H, Sack U, Winkler J, Stiehl P, Schauer J, Wolff G. Source: Respiratory Medicine. 2002 September; 96(9): 751-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12243323
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Basic fibroblast growth factor and its receptors in idiopathic pulmonary fibrosis and lymphangioleiomyomatosis. Author(s): Inoue Y, King TE Jr, Barker E, Daniloff E, Newman LS. Source: American Journal of Respiratory and Critical Care Medicine. 2002 September 1; 166(5): 765-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12204879
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B-Cell epitope mapping of DNA topoisomerase I defines epitopes strongly associated with pulmonary fibrosis in systemic sclerosis. Author(s): Rizou C, Ioannidis JP, Panou-Pomonis E, Sakarellos-Daitsiotis M, Sakarellos C, Moutsopoulos HM, Vlachoyiannopoulos PG. Source: American Journal of Respiratory Cell and Molecular Biology. 2000 March; 22(3): 344-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10696071
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Bepridil-induced pulmonary fibrosis. Author(s): Vasilomanolakis EC, Goldberg NM. Source: American Heart Journal. 1993 October; 126(4): 1016-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8213425
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Biochemical and cellular mechanisms of pulmonary fibrosis. Author(s): Richards RJ, Masek LC, Brown RF. Source: Toxicologic Pathology. 1991; 19(4 Pt 1): 526-39. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1687625
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Biological effects of transforming growth factor-beta(1) in idiopathic pulmonary fibrosis may be regulated by the activation of latent transforming growth factorbeta(1) and the differential expression of transforming growth factor-beta receptors. Author(s): Khalil N, O'Connor R, Gold LI, Parekh T, Raghu G. Source: Chest. 2001 July; 120(1 Suppl): 48S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11451912
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Bipolar affective disorder and idiopathic pulmonary fibrosis. Author(s): Bhandari S, Samellas D. Source: The Journal of Clinical Psychiatry. 2001 July; 62(7): 574-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11488375
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Bleomycin hydrolase and a genetic locus within the MHC affect risk for pulmonary fibrosis in mice. Author(s): Haston CK, Wang M, Dejournett RE, Zhou X, Ni D, Gu X, King TM, Weil MM, Newman RA, Amos CI, Travis EL. Source: Human Molecular Genetics. 2002 August 1; 11(16): 1855-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12140188
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Bleomycin: a pharmacologic tool in the study of the pathogenesis of interstitial pulmonary fibrosis. Author(s): Lazo JS, Hoyt DG, Sebti SM, Pitt BR. Source: Pharmacology & Therapeutics. 1990; 47(3): 347-58. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1705351
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Bleomycin-induced chronic lung damage does not resemble human idiopathic pulmonary fibrosis. Author(s): Borzone G, Moreno R, Urrea R, Meneses M, Oyarzun M, Lisboa C. Source: American Journal of Respiratory and Critical Care Medicine. 2001 June; 163(7): 1648-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11401889
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Bleomycin-induced pulmonary fibrosis in a patient with rheumatoid arthritis. A possible synergistic effect? Author(s): Aitken ML, Dugowson C, Schmidt RA, Fer M. Source: The Western Journal of Medicine. 1989 March; 150(3): 344-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2472035
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Bronchiolitis obliterans syndrome in single lung transplant recipients--patients with emphysema versus patients with idiopathic pulmonary fibrosis. Author(s): Haider Y, Yonan N, Mogulkoc N, Carroll KB, Egan JJ. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2002 March; 21(3): 327-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11897520
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Bronchoalveolar glutathione and nitrite/nitrate in idiopathic pulmonary fibrosis and sarcoidosis. Author(s): Montaldo C, Cannas E, Ledda M, Rosetti L, Congiu L, Atzori L. Source: Sarcoidosis Vasc Diffuse Lung Dis. 2002 March; 19(1): 54-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12002386
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Bronchoalveolar lavage as a possible cause of acute exacerbation in idiopathic pulmonary fibrosis patients. Author(s): Hiwatari N, Shimura S, Takishima T, Shirato K. Source: The Tohoku Journal of Experimental Medicine. 1994 December; 174(4): 379-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7732520
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Bronchoalveolar lavage cytology in pulmonary fibrosis associated with neurofibromatosis. Author(s): Meyer FJ, Teschler H, Schnabel R, Costabel U. Source: Respiratory Medicine. 1996 July; 90(6): 365-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8759482
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Bronchoalveolar lavage fluid protein composition in patients with sarcoidosis and idiopathic pulmonary fibrosis: a two-dimensional electrophoretic study. Author(s): Magi B, Bini L, Perari MG, Fossi A, Sanchez JC, Hochstrasser D, Paesano S, Raggiaschi R, Santucci A, Pallini V, Rottoli P. Source: Electrophoresis. 2002 September; 23(19): 3434-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12373774
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Bronchoalveolar lavage lipids in idiopathic pulmonary fibrosis. Author(s): Low RB. Source: Chest. 1989 January; 95(1): 3-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2909354
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Bronchoalveolar lavage--cellular characteristics in patients with idiopathic pulmonary fibrosis and sarcoidosis. Author(s): Behera D, D'Souza G, Rajwanshi A, Jindal SK. Source: Indian J Chest Dis Allied Sci. 1990 April-June; 32(2): 107-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2083957
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Bronchoalveolar macrophages from patients with idiopathic pulmonary fibrosis are unable to kill facultative intracellular bacteria. Author(s): Savici D, Campbell PA, King TE Jr. Source: Am Rev Respir Dis. 1989 January; 139(1): 22-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2492173
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Cancer in interstitial pulmonary fibrosis and sarcoidosis. Author(s): Sharma OP, Lamb C. Source: Current Opinion in Pulmonary Medicine. 2003 September; 9(5): 398-401. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12904710
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Case-control study of idiopathic pulmonary fibrosis and environmental exposures. Author(s): Mullen J, Hodgson MJ, DeGraff CA, Godar T. Source: Journal of Occupational and Environmental Medicine / American College of Occupational and Environmental Medicine. 1998 April; 40(4): 363-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9571528
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Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Author(s): Collard HR, King TE Jr, Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. Source: American Journal of Respiratory and Critical Care Medicine. 2003 September 1; 168(5): 538-42. Epub 2003 May 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12773325
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Circulating KL-6 predicts the outcome of rapidly progressive idiopathic pulmonary fibrosis. Author(s): Yokoyama A, Kohno N, Hamada H, Sakatani M, Ueda E, Kondo K, Hirasawa Y, Hiwada K. Source: American Journal of Respiratory and Critical Care Medicine. 1998 November; 158(5 Pt 1): 1680-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9817725
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Clinical evaluation of serum type IV collagen 7S in idiopathic pulmonary fibrosis. Author(s): Kasuga I, Yonemaru M, Kiyokawa H, Ichinose Y, Toyama K. Source: Respirology (Carlton, Vic.). 1996 December; 1(4): 277-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9441116
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Clinical response of rheumatoid arthritis-associated pulmonary fibrosis to tumor necrosis factor-alpha inhibition. Author(s): Vassallo R, Matteson E, Thomas CF Jr. Source: Chest. 2002 September; 122(3): 1093-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12226061
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Clinical, laboratory and radiological findings in pulmonary fibrosis with and without connective tissue disease. Author(s): Renzoni E, Rottoli P, Coviello G, Perari MG, Galeazzi M, Vagliasindi M. Source: Clinical Rheumatology. 1997 November; 16(6): 570-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9456009
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Clinicopathological and therapeutic patterns of idiopathic pulmonary fibrosis in Kuwait: a prospective study. Author(s): Khadadah ME, Onadeko BO, Abul AT, Behbehan NA, Cerna M, Cherian JM, Adesina O, Maradni N, Jayakrishnan B. Source: Int J Clin Pract. 2003 December; 57(10): 879-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14712890
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Colchicine versus prednisone in the treatment of idiopathic pulmonary fibrosis. A randomized prospective study. Members of the Lung Study Group. Author(s): Douglas WW, Ryu JH, Swensen SJ, Offord KP, Schroeder DR, Caron GM, DeRemee RA. Source: American Journal of Respiratory and Critical Care Medicine. 1998 July; 158(1): 220-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9655733
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Colchicine, D-penicillamine, and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial. Author(s): Selman M, Carrillo G, Salas J, Padilla RP, Perez-Chavira R, Sansores R, Chapela R. Source: Chest. 1998 August; 114(2): 507-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9726738
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Colocalization of CA19-9 and KL-6 to epithelial cells in dilated bronchioles in a patient with idiopathic pulmonary fibrosis complicated by diffuse alveolar damage. Author(s): Shimizu Y, Hamada T, Tanaka Y, Sasaki A, Nemoto T. Source: Respirology (Carlton, Vic.). 2002 September; 7(3): 281-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12153695
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Comparison of the functional results of single lung transplantation for pulmonary fibrosis and chronic airway obstruction. Author(s): Chacon RA, Corris PA, Dark JH, Gibson GJ. Source: Thorax. 1998 January; 53(1): 43-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9577521
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Complement receptor 1 gene polymorphisms are associated with idiopathic pulmonary fibrosis. Author(s): Zorzetto M, Ferrarotti I, Trisolini R, Agli LL, Scabini R, Novo M, De Silvestri A, Patelli M, Martinetti M, Cuccia M, Poletti V, Pozzi E, Luisetti M. Source: American Journal of Respiratory and Critical Care Medicine. 2003 August 1; 168(3): 330-4. Epub 2003 May 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12773320
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Computerized quantitative color analysis for histological study of pulmonary fibrosis. Author(s): Carai A, Diaz G, Santa Cruz R, Santa Cruz G. Source: Anticancer Res. 2002 November-December; 22(6C): 3889-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12553009
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Corticosteroids for idiopathic pulmonary fibrosis. Author(s): Richeldi L, Davies HR, Ferrara G, Franco F. Source: Cochrane Database Syst Rev. 2003; (3): Cd002880. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12917934
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CXC chemokines in angiogenesis related to pulmonary fibrosis. Author(s): Strieter RM, Belperio JA, Keane MP. Source: Chest. 2002 December; 122(6 Suppl): 298S-301S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12475804
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CXC chemokines in vascular remodeling related to pulmonary fibrosis. Author(s): Strieter RM, Belperio JA, Keane MP. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S67-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14503558
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Cyclophosphamide pulse therapy in idiopathic pulmonary fibrosis. Author(s): Kolb M, Kirschner J, Riedel W, Wirtz H, Schmidt M. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1998 December; 12(6): 1409-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9877500
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Cyclosporin A followed by the treatment of acute exacerbation of idiopathic pulmonary fibrosis with corticosteroid. Author(s): Inase N, Sawada M, Ohtani Y, Miyake S, Isogai S, Sakashita H, Miyazaki Y, Yoshizawa Y. Source: Intern Med. 2003 July; 42(7): 565-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879947
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Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF-beta and IL-10. Author(s): Bergeron A, Soler P, Kambouchner M, Loiseau P, Milleron B, Valeyre D, Hance AJ, Tazi A. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 July; 22(1): 69-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12882453
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Decreased level of vascular endothelial growth factor in bronchoalveolar lavage fluid of normal smokers and patients with pulmonary fibrosis. Author(s): Koyama S, Sato E, Haniuda M, Numanami H, Nagai S, Izumi T. Source: American Journal of Respiratory and Critical Care Medicine. 2002 August 1; 166(3): 382-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12153975
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Defect of hepatocyte growth factor secretion by fibroblasts in idiopathic pulmonary fibrosis. Author(s): Marchand-Adam S, Marchal J, Cohen M, Soler P, Gerard B, Castier Y, Leseche G, Valeyre D, Mal H, Aubier M, Dehoux M, Crestani B. Source: American Journal of Respiratory and Critical Care Medicine. 2003 November 15; 168(10): 1156-61. Epub 2003 August 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12947024
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Detection of adenovirus E1A DNA in pulmonary fibrosis using nested polymerase chain reaction. Author(s): Kuwano K, Nomoto Y, Kunitake R, Hagimoto N, Matsuba T, Nakanishi Y, Hara N. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1997 July; 10(7): 1445-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9230228
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Detection of anti-ADAM 10 antibody in serum of a patient with pulmonary fibrosis associated with dermatomyositis. Author(s): Fujita J, Takeuchi T, Dobashi N, Ohtsuki Y, Tokuda M, Takahara J. Source: Annals of the Rheumatic Diseases. 1999 December; 58(12): 770-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10577965
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Detection of anti-cytokeratin 8 antibody in the serum of patients with cryptogenic fibrosing alveolitis and pulmonary fibrosis associated with collagen vascular disorders. Author(s): Dobashi N, Fujita J, Ohtsuki Y, Yamadori I, Yoshinouchi T, Kamei T, Tokuda M, Hojo S, Okada H, Takahara J. Source: Thorax. 1998 November; 53(11): 969-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10193397
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Detection of antivimentin antibody in sera of patients with idiopathic pulmonary fibrosis and non-specific interstitial pneumonia. Author(s): Yang Y, Fujita J, Bandoh S, Ohtsuki Y, Yamadori I, Yoshinouchi T, Ishida T. Source: Clinical and Experimental Immunology. 2002 April; 128(1): 169-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11982605
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Detection of HCV-RNA in bronchoalveolar lavage from a woman with pulmonary fibrosis. Author(s): Brunetti G, Delmastro M, Nava S, Pignatti P, Bossi A, Gatti M, Furione M. Source: Respiratory Medicine. 2003 June; 97(6): 736-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12814163
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Determinants of response to immunosuppressive therapy in idiopathic pulmonary fibrosis. Author(s): van Oortegem K, Wallaert B, Marquette CH, Ramon P, Perez T, Lafitte JJ, Tonnel AB. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1994 November; 7(11): 1950-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7875264
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Determinants of survival in idiopathic pulmonary fibrosis. Author(s): Schwartz DA, Helmers RA, Galvin JR, Van Fossen DS, Frees KL, Dayton CS, Burmeister LF, Hunninghake GW. Source: American Journal of Respiratory and Critical Care Medicine. 1994 February; 149(2 Pt 1): 450-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8306044
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Determination of various cytokines and type III procollagen aminopeptide levels in bronchoalveolar lavage fluid of the patients with pulmonary fibrosis: inverse correlation between type III procollagen aminopeptide and interferon-gamma in progressive patients. Author(s): Kuroki S, Ohta A, Sueoka N, Katoh O, Yamada H, Yamaguchi M. Source: British Journal of Rheumatology. 1995 January; 34(1): 31-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7881835
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Diabetes mellitus may increase risk for idiopathic pulmonary fibrosis. Author(s): Enomoto T, Usuki J, Azuma A, Nakagawa T, Kudoh S. Source: Chest. 2003 June; 123(6): 2007-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796182
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Differential mRNA expression of insulin-like growth factor-1 splice variants in patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. Author(s): Bloor CA, Knight RA, Kedia RK, Spiteri MA, Allen JT. Source: American Journal of Respiratory and Critical Care Medicine. 2001 July 15; 164(2): 265-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11463599
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Differential role of neutrophils and alveolar macrophages in hepatocyte growth factor production in pulmonary fibrosis. Author(s): Crestani B, Dehoux M, Hayem G, Lecon V, Hochedez F, Marchal J, Jaffre S, Stern JB, Durand G, Valeyre D, Fournier M, Aubier M. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 2002 August; 82(8): 1015-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12177240
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Diffuse pulmonary fibrosis and the Hermansky-Pudlak syndrome: clinical course and postmortem findings. Author(s): Reynolds SP, Davies BH, Gibbs AR. Source: Thorax. 1994 June; 49(6): 617-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8016804
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Direct measurement of IGF-I and IGFBP-3 in bronchoalveolar lavage fluid from idiopathic pulmonary fibrosis. Author(s): Pala L, Giannini S, Rosi E, Cresci B, Scano G, Mohan S, Duranti R, Rotella CM. Source: J Endocrinol Invest. 2001 December; 24(11): 856-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11817709
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Direct thrombin inhibition reduces lung collagen, accumulation, and connective tissue growth factor mRNA levels in bleomycin-induced pulmonary fibrosis. Author(s): Howell DC, Goldsack NR, Marshall RP, McAnulty RJ, Starke R, Purdy G, Laurent GJ, Chambers RC. Source: American Journal of Pathology. 2001 October; 159(4): 1383-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11583966
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Disseminated pulmonary ossification in end-stage pulmonary fibrosis: CT demonstration. Author(s): Gevenois PA, Abehsera M, Knoop C, Jacobovitz D, Estenne M. Source: Ajr. American Journal of Roentgenology. 1994 June; 162(6): 1303-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8191986
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Distinct expression patterns of CD44 isoforms during human lung development and in pulmonary fibrosis. Author(s): Kasper M, Gunthert U, Dall P, Kayser K, Schuh D, Haroske G, Muller M. Source: American Journal of Respiratory Cell and Molecular Biology. 1995 December; 13(6): 648-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7576702
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Does idiopathic pulmonary fibrosis increase lung cancer risk? Author(s): Samet JM. Source: American Journal of Respiratory and Critical Care Medicine. 2000 January; 161(1): 1-2. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10619788
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Dyspnea scales as a measure of health-related quality of life in patients with idiopathic pulmonary fibrosis. Author(s): Baddini Martinez JA, Martinez TY, Lovetro Galhardo FP, de Castro Pereira CA. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2002 June; 8(6): Cr405-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12070430
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Effect of D-penicillamine on pulmonary fibrosis in patients with systemic sclerosis. Author(s): Jinnin M, Ihn H, Asano Y, Yamane K, Yazawa N, Tamaki K. Source: Annals of the Rheumatic Diseases. 2003 October; 62(10): 1019-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12972489
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Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome. Author(s): Gahl WA, Brantly M, Troendle J, Avila NA, Padua A, Montalvo C, Cardona H, Calis KA, Gochuico B. Source: Molecular Genetics and Metabolism. 2002 July; 76(3): 234-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12126938
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Effect of prolonged low-dose methylprednisolone therapy in acute exacerbation of idiopathic pulmonary fibrosis. Author(s): Nishiyama O, Shimizu M, Ito Y, Kume H, Suzuki R, Yokoi T, Yamaki K. Source: Respiratory Care. 2001 July; 46(7): 698-701. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11403701
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Effect of the prone position on patients with hydrostatic pulmonary edema compared with patients with acute respiratory distress syndrome and pulmonary fibrosis. Author(s): Nakos G, Tsangaris I, Kostanti E, Nathanail C, Lachana A, Koulouras V, Kastani D. Source: American Journal of Respiratory and Critical Care Medicine. 2000 February; 161(2 Pt 1): 360-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10673172
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Effects of tamoxifen on pulmonary fibrosis after cobalt-60 radiotherapy in breast cancer patients. Author(s): Koc M, Polat P, Suma S. Source: Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. 2002 August; 64(2): 171-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12242127
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Elevated serum and BAL cytokeratin 19 fragment in pulmonary fibrosis and acute interstitial pneumonia. Author(s): Dobashi N, Fujita J, Ohtsuki Y, Yamadori I, Yoshinouchi T, Kamei T, Takahara J. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1999 September; 14(3): 574-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10543277
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Elevated serum KL-6 levels in patients with systemic sclerosis: association with the severity of pulmonary fibrosis. Author(s): Sato S, Nagaoka T, Hasegawa M, Nishijima C, Takehara K. Source: Dermatology (Basel, Switzerland). 2000; 200(3): 196-201. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10828626
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Elevation of anti-cytokeratin 18 antibody and circulating cytokeratin 18: anticytokeratin 18 antibody immune complexes in sera of patients with idiopathic pulmonary fibrosis. Author(s): Dobashi N, Fujita J, Murota M, Ohtsuki Y, Yamadori I, Yoshinouchi T, Ueda R, Bandoh S, Kamei T, Nishioka M, Ishida T, Takahara J. Source: Lung. 2000; 178(3): 171-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10871435
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Elevation of anti-cytokeratin 19 antibody in sera of the patients with idiopathic pulmonary fibrosis and pulmonary fibrosis associated with collagen vascular disorders. Author(s): Fujita J, Dobashi N, Ohtsuki Y, Yamadori I, Yoshinouchi T, Kamei T, Tokuda M, Hojo S, Okada H, Takahara J. Source: Lung. 1999; 177(5): 311-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10467022
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ENA-78 is an important angiogenic factor in idiopathic pulmonary fibrosis. Author(s): Keane MP, Belperio JA, Burdick MD, Lynch JP, Fishbein MC, Strieter RM. Source: American Journal of Respiratory and Critical Care Medicine. 2001 December 15; 164(12): 2239-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11751193
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Enhanced insulin-like growth factor binding protein-related protein 2 (Connective tissue growth factor) expression in patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. Author(s): Allen JT, Knight RA, Bloor CA, Spiteri MA. Source: American Journal of Respiratory Cell and Molecular Biology. 1999 December; 21(6): 693-700. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10572066
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Eosinophil chemotactic activity in bronchoalveolar lavage from idiopathic pulmonary fibrosis is dependent on cytokine priming of eosinophils. Author(s): Boomars KA, Schweizer RC, Zanen P, van den Bosch JM, Lammers JW, Koenderman L. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1998 May; 11(5): 1009-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9648948
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Eosinophil priming and migration in idiopathic pulmonary fibrosis. Author(s): Kroegel C, Foerster M, Grahmann PR, Braun R. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1998 May; 11(5): 999-1001. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9648945
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Epstein-Barr virus and wild p53 in idiopathic pulmonary fibrosis. Author(s): Lok SS, Stewart JP, Kelly BG, Hasleton PS, Egan JJ. Source: Respiratory Medicine. 2001 October; 95(10): 787-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11601742
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Erythropoietic response to hypoxaemia in diffuse idiopathic pulmonary fibrosis, as opposed to chronic obstructive pulmonary disease. Author(s): Tassiopoulos S, Kontos A, Konstantopoulos K, Hadzistavrou C, Vaiopoulos G, Aessopos A, Tassiopoulos T. Source: Respiratory Medicine. 2001 June; 95(6): 471-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11421504
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Evaluation and management of pulmonary fibrosis in scleroderma. Author(s): White B. Source: Curr Rheumatol Rep. 2002 April; 4(2): 108-12. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11890875
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Evaluation of the short-form 36-item questionnaire to measure health-related quality of life in patients with idiopathic pulmonary fibrosis. Author(s): Martinez TY, Pereira CA, dos Santos ML, Ciconelli RM, Guimaraes SM, Martinez JA. Source: Chest. 2000 June; 117(6): 1627-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10858394
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Evidence of type II pneumocyte apoptosis in the pathogenesis of idiopathic pulmonary fibrosis (IFP)/usual interstitial pneumonia (UIP). Author(s): Barbas-Filho JV, Ferreira MA, Sesso A, Kairalla RA, Carvalho CR, Capelozzi VL. Source: Journal of Clinical Pathology. 2001 February; 54(2): 132-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11215282
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Expression and alteration of ras and p53 proteins in patients with lung carcinoma accompanied by idiopathic pulmonary fibrosis. Author(s): Takahashi T, Munakata M, Ohtsuka Y, Nisihara H, Nasuhara Y, KamachiSatoh A, Dosaka-Akita H, Homma Y, Kawakami Y. Source: Cancer. 2002 August 1; 95(3): 624-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12209756
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Expression of bcl-2 protein in bronchoalveolar lavage cell populations from patients with idiopathic pulmonary fibrosis. Author(s): Mermigkis CM, Tsakanika K, Polychronopoulos V, Karagianidis N, Mermigkis D, Bouros D. Source: Acta Cytol. 2001 November-December; 45(6): 914-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11726117
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Familial pulmonary fibrosis in the United States. Author(s): Wahidi MM, Speer MC, Steele MP, Brown KK, Schwarz MI, Schwartz DA. Source: Chest. 2002 March; 121(3 Suppl): 30S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11893669
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Fatal acute pulmonary fibrosis in a patient treated by danazol for thrombocytopenia. Author(s): Grange MJ, Dombret MC, Fantin B, Gougerot-Pocidalo MA. Source: American Journal of Hematology. 1996 October; 53(2): 149. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8892750
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Fatal interstitial pulmonary fibrosis in anti-Jo-1-negative amyopathic dermatomyositis. Author(s): High WA, Cohen JB, Murphy BA, Costner MI. Source: Journal of the American Academy of Dermatology. 2003 August; 49(2): 295-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12894081
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Fatal pulmonary fibrosis after a low cumulated dose of bleomycin: role of alpha1antitrypsin deficiency? Author(s): Alliot C, Tabuteau S, Desablens B, Aubry P, Andrejak M. Source: American Journal of Hematology. 1999 November; 62(3): 198-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10539931
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Fatal pulmonary fibrosis associated with induction chemotherapy with carboplatin and vinorelbine followed by CHART radiotherapy for locally advanced non-small cell lung cancer. Author(s): Kirkbride P, Hatton M, Lorigan P, Joyce P, Fisher P. Source: Clin Oncol (R Coll Radiol). 2002 October; 14(5): 361-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12555874
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Fatal pulmonary fibrosis complicating low dose methotrexate therapy for rheumatoid arthritis. Author(s): van der Veen MJ, Dekker JJ, Dinant HJ, van Soesbergen RM, Bijlsma JW. Source: The Journal of Rheumatology. 1995 September; 22(9): 1766-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8523359
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Fatal pulmonary fibrosis from low-dose bleomycin therapy. Author(s): Bechard DE, Fairman RP, DeBlois GG, Via CT. Source: Southern Medical Journal. 1987 May; 80(5): 646-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2437659
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Features of idiopathic pulmonary fibrosis with organizing pneumonia. Author(s): Nagata N, Nagatomo H, Yoshii C, Nikaido Y, Kido M. Source: Respiration; International Review of Thoracic Diseases. 1997; 64(5): 331-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9311048
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Ferruginous bodies and pulmonary fibrosis in dead low to moderately exposed asbestos cement workers: histological examination. Author(s): Johansson LG, Albin MP, Jakobsson KM, Welinder HE, Ranstam PJ, Attewell RG. Source: Br J Ind Med. 1987 August; 44(8): 550-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3651354
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Fibroblast phenotypes in pulmonary fibrosis. Author(s): Phan SH. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S87-92. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14503563
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Fibroblast-alveolar cell interactions in sarcoidosis and idiopathic pulmonary fibrosis: evidence for stimulatory and inhibitory cytokine production by alveolar cells. Author(s): de Rochemonteix-Galve B, Dayer JM, Junod AF. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1990 June; 3(6): 653-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2199208
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Four cases of anti-myeloperoxidase antibody-related rapidly progressive glomerulonephritis during the course of idiopathic pulmonary fibrosis. Author(s): Hiromura K, Nojima Y, Kitahara T, Ueki K, Maezawa A, Kawai H, Yano S, Naruse T. Source: Clinical Nephrology. 2000 May; 53(5): 384-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11305812
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Frequent genetic alterations at the microsatellite level in cytologic sputum samples of patients with idiopathic pulmonary fibrosis. Author(s): Vassilakis DA, Sourvinos G, Spandidos DA, Siafakas NM, Bouros D. Source: American Journal of Respiratory and Critical Care Medicine. 2000 September; 162(3 Pt 1): 1115-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10988139
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From anti-inflammatory drugs through antifibrotic agents to lung transplantation: a long road of research, clinical attempts, and failures in the treatment of idiopathic pulmonary fibrosis. Author(s): Selman M. Source: Chest. 2002 September; 122(3): 759-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12226006
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Future research directions in idiopathic pulmonary fibrosis: summary of a National Heart, Lung, and Blood Institute working group. Author(s): Crystal RG, Bitterman PB, Mossman B, Schwarz MI, Sheppard D, Almasy L, Chapman HA, Friedman SL, King TE Jr, Leinwand LA, Liotta L, Martin GR, Schwartz DA, Schultz GS, Wagner CR, Musson RA. Source: American Journal of Respiratory and Critical Care Medicine. 2002 July 15; 166(2): 236-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12119236
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Gallium-67 citrate scanning in the staging of idiopathic pulmonary fibrosis: Correlation and physiologic and morphologic features and bronchoalveolar lavage. Author(s): Line BR, Fulmer JD, Reynolds HY, Roberts WC, Jones AE, Harris EK, Crystal RG. Source: Am Rev Respir Dis. 1978 August; 118(2): 355-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=697186
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Gas exchange at a given degree of volume restriction is different in sarcoidosis and idiopathic pulmonary fibrosis. Author(s): Dunn TL, Watters LC, Hendrix C, Cherniack RM, Schwarz MI, King TE Jr. Source: The American Journal of Medicine. 1988 August; 85(2): 221-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3135751
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Gastrin-releasing peptide-like immunoreactive substance in bronchoalveolar lavage of idiopathic pulmonary fibrosis and sarcoidosis. Author(s): Takeyama M, Nagai S, Kondo K, Morikawa N, Mio T, Satake N, Kitaichi M, Izumi T. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1993 March; 6(3): 418-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8472833
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Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Author(s): Zuo F, Kaminski N, Eugui E, Allard J, Yakhini Z, Ben-Dor A, Lollini L, Morris D, Kim Y, DeLustro B, Sheppard D, Pardo A, Selman M, Heller RA. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 April 30; 99(9): 6292-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11983918
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Genetic factors in idiopathic pulmonary fibrosis: transforming growth factor-beta implicated at last. Author(s): Whyte MK. Source: American Journal of Respiratory and Critical Care Medicine. 2003 August 15; 168(4): 410-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12912730
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Genetic predisposition of idiopathic pulmonary fibrosis. Author(s): Mageto YN, Raghu G. Source: Current Opinion in Pulmonary Medicine. 1997 September; 3(5): 336-40. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9331534
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Glucocorticoid receptors in bronchoalveolar cells from patients with idiopathic pulmonary fibrosis. Author(s): Ozaki T, Nakayama T, Ishimi H, Kawano T, Yasuoka S, Tsubura E. Source: Am Rev Respir Dis. 1982 December; 126(6): 968-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7181237
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Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Author(s): Cantin AM, Hubbard RC, Crystal RG. Source: Am Rev Respir Dis. 1989 February; 139(2): 370-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2913886
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Glutathione deficiency of the lower respiratory tract in patients with idiopathic pulmonary fibrosis. Author(s): Beeh KM, Beier J, Haas IC, Kornmann O, Micke P, Buhl R. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 June; 19(6): 1119-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12108866
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Granular pneumocyte and pulmonary fibrosis. Author(s): Watanabe F, Mitchell MM, Renzetti AD Jr. Source: Chest. 1972 October; 62(4): 400-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5077996
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Granulocyte-colony stimulating factor levels in bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis. Author(s): Ashitani J, Mukae H, Taniguchi H, Ihi T, Kadota J, Kohno S, Matsukura S. Source: Thorax. 1999 November; 54(11): 1015-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10525561
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Ground glass attenuation on CT in patients with idiopathic pulmonary fibrosis. Author(s): Lynch DA. Source: Chest. 1996 August; 110(2): 312-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8697823
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Haemodynamic sequelae of pulmonary fibrosis following intratracheal bleomycin in rats. Author(s): Williams JH Jr, Bodell P, Hosseini S, Tran H, Baldwin KM. Source: Cardiovascular Research. 1992 April; 26(4): 401-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1379125
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Hemodynamic responses to electroconvulsive therapy in a hypertensive patient with end-stage pulmonary fibrosis. Author(s): Viguera A, Welch C, Bigatello L, Drop LJ. Source: Anesthesia and Analgesia. 1998 September; 87(3): 737-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9728867
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Hepatocyte growth factor and idiopathic pulmonary fibrosis. Author(s): Fujita J, Hojo S, Yamaji Y, Takahara J, Yamadori I. Source: Chest. 1996 May; 109(5): 1413. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8625709
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Hepatocyte growth factor and neutrophil elastase in idiopathic pulmonary fibrosis. Author(s): Hojo S, Fujita J, Yoshinouchi T, Yamanouchi H, Kamei T, Yamadori I, Otsuki Y, Ueda N, Takahara J. Source: Respiratory Medicine. 1997 October; 91(9): 511-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9415350
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Hepatocyte growth factor attenuates collagen accumulation in a murine model of pulmonary fibrosis. Author(s): Dohi M, Hasegawa T, Yamamoto K, Marshall BC. Source: American Journal of Respiratory and Critical Care Medicine. 2000 December; 162(6): 2302-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11112155
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Hermansky-Pudlak syndrome with colitis and pulmonary fibrosis. Author(s): Sandberg-Gertzen H, Eid R, Jarnerot G. Source: Scandinavian Journal of Gastroenterology. 1999 October; 34(10): 1055-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10563678
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Hermansky-Pudlak syndrome with diffuse pulmonary fibrosis: radiologic-pathologic correlation. Author(s): Shimizu K, Matsumoto T, Miura G, Shimizu A, Awaya H, Matsunaga N, Ariyoshi I, Isiglo K. Source: Journal of Computer Assisted Tomography. 1998 March-April; 22(2): 249-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9530389
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Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis. Author(s): Tang YW, Johnson JE, Browning PJ, Cruz-Gervis RA, Davis A, Graham BS, Brigham KL, Oates JA Jr, Loyd JE, Stecenko AA. Source: Journal of Clinical Microbiology. 2003 June; 41(6): 2633-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791891
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Heterogeneity of pulmonary fibrosis: interstitial pneumonias and sarcoidosis. Author(s): Nagai S, Nagao T, Hoshino Y, Hamada K. Source: Current Opinion in Pulmonary Medicine. 2001 September; 7(5): 262-71. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11584174
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Heterogeneous point mutations of the p53 gene in pulmonary fibrosis. Author(s): Hojo S, Fujita J, Yamadori I, Kamei T, Yoshinouchi T, Ohtsuki Y, Okada H, Bandoh S, Yamaji Y, Takahara J, Fukui T, Kinoshita M. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1998 December; 12(6): 1404-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9877499
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Higher doses of inhaled nitric oxide might be less effective in improving oxygenation in a patient with interstitial pulmonary fibrosis. Author(s): Maruyama K, Kobayasi H, Taguchi O, Chikusa H, Muneyuki M. Source: Anesthesia and Analgesia. 1995 July; 81(1): 210-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7598271
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High-resolution CT and pulmonary function tests in collagen vascular disease: comparison with idiopathic pulmonary fibrosis. Author(s): Johkoh T, Ikezoe J, Kohno N, Takeuchi N, Yamagami H, Tomiyama N, Kondoh H, Kido S, Arisawa J, Kozuka T. Source: European Journal of Radiology. 1994 May; 18(2): 113-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8055981
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High-resolution CT of asbestosis and idiopathic pulmonary fibrosis. Author(s): Akira M, Yamamoto S, Inoue Y, Sakatani M. Source: Ajr. American Journal of Roentgenology. 2003 July; 181(1): 163-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12818850
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High-resolution CT: what is it good for in pulmonary fibrosis? Author(s): Wilcox A. Source: Current Opinion in Pulmonary Medicine. 2003 September; 9(5): 431-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12904716
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Histamine levels in bronchoalveolar lavage from patients with asthma, sarcoidosis, and idiopathic pulmonary fibrosis. Author(s): Rankin JA, Kaliner M, Reynolds HY. Source: The Journal of Allergy and Clinical Immunology. 1987 February; 79(2): 371-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2434547
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HLA association with sarcoidosis and diffuse interstitial pulmonary fibrosis. Author(s): Mahbubani V, Trikannad VS, Sainani GS. Source: J Assoc Physicians India. 1995 January; 43(1): 28-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9282635
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How long do patients with cor pulmonale secondary to pulmonary fibrosis survive? Author(s): Syabbalo NC. Source: Chest. 1991 January; 99(1): 263-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1984977
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Hyaluronan and procollagen type III aminoterminal peptide in serum and bronchoalveolar lavage fluid from patients with pulmonary fibrosis. Author(s): Milman N, Kristensen MS, Bentsen K. Source: Apmis : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica. 1995 October; 103(10): 749-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8534435
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Hyaluronan and type III procollagen peptide concentrations in bronchoalveolar lavage fluid in idiopathic pulmonary fibrosis. Author(s): Bjermer L, Lundgren R, Hallgren R. Source: Thorax. 1989 February; 44(2): 126-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2928996
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Hyperplastic epithelial foci in honeycomb lesions in idiopathic pulmonary fibrosis. Author(s): Qunn L, Takemura T, Ikushima S, Ando T, Yanagawa T, Akiyama O, Oritsu M, Tanaka N, Kuroki T. Source: Virchows Archiv : an International Journal of Pathology. 2002 September; 441(3): 271-8. Epub 2002 March 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12242524
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Idiopathic nonspecific interstitial pneumonia/fibrosis: comparison with idiopathic pulmonary fibrosis and BOOP. Author(s): Nagai S, Kitaichi M, Itoh H, Nishimura K, Izumi T, Colby TV. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1998 November; 12(5): 1010-9. Erratum In: Eur Respir J 1999 March; 13(3): 711. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9863989
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Idiopathic pulmonary fibrosis and cyclosporine: a lesson from single-lung transplantation. Author(s): Lok SS, Smith E, Doran HM, Sawyer R, Yonan N, Egan JJ. Source: Chest. 1998 November; 114(5): 1478-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9824034
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Idiopathic pulmonary fibrosis associated with rectal carcinoma--a paraneoplastic syndrome or coincidence? Author(s): Haviv YS, Kramer MR, Safadi R. Source: The American Journal of Gastroenterology. 1998 May; 93(5): 838-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9625143
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Idiopathic pulmonary fibrosis in transplantation. Author(s): Jankowich MD. Source: Chest. 2003 December; 124(6): 2404; Author Reply 2404-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14665532
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Idiopathic pulmonary fibrosis vs. pulmonary involvement of collagen vascular disease: HRCT findings. Author(s): Lim MK, Im JG, Ahn JM, Kim JH, Lee SK, Yeon KM, Han MC. Source: Journal of Korean Medical Science. 1997 December; 12(6): 492-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9443086
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Idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis. Author(s): Fellrath JM, du Bois RM. Source: Clinical and Experimental Medicine. 2003 September; 3(2): 65-83. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14598183
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Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Author(s): Katzenstein AL, Myers JL. Source: American Journal of Respiratory and Critical Care Medicine. 1998 April; 157(4 Pt 1): 1301-15. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9563754
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Idiopathic pulmonary fibrosis: current and future treatment options. Author(s): Davies HR, Richeldi L. Source: American Journal of Respiratory Medicine : Drugs, Devices, and Other Interventions. 2002; 1(3): 211-24. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14720059
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Idiopathic pulmonary fibrosis: current concepts. Author(s): Ryu JH, Colby TV, Hartman TE. Source: Mayo Clinic Proceedings. 1998 November; 73(11): 1085-101. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9818046
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Idiopathic pulmonary fibrosis: predicting response to therapy and survival. Author(s): Gay SE, Kazerooni EA, Toews GB, Lynch JP 3rd, Gross BH, Cascade PN, Spizarny DL, Flint A, Schork MA, Whyte RI, Popovich J, Hyzy R, Martinez FJ. Source: American Journal of Respiratory and Critical Care Medicine. 1998 April; 157(4 Pt 1): 1063-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9563720
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Idiopathic pulmonary fibrosis: prognostic indicators. Author(s): Chhabra SK. Source: Indian J Chest Dis Allied Sci. 1998 July-September; 40(3): 159-61. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9919834
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Idiopathic pulmonary fibrosis: survival in population based and hospital based cohorts. Author(s): Mapel DW, Hunt WC, Utton R, Baumgartner KB, Samet JM, Coultas DB. Source: Thorax. 1998 June; 53(6): 469-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9713446
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Images in clinical medicine. Progression of idiopathic pulmonary fibrosis. Author(s): Abou Jawde RM, Al-Ashkar F. Source: The New England Journal of Medicine. 2004 January 8; 350(2): 165. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14711915
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Immunohistochemical localisation of advanced glycation end products in pulmonary fibrosis. Author(s): Matsuse T, Ohga E, Teramoto S, Fukayama M, Nagai R, Horiuchi S, Ouchi Y. Source: Journal of Clinical Pathology. 1998 July; 51(7): 515-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9797728
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Immunological characterization of heterochromatin protein p25beta autoantibodies and relationship with centromere autoantibodies and pulmonary fibrosis in systemic scleroderma. Author(s): Furuta K, Hildebrandt B, Matsuoka S, Kiyosawa K, Reimer G, Luderschmidt C, Chan EK, Tan EM. Source: Journal of Molecular Medicine (Berlin, Germany). 1998 January; 76(1): 54-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9462868
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Increased expression of proinflammatory chemokines in bronchoalveolar lavage cells of patients with progressing idiopathic pulmonary fibrosis and sarcoidosis. Author(s): Ziegenhagen MW, Schrum S, Zissel G, Zipfel PF, Schlaak M, MullerQuernheim J. Source: Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research. 1998 June; 46(5): 223-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9676055
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Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Author(s): Tobin RW, Pope CE 2nd, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Source: American Journal of Respiratory and Critical Care Medicine. 1998 December; 158(6): 1804-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9847271
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Increased surfactant protein-A levels in patients with newly diagnosed idiopathic pulmonary fibrosis. Author(s): Phelps DS, Umstead TM, Mejia M, Carrillo G, Pardo A, Selman M. Source: Chest. 2004 February; 125(2): 617-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14769746
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Interferon-gamma toxicity in idiopathic pulmonary fibrosis. Author(s): O'Connor TM, Bredin CP. Source: American Journal of Respiratory and Critical Care Medicine. 2004 February 1; 169(3): 428. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14739137
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Interleukin-8 expression in bronchoalveolar lavage cells in the evaluation of alveolitis in idiopathic pulmonary fibrosis. Author(s): Xaubet A, Agusti C, Luburich P, Barbera JA, Carrion M, Ayuso MC, Roca J, Rodriguez-Roisin R. Source: Respiratory Medicine. 1998 February; 92(2): 338-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9616535
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Lack of association between antihistone antibodies and pulmonary fibrosis in patients with systemic sclerosis: comment on the article by Sato et al. Author(s): Dick T, Bartz-Bazzanella P, Genth E. Source: Arthritis and Rheumatism. 1995 July; 38(7): 1024-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7612035
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Lack of evidence for a role of Epstein-Barr virus in the increase of lung cancer in idiopathic pulmonary fibrosis. Author(s): Hayakawa H, Shirai M, Uchiyama H, Imokawa S, Suda T, Chida K, Muro H. Source: Respiratory Medicine. 2003 March; 97(3): 281-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12645836
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Laminin-5 gamma2 chain in cryptogenic organizing pneumonia and idiopathic pulmonary fibrosis. Author(s): Lappi-Blanco E, Kaarteenaho-Wiik R, Salo S, Sormunen R, Maatta M, AutioHarmainen H, Soini Y, Paakko P. Source: American Journal of Respiratory and Critical Care Medicine. 2004 January 1; 169(1): 27-33. Epub 2003 September 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14500258
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Levels of cytokeratin 19 fragments in bronchoalveolar lavage fluid correlate to the intensity of neutrophil and eosinophil-alveolitis in patients with idiopathic pulmonary fibrosis. Author(s): Inage M, Nakamura H, Kato S, Saito H, Abe S, Hino T, Tomoike H. Source: Respiratory Medicine. 2000 February; 94(2): 155-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10714422
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Loss of lymphocyte modulatory control by surfactant lipid extracts from acute hypersensitivity pneumonitis: comparison with sarcoidosis and idiopathic pulmonary fibrosis. Author(s): Lesur O, Mancini NM, Janot C, Chabot F, Boitout A, Polu JM, Gerard H. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1994 November; 7(11): 1944-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7875263
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Lung and chest wall mechanics in ventilated patients with end stage idiopathic pulmonary fibrosis. Author(s): Nava S, Rubini F. Source: Thorax. 1999 May; 54(5): 390-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10212101
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Lung cancer associated with diffuse pulmonary fibrosis: CT-pathologic correlation. Author(s): Sakai S, Ono M, Nishio T, Kawarada Y, Nagashima A, Toyoshima S. Source: Journal of Thoracic Imaging. 2003 April; 18(2): 67-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12700479
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Lung cancer in patients with idiopathic pulmonary fibrosis. Author(s): Nagai A, Chiyotani A, Nakadate T, Konno K. Source: The Tohoku Journal of Experimental Medicine. 1992 July; 167(3): 231-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1488744
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Lung cancer in patients with idiopathic pulmonary fibrosis. Author(s): Park J, Kim DS, Shim TS, Lim CM, Koh Y, Lee SD, Kim WS, Kim WD, Lee JS, Song KS. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 June; 17(6): 1216-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11491167
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Lung cancer in patients with idiopathic pulmonary fibrosis: CT findings. Author(s): Lee HJ, Im JG, Ahn JM, Yeon KM. Source: Journal of Computer Assisted Tomography. 1996 November-December; 20(6): 979-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8933802
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Lung function tests in patients with idiopathic pulmonary fibrosis. Are they helpful for predicting outcome? Author(s): Erbes R, Schaberg T, Loddenkemper R. Source: Chest. 1997 January; 111(1): 51-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8995992
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Lung interleukin-4 gene expression in a murine model of bleomycin-induced pulmonary fibrosis. Author(s): Gharaee-Kermani M, Nozaki Y, Hatano K, Phan SH. Source: Cytokine. 2001 August 7; 15(3): 138-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11554783
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Lung transplantation for chemotherapy-induced pulmonary fibrosis. Author(s): Santamauro JT, Stover DE, Jules-Elysee K, Maurer JR. Source: Chest. 1994 January; 105(1): 310-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8275763
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Lymphocyte subsets in lung tissues of non-specific interstitial pneumonia and pulmonary fibrosis associated with collagen vascular disorders: correlation with CD4/CD8 ratio in bronchoalveolar lavage. Author(s): Yamadori I, Fujita J, Kajitani H, Bandoh S, Tokuda M, Yang Y, Ohtsuki Y, Yoshinouchi T, Kamei T, Ishida T. Source: Lung. 2000 November-December; 178(6): 361-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11361059
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Management of idiopathic pulmonary fibrosis: prognostic indicators. Author(s): du Bois RM. Source: Monaldi Arch Chest Dis. 1997 December; 52(6): 547-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9550864
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MAP kinase activation and apoptosis in lung tissues from patients with idiopathic pulmonary fibrosis. Author(s): Yoshida K, Kuwano K, Hagimoto N, Watanabe K, Matsuba T, Fujita M, Inoshima I, Hara N. Source: The Journal of Pathology. 2002 November; 198(3): 388-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12375272
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Mapping of topoisomerase II alpha epitopes recognized by autoantibodies in idiopathic pulmonary fibrosis. Author(s): Grigolo B, Mazzetti I, Borzi RM, Hickson ID, Fabbri M, Fasano L, Meliconi R, Facchini A. Source: Clinical and Experimental Immunology. 1998 December; 114(3): 339-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9844041
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Marked elevation of CA19-9 in a patient with idiopathic pulmonary fibrosis: CA19-9 as a bad prognostic factor. Author(s): Fujita J, Obayashi Y, Yamadori I, Ohtsuki Y, Miyawaki H, Hojo S, Furukawa Y, Takahara J. Source: Respirology (Carlton, Vic.). 1998 September; 3(3): 211-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9767623
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Measurement of hepatocyte growth factor in serum and bronchoalveolar lavage fluid in patients with pulmonary fibrosis. Author(s): Yamanouchi H, Fujita J, Yoshinouchi T, Hojo S, Kamei T, Yamadori I, Ohtsuki Y, Ueda N, Takahara J. Source: Respiratory Medicine. 1998 February; 92(2): 273-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9616525
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Mechanical ventilation in patients with pulmonary fibrosis. Author(s): Stern JB, Mal H. Source: American Journal of Respiratory and Critical Care Medicine. 2003 June 15; 167(12): 1718-9; Author Reply 1719. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796057
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Mechanism of structural remodeling in pulmonary fibrosis. Author(s): Fukuda Y, Mochimaru H, Terasaki Y, Kawamoto M, Kudoh S. Source: Chest. 2001 July; 120(1 Suppl): 41S-43S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11451909
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Mechanisms of colchicine effect in the treatment of asbestosis and idiopathic pulmonary fibrosis. Author(s): Addrizzo-Harris DJ, Harkin TJ, Tchou-Wong KM, McGuinness G, Goldring R, Cheng D, Rom DW. Source: Lung. 2002; 180(2): 61-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12172901
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Mechanisms of pulmonary fibrosis: conference summary. Author(s): Strieter RM. Source: Chest. 2001 July; 120(1 Suppl): 77S-85S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11451940
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Medical treatment for idiopathic pulmonary fibrosis. Author(s): Wallaert B, Salez F, Lamblin C, Roboubi R. Source: Monaldi Arch Chest Dis. 1997 December; 52(6): 552-6. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9550865
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Metalloproteinase and growth factor interactions: do they play a role in pulmonary fibrosis? Author(s): Winkler MK, Fowlkes JL. Source: American Journal of Physiology. Lung Cellular and Molecular Physiology. 2002 July; 283(1): L1-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12060555
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Microarray analysis of idiopathic pulmonary fibrosis. Author(s): Kaminski N. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S32-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14503551
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Microsatellite instability in transforming growth factor-beta 1 type II receptor gene in alveolar lining epithelial cells of idiopathic pulmonary fibrosis. Author(s): Mori M, Kida H, Morishita H, Goya S, Matsuoka H, Arai T, Osaki T, Tachibana I, Yamamoto S, Sakatani M, Ito M, Ogura T, Hayashi S. Source: American Journal of Respiratory Cell and Molecular Biology. 2001 April; 24(4): 398-404. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11306432
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Mixed myelodysplastic syndrome and myeloproliferative disorder with bone marrow and pulmonary fibrosis: the role of megakaryocytes. Author(s): Rosenstingl S, Brouland JP, Zini JM, Tobelem G, Dupuy E. Source: Acta Haematologica. 2003; 109(3): 145-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12714825
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Molecular mechanisms of pulmonary fibrosis and current treatment. Author(s): Kuwano K, Hagimoto N, Hara N. Source: Current Molecular Medicine. 2001 November; 1(5): 551-73. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11899231
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Molecular mechanisms of pulmonary fibrosis. Author(s): Pardo A, Selman M. Source: Frontiers in Bioscience : a Journal and Virtual Library. 2002 August 1; 7: D174361. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12133818
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Molecular targets in drugs discovery in idiopathic pulmonary fibrosis. Work in progress. Author(s): Bitterman PB. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S98-101. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14503565
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Morphometric analysis of insulin-like growth factor-I localization in lung tissues of patients with idiopathic pulmonary fibrosis. Author(s): Uh ST, Inoue Y, King TE Jr, Chan ED, Newman LS, Riches DW. Source: American Journal of Respiratory and Critical Care Medicine. 1998 November; 158(5 Pt 1): 1626-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9817718
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MYCL1, FHIT, SPARC, p16(INK4) and TP53 genes associated to lung cancer in idiopathic pulmonary fibrosis. Author(s): Demopoulos K, Arvanitis DA, Vassilakis DA, Siafakas NM, Spandidos DA. Source: Journal of Cellular and Molecular Medicine. 2002 April-June; 6(2): 215-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12169206
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Myeloperoxidase anti-neutrophil cytoplasmic autoantibodies (MPO-ANCA)-related rapidly progressive glomerulonephritis (RPGN) and pulmonary fibrosis (PF) with dissociated evolution. Author(s): Souid M, Terki NH, Nochy D, Hillion D. Source: Clinical Nephrology. 2001 April; 55(4): 337-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11334325
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Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland. Author(s): Hodgson U, Laitinen T, Tukiainen P. Source: Thorax. 2002 April; 57(4): 338-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11923553
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Neutrophil chemotactic factors in the respiratory tract of patients with chronic airway diseases or idiopathic pulmonary fibrosis. Author(s): Ozaki T, Hayashi H, Tani K, Ogushi F, Yasuoka S, Ogura T. Source: Am Rev Respir Dis. 1992 January; 145(1): 85-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1309969
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Neutrophil elastase: alpha-1-proteinase inhibitor complex in serum and bronchoalveolar lavage fluid in patients with pulmonary fibrosis. Author(s): Yamanouchi H, Fujita J, Hojo S, Yoshinouchi T, Kamei T, Yamadori I, Ohtsuki Y, Ueda N, Takahara J. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1998 January; 11(1): 120-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9543280
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Neutrophil inflammation and activation in bronchiectasis: comparison with pneumonia and idiopathic pulmonary fibrosis. Author(s): Schaaf B, Wieghorst A, Aries SP, Dalhoff K, Braun J. Source: Respiration; International Review of Thoracic Diseases. 2000; 67(1): 52-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10705263
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Neutrophil restraint by green tea: inhibition of inflammation, associated angiogenesis, and pulmonary fibrosis. Author(s): Dona M, Dell'Aica I, Calabrese F, Benelli R, Morini M, Albini A, Garbisa S. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 April 15; 170(8): 4335-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12682270
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Neutrophilic alveolitis in idiopathic pulmonary fibrosis. The role of interleukin-8. Author(s): Lynch JP 3rd, Standiford TJ, Rolfe MW, Kunkel SL, Strieter RM. Source: Am Rev Respir Dis. 1992 June; 145(6): 1433-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1596015
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Neutrophilic inflammation in induced sputum of patients with idiopathic pulmonary fibrosis. Author(s): Beeh KM, Beier J, Kornmann O, Buhl R. Source: Sarcoidosis Vasc Diffuse Lung Dis. 2003 June; 20(2): 138-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12870724
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New approaches to the treatment of pulmonary fibrosis. Author(s): DeRemee RA. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1994 March; 7(3): 427-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8013595
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New insights into the pathogenesis of interstitial pulmonary fibrosis. Author(s): Jimenez SA. Source: Thorax. 1994 March; 49(3): 193-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8202871
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Nitric oxide derivative in bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis. Author(s): Behera D, Kaur S, Sathyanarayana G, Bhatnagar A, Majumdar S. Source: Indian J Chest Dis Allied Sci. 2002 January-March; 44(1): 21-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11845929
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Nonsteroidal therapy for idiopathic pulmonary fibrosis. Author(s): Baughman RP, Alabi FO. Source: Current Opinion in Pulmonary Medicine. 2001 September; 7(5): 309-13. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11584181
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Onset and progression of idiopathic pulmonary fibrosis in a renal transplant recipient. A case report. Author(s): Battista G, Zompatori M, Fasano L, Campieri C, Di Scioscio V. Source: Radiol Med (Torino). 2003 July-August; 106(1-2): 103-7. English, Italian. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12951557
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Open-label compassionate use one year-treatment with pirfenidone to patients with chronic pulmonary fibrosis. Author(s): Nagai S, Hamada K, Shigematsu M, Taniyama M, Yamauchi S, Izumi T. Source: Intern Med. 2002 December; 41(12): 1118-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12521199
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Operation for lung cancer in patients with idiopathic pulmonary fibrosis: surgical contraindication? Author(s): Fujimoto T, Okazaki T, Matsukura T, Hanawa T, Yamashita N, Nishimura K, Kuwabara M, Matsubara Y. Source: The Annals of Thoracic Surgery. 2003 November; 76(5): 1674-8; Discussion 1679. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14602310
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Outcome of mechanical ventilation for acute respiratory failure in patients with pulmonary fibrosis. Author(s): Fumeaux T, Rothmeier C, Jolliet P. Source: Intensive Care Medicine. 2001 December; 27(12): 1868-74. Epub 2001 October 31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11797021
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Outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit. Author(s): Saydain G, Islam A, Afessa B, Ryu JH, Scott JP, Peters SG. Source: American Journal of Respiratory and Critical Care Medicine. 2002 September 15; 166(6): 839-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12231494
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Outpatient inhaled nitric oxide in a patient with idiopathic pulmonary fibrosis: a bridge to lung transplantation. Author(s): Yung GL, Kriett JM, Jamieson SW, Johnson FW, Newhart J, Kinninger K, Channick RN. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2001 November; 20(11): 1224-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11704484
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Overexpression of matrix metalloproteinase-7 in pulmonary fibrosis. Author(s): Cosgrove GP, Schwarz MI, Geraci MW, Brown KK, Worthen GS. Source: Chest. 2002 March; 121(3 Suppl): 25S-26S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11893661
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Overexpression of tumor necrosis factor-alpha diminishes pulmonary fibrosis induced by bleomycin or transforming growth factor-beta. Author(s): Fujita M, Shannon JM, Morikawa O, Gauldie J, Hara N, Mason RJ. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 December; 29(6): 669-76. Epub 2003 June 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12816730
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Overlap connective tissue disease, pulmonary fibrosis, and extensive subcutaneous calcification. Author(s): Chan AT, Wordsworth BP, McNally J. Source: Annals of the Rheumatic Diseases. 2003 July; 62(7): 690-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12810445
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Predictive value of response to treatment of T-lymphocyte subpopulations in idiopathic pulmonary fibrosis. Author(s): Fireman E, Vardinon N, Burke M, Spizer S, Levin S, Endler A, Stav D, Topilsky M, Mann A, Schwarz Y, Kivity S, Greif J. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1998 March; 11(3): 706-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9596125
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Pulmonary fibrosis of sarcoidosis. New approaches, old ideas. Author(s): Moller DR. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S37-41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14503552
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Pulmonary fibrosis secondary to administration of mycophenolate mofetil. Author(s): Morrissey P, Gohh R, Madras P, Monaco AP. Source: Transplantation. 1998 May 27; 65(10): 1414. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9625032
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Pulmonary fibrosis with predominant CD8 lymphocytic alveolitis and anti-Jo-1 antibodies. Author(s): Sauty A, Rochat T, Schoch OD, Hamacher J, Kurt AM, Dayer JM, Nicod LP. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1997 December; 10(12): 2907-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9493684
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Pulmonary fibrosis: cytokines in the balance. Author(s): Coker RK, Laurent GJ. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1998 June; 11(6): 1218-21. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9657557
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Pulmonary function tests and CT scan in the management of idiopathic pulmonary fibrosis. Author(s): Xaubet A, Agusti C, Luburich P, Roca J, Monton C, Ayuso MC, Barbera JA, Rodriguez-Roisin R. Source: American Journal of Respiratory and Critical Care Medicine. 1998 August; 158(2): 431-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9700117
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Quality of life of idiopathic pulmonary fibrosis patients. Author(s): De Vries J, Kessels BL, Drent M. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 May; 17(5): 954-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11488332
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Quantification of idiopathic pulmonary fibrosis using computed tomography and histology. Author(s): Coxson HO, Hogg JC, Mayo JR, Behzad H, Whittall KP, Schwartz DA, Hartley PG, Galvin JR, Wilson JS, Hunninghake GW. Source: American Journal of Respiratory and Critical Care Medicine. 1997 May; 155(5): 1649-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9154871
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Quantitative assessment of lung pathology in idiopathic pulmonary fibrosis. The BAL Cooperative Group Steering Committee. Author(s): Cherniack RM, Colby TV, Flint A, Thurlbeck WM, Waldron J, Ackerson L, King TE Jr. Source: Am Rev Respir Dis. 1991 October; 144(4): 892-900. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1718192
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Quantitative CT indexes in idiopathic pulmonary fibrosis: relationship with physiologic impairment. Author(s): Best AC, Lynch AM, Bozic CM, Miller D, Grunwald GK, Lynch DA. Source: Radiology. 2003 August; 228(2): 407-14. Epub 2003 June 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12802000
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Radiographic evidence of pulmonary fibrosis and possible etiologic factors at a nickel refinery in Norway. Author(s): Berge SR, Skyberg K. Source: Journal of Environmental Monitoring : Jem. 2003 August; 5(4): 681-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12948249
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Raised plasma concentrations of alpha-defensins in patients with idiopathic pulmonary fibrosis. Author(s): Mukae H, Iiboshi H, Nakazato M, Hiratsuka T, Tokojima M, Abe K, Ashitani J, Kadota J, Matsukura S, Kohno S. Source: Thorax. 2002 July; 57(7): 623-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12096207
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Recognition and treatment of idiopathic pulmonary fibrosis. Author(s): Nicod LP. Source: Drugs. 1998 April; 55(4): 555-62. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9561344
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Regulation of the effects of TGF-beta 1 by activation of latent TGF-beta 1 and differential expression of TGF-beta receptors (T beta R-I and T beta R-II) in idiopathic pulmonary fibrosis. Author(s): Khalil N, Parekh TV, O'Connor R, Antman N, Kepron W, Yehaulaeshet T, Xu YD, Gold LI. Source: Thorax. 2001 December; 56(12): 907-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11713352
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Respiratory epithelium in usual interstitial pneumonia/idiopathic pulmonary fibrosis: spark or destructive flame? Author(s): Myers JL, Selman M. Source: American Journal of Respiratory and Critical Care Medicine. 2004 January 1; 169(1): 3-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14695101
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Respiratory reovirus 1/L induction of diffuse alveolar damage: pulmonary fibrosis is not modulated by corticosteroids in acute respiratory distress syndrome in mice. Author(s): London L, Majeski EI, Altman-Hamamdzic S, Enockson C, Paintlia MK, Harley RA, London SD. Source: Clinical Immunology (Orlando, Fla.). 2002 June; 103(3 Pt 1): 284-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12173303
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Risk of chemotherapy-induced pulmonary fibrosis is associated with polymorphic tumour necrosis factor-a2 gene. Author(s): Libura J, Bettens F, Radkowski A, Tiercy JM, Piguet PF. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2002 May; 19(5): 912-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12030733
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Roger S. Mitchell lecture. Uses of expression microarrays in studies of pulmonary fibrosis, asthma, acute lung injury, and emphysema. Author(s): Sheppard D. Source: Chest. 2002 March; 121(3 Suppl): 21S-25S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11893658
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Role of oxidative stress in pulmonary fibrosis. Author(s): Mastruzzo C, Crimi N, Vancheri C. Source: Monaldi Arch Chest Dis. 2002 June-August; 57(3-4): 173-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12619377
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Role of thrombin and its major cellular receptor, protease-activated receptor-1, in pulmonary fibrosis. Author(s): Howell DC, Laurent GJ, Chambers RC. Source: Biochemical Society Transactions. 2002 April; 30(2): 211-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12023853
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Serial evaluation of high-resolution computed tomography findings in patients with idiopathic pulmonary fibrosis in usual interstitial pneumonia. Author(s): Nagao T, Nagai S, Hiramoto Y, Hamada K, Shigematsu M, Hayashi M, Izumi T, Mishima M. Source: Respiration; International Review of Thoracic Diseases. 2002; 69(5): 413-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12232448
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Serum level of interleukin 8 is elevated in idiopathic pulmonary fibrosis and indicates disease activity. Author(s): Ziegenhagen MW, Zabel P, Zissel G, Schlaak M, Muller-Quernheim J. Source: American Journal of Respiratory and Critical Care Medicine. 1998 March; 157(3 Pt 1): 762-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9517588
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Spectrum and diagnosis of idiopathic pulmonary fibrosis. Author(s): Maheshwari U, Gupta D, Aggarwal AN, Jindal SK. Source: Indian J Chest Dis Allied Sci. 2004 January-March; 46(1): 23-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14870865
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Sputum matrix metalloproteinase-9, tissue inhibitor of metalloprotinease-1, and their molar ratio in patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and healthy subjects. Author(s): Beeh KM, Beier J, Kornmann O, Buhl R. Source: Respiratory Medicine. 2003 June; 97(6): 634-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12814147
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Suboptimal erythropoietic response to hypoxemia in idiopathic pulmonary fibrosis. Author(s): Tsantes A, Tassiopoulos S, Papadhimitriou SI, Bonovas S, Kavalierou L, Vaiopoulos G, Meletis I. Source: Chest. 2003 August; 124(2): 548-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12907541
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Successful outcome of pregnancy in idiopathic pulmonary fibrosis. Author(s): Sharma CP, Aggarwal AN, Vashisht K, Jindal SK. Source: J Assoc Physicians India. 2002 November; 50: 1446-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12583483
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Surfactant protein A and B genetic variants predispose to idiopathic pulmonary fibrosis. Author(s): Selman M, Lin HM, Montano M, Jenkins AL, Estrada A, Lin Z, Wang G, DiAngelo SL, Guo X, Umstead TM, Lang CM, Pardo A, Phelps DS, Floros J. Source: Human Genetics. 2003 November; 113(6): 542-50. Epub 2003 September 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13680361
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Surfactant protein-A in lung lavage fluid obtained from patients with idiopathic pulmonary fibrosis. Author(s): Behera D, Kaur S, Sathyanarayana G, Majumdar S. Source: J Assoc Physicians India. 2002 November; 50: 1409-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12583473
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Survival benefit of lung transplantation for patients with idiopathic pulmonary fibrosis. Author(s): Thabut G, Mal H, Castier Y, Groussard O, Brugiere O, Marrash-Chahla R, Leseche G, Fournier M. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 August; 126(2): 46975. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12928646
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Systemic immune cell activation in a subgroup of patients with idiopathic pulmonary fibrosis. Author(s): Homolka J, Ziegenhagen MW, Gaede KI, Entzian P, Zissel G, MullerQuernheim J. Source: Respiration; International Review of Thoracic Diseases. 2003 May-June; 70(3): 262-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12915745
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The assessment of anti-endothelial cell antibodies in scleroderma-associated pulmonary fibrosis. A study of indirect immunofluorescent and western blot analysis in 49 patients with scleroderma. Author(s): Wusirika R, Ferri C, Marin M, Knight DA, Waldman WJ, Ross P Jr, Magro CM. Source: American Journal of Clinical Pathology. 2003 October; 120(4): 596-606. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14560571
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The bone marrow leaves its scar: new concepts in pulmonary fibrosis. Author(s): Dunsmore SE, Shapiro SD. Source: The Journal of Clinical Investigation. 2004 January; 113(2): 180-2. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14722608
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The epithelial/fibroblastic pathway in the pathogenesis of idiopathic pulmonary fibrosis. Author(s): Selman M, Pardo A. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S93-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14503564
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The increase in serum soluble ST2 protein upon acute exacerbation of idiopathic pulmonary fibrosis. Author(s): Tajima S, Oshikawa K, Tominaga S, Sugiyama Y. Source: Chest. 2003 October; 124(4): 1206-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14555548
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The matrix unloaded: aerosolized heparin or urokinase for pulmonary fibrosis. Author(s): Idell S. Source: American Journal of Respiratory and Critical Care Medicine. 2003 December 1; 168(11): 1268-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14644921
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The prognosis of idiopathic pulmonary fibrosis. Author(s): Perez A, Rogers RM, Dauber JH. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S19-26. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14503549
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The role of cytokines in the development of pulmonary fibrosis in preterm infants. Author(s): Watts CL. Source: Pediatr Pulmonol Suppl. 1997; 16: 31-2. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9443186
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The role of eosinophils in pulmonary fibrosis (Review). Author(s): Gharaee-Kermani M, Phan SH. Source: International Journal of Molecular Medicine. 1998 January; 1(1): 43-53. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9852197
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The role of gp130/IL-6 cytokines in the development of pulmonary fibrosis: critical determinants of disease susceptibility and progression? Author(s): Knight DA, Ernst M, Anderson GP, Moodley YP, Mutsaers SE. Source: Pharmacology & Therapeutics. 2003 September; 99(3): 327-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12951164
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The role of heme oxygenase-1 in pulmonary fibrosis. Author(s): Morse D. Source: American Journal of Respiratory Cell and Molecular Biology. 2003 September; 29(3 Suppl): S82-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14503562
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Ultrastructural study on human lung in alveolitis versus pulmonary fibrosis. Author(s): Fischer B, Morgenroth K. Source: Clin Investig. 1993 June; 71(6): 452-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8353404
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Unilateral acute exacerbation of pulmonary fibrosis in association with Sjogren's syndrome. Author(s): Takahashi T, Satoh M, Satoh H. Source: Intern Med. 1996 October; 35(10): 811-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8933193
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Unilateral metachronous lung cancers in a patient with idiopathic pulmonary fibrosis. Author(s): Kirishima K, Satoh H, Yamashita YT, Ohtsuka M, Sekizawa K. Source: Oncol Rep. 1999 July-August; 6(4): 763-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10373652
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Unusually high plasma CEA values in a patient with idiopathic pulmonary fibrosis. Author(s): Harari S, Costantini M, Ghio P, Scoccia S. Source: Int J Biol Markers. 1994 July-September; 9(3): 150. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7829896
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Upper lobe pulmonary fibrosis associated with high-dose chemotherapy containing BCNU for bone marrow transplantation. Author(s): Parish JM, Muhm JR, Leslie KO. Source: Mayo Clinic Proceedings. 2003 May; 78(5): 630-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12744552
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Upregulation of Fas-signalling molecules in lung epithelial cells from patients with idiopathic pulmonary fibrosis. Author(s): Maeyama T, Kuwano K, Kawasaki M, Kunitake R, Hagimoto N, Matsuba T, Yoshimi M, Inoshima I, Yoshida K, Hara N. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2001 February; 17(2): 180-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11334117
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Urine thrombomodulin in patients with idiopathic pulmonary fibrosis. Author(s): Iguchi M, Goto H, Goto M, Shinno H. Source: Chest. 1998 March; 113(3): 849. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9515877
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Use of oligonucleotide microarrays to analyze gene expression patterns in pulmonary fibrosis reveals distinct patterns of gene expression in mice and humans. Author(s): Kaminski N, Zuo F, Cojocaro G, Yakhini Z, Ben-Dor A, Morris D, Sheppard D, Pardo A, Selman M, Heller RA. Source: Chest. 2002 March; 121(3 Suppl): 31S-32S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11893671
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Usual interstitial pneumonia: idiopathic pulmonary fibrosis versus collagen vascular diseases. Author(s): Nagao T, Nagai S, Kitaichi M, Hayashi M, Shigematsu M, Tsutsumi T, Satake N, Izumi T. Source: Respiration; International Review of Thoracic Diseases. 2001; 68(2): 151-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11287829
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Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Author(s): Hunninghake GW, Zimmerman MB, Schwartz DA, King TE Jr, Lynch J, Hegele R, Waldron J, Colby T, Muller N, Lynch D, Galvin J, Gross B, Hogg J, Toews G, Helmers R, Cooper JA Jr, Baughman R, Strange C, Millard M. Source: American Journal of Respiratory and Critical Care Medicine. 2001 July 15; 164(2): 193-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11463586
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Viruses and idiopathic pulmonary fibrosis. Author(s): Lok SS, Egan JJ. Source: Monaldi Arch Chest Dis. 2000 April; 55(2): 146-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10949877
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Viruses and idiopathic pulmonary fibrosis. Author(s): Egan JJ, Woodcock AA, Stewart JP. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 1997 July; 10(7): 1433-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9230225
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What is pulmonary fibrosis, and how is it treated? Author(s): Gross TJ. Source: Health News. 2003 February; 9(2): 12. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12632551
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What is pulmonary fibrosis? Author(s): Murray JC, Laurent GJ. Source: Thorax. 1988 January; 43(1): 9-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3281309
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Widespread pulmonary fibrosis as a major clinical manifestation of chronic graftversus-host disease. Author(s): Atkinson K, Bryant D, Delprado W, Biggs J. Source: Bone Marrow Transplantation. 1989 January; 4(1): 129-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2647179
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Wnt signaling and pulmonary fibrosis. Author(s): Morrisey EE. Source: American Journal of Pathology. 2003 May; 162(5): 1393-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12707021
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CHAPTER 2. NUTRITION AND PULMONARY FIBROSIS Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and pulmonary fibrosis.
Finding Nutrition Studies on Pulmonary 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 “pulmonary 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 information is typical of that found when using the “Full IBIDS Database” to search for “pulmonary fibrosis” (or a synonym): •
Attenuation of amiodarone-induced pulmonary fibrosis by vitamin E is associated with suppression of transforming growth factor-beta1 gene expression but not prevention of mitochondrial dysfunction. Author(s): Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada. Source: Card, J W Racz, W J Brien, J F Massey, T E J-Pharmacol-Exp-Ther. 2003 January; 304(1): 277-83 0022-3565
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Attenuation of bleomycin-induced pulmonary fibrosis by a catalytic antioxidant metalloporphyrin. Author(s): Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Source: Oury, T D Thakker, K Menache, M Chang, L Y Crapo, J D Day, B J Am-J-RespirCell-Mol-Biol. 2001 August; 25(2): 164-9 1044-1549
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Consideration of mycophenolate mofetil for idiopathic pulmonary fibrosis. Author(s): Brain and Perception Laboratory, University of California, San Diego, La Jolla 92093-0109, USA.
[email protected] Source: Altschuler, E L Med-Hypotheses. 2001 December; 57(6): 701-2 0306-9877
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Decreased collagenase production by fibroblasts derived from idiopathic pulmonary fibrosis. Author(s): Facultad de Ciencias, Universidad Nacional Autonoma de Mexico. Source: Pardo, A Selman, M Matrix-Suppl. 1992; 1417-8 0940-1199
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Dietary fish oil inhibits bleomycin-induced pulmonary fibrosis in the rat. Author(s): Department of Medicine, University of Alabama, Birmingham 35294. Source: Kennedy, J I Chandler, D B Fulmer, J D Wert, M B Grizzle, W E Exp-Lung-Res. 1989 March; 15(2): 315-29 0190-2148
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Effects of dietary fats on bleomycin-induced pulmonary fibrosis. Source: Kennedy, J I Chandler, D B Fulmer, J D Wert, M B Grizzle, W E Exp-Lung-Res. 1987; 12(2): 149-61 0190-2148
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Effects of dimethyl sulfoxide (DMSO) on pulmonary fibrosis in rats and mice. Author(s): Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Illinois, Urbana 61801. Source: Haschek, W M Baer, K E Rutherford, J E Toxicology. 1989 February; 54(2): 197205 0300-483X
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Induction of pulmonary fibrosis in organ-cultured rat lung by cadmium chloride and transforming growth factor-beta1. Author(s): Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC. Source: Lin, C J Yang, P C Hsu, M T Yew, F H Liu, T Y Shun, C T Tyan, S W Lee, T C Toxicology. 1998 May 15; 127(1-3): 157-66 0300-483X
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Induction of unilateral pulmonary fibrosis in the rat by cadmium chloride. Author(s): Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia. Source: Frankel, F R Steeger, J R Damiano, V V Sohn, M Oppenheim, D Weinbaum, G Am-J-Respir-Cell-Mol-Biol. 1991 October; 5(4): 385-94 1044-1549
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Interaction of IL-13 and C10 in the pathogenesis of bleomycin-induced pulmonary fibrosis. Author(s): Department of Medicine, Division of Pulmonary and Critical Care Medicine, UCLA School of Medicine, Los Angeles, California 90095, USA. Source: Belperio, J A Dy, M Burdick, M D Xue, Y Y Li, K Elias, J A Keane, M P Am-JRespir-Cell-Mol-Biol. 2002 October; 27(4): 419-27 1044-1549
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Pleuropulmonary fibrosis due to bromocriptine treatment for Parkinson's disease. Author(s): Department of Neurology, Repatriation General Hospital, Brisbane. Source: Todman, D H Oliver, W A Edwards, R L Clin-Exp-Neurol. 1990; 2779-82 01966383
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Pulmonary fibrosis associated with occupational exposure to hard metal at a metalcoating plant--Connecticut, 1989. Source: Anonymous MMWR-Morb-Mortal-Wkly-Repage 1992 January 31; 41(4): 65-7 0149-2195
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Radioimmunotherapy using vascular targeted 213Bi: the role of tumor necrosis factor alpha in the development of pulmonary fibrosis. Author(s): Life Sciences Division, Oak Ridge National Laboratory, Tennessee 378316101, USA. Source: Davis, I A Kennel, S J Clin-Cancer-Res. 1999 October; 5(10 Suppl): 3160s-3164s 1078-0432
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The effect of huoxue huayu drugs on radiation pneumonitis and pulmonary fibrosis. Source: Shen, Y Li, D H Liu, J W Zhan, Q M Yang, C Z Guo, R Deng, J S Proc-ChinAcad-Med-Sci-Peking-Union-Med-Coll. 1988; 3(3): 139-43 0258-8757
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The protective effect of colchicine on bleomycin-induced pulmonary fibrosis in rats. Author(s): PUMC Hospital, CAMS, Beijing. Source: Zhang, L Zhu, Y Luo, W Xi, P Yan, Y Chin-Med-Sci-J. 1992 March; 7(1): 58-60 1001-9294
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The role of sodium cromolyn in treatment of paraquat-induced pulmonary fibrosis in rat. Author(s): Department of Pharmacology and Toxicology, School of Pharmacy, Ahwaz University of Medical Sciences, Ahwaz, Iran.
[email protected] Source: Hemmati, A A Nazari, Z Motlagh, M E Goldasteh, S Pharmacol-Res. 2002 September; 46(3): 229-34 1043-6618
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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WebMDHealth: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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CHAPTER 3. DISSERTATIONS ON PULMONARY FIBROSIS Overview In this chapter, we will give you a bibliography on recent dissertations relating to pulmonary 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 “pulmonary fibrosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on pulmonary fibrosis, we have not necessarily excluded non-medical dissertations in this bibliography.
Dissertations on Pulmonary 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 pulmonary 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: •
The Role of Il-13 in Pulmonary Fibrosis by Jakubzick, Claudia Virginia; PhD from University of Michigan, 2003, 203 pages http://wwwlib.umi.com/dissertations/fullcit/3106090
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 4. CLINICAL TRIALS AND PULMONARY FIBROSIS Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning pulmonary fibrosis.
Recent Trials on Pulmonary Fibrosis The following is a list of recent trials dedicated to pulmonary fibrosis.8 Further information on a trial is available at the Web site indicated. •
Clinical and Basic Investigations into Hermansky-Pudlak Syndrome Condition(s): Albinism; Intestinal Disease; Kidney Disease; Myocardial Disease; Pulmonary Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): National Human Genome Research Institute (NHGRI) Purpose - Excerpt: Hermansky-Pudlak Syndrome (HPS) is an inherited disease which results in decreased pigmentation (oculocutaneous albinism), bleeding problems due to a platelet abnormality (platelet storage pool defect), and storage of an abnormal fatprotein compound (lysosomal accumulation of ceroid lipofuscin). The disease can cause poor functioning of the lungs, intestine, kidneys, or heart. The major complication of the disease is pulmonary fibrosis and typically causes death in patients ages 40 - 50 years old. The disorder is common in Puerto Rico, where many of the clinical research studies on the disease have been conducted. Neither the full extent of the disease nor the basic cause of the disease is known. There is no known treatment for HPS. The purpose of this study is to perform research into the medical complications of HPS and begin to understand what causes these complications. Researchers will clinically evaluate patients with HPS of all ethnic backgrounds. They will obtain cells, blood components (plasma), and urine for future studies. Genetic tests (mutation analysis) to detect HPScausing genes will also be conducted. Study Type: Observational Contact(s): see Web site below
8
These are listed at www.ClinicalTrials.gov.
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Web Site: http://clinicaltrials.gov/ct/show/NCT00001456 •
Efficacy and safety of oral bosentan in patients with Idiopathic Pulmonary Fibrosis Condition(s): Idiopathic Pulmonary Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): Actelion Purpose - Excerpt: Endothelin-1 (ET-1) is expressed in a variety of pulmonary pathological conditions including pulmonary vascular disease and pulmonary fibrosis. Bosentan (an oral dual ET-1 receptor antagonist) could delay the progression of idiopathic pulmonary fibrosis (IPF), a condition for which no established treatment is available. The present trial investigates a possible use of bosentan, which is currently approved for the treatment of symptoms of pulmonary arterial hypertension (PAH) WHO class III and IV, to a new category of patients suffering from IPF. Phase(s): Phase II; Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00071461
•
Efficacy and safety of oral bosentan in pulmonary fibrosis associated with scleroderma Condition(s): Pulmonary Fibrosis; Scleroderma, Systemic Study Status: This study is currently recruiting patients. Sponsor(s): Actelion Purpose - Excerpt: Clinical and experimental studies suggest that bosentan could delay the progression of interstitial lung disease (ILD) associated with systemic sclerosis (SSc), a condition for which no established efficacious treatment is available. The present trial investigates a possible use of oral bosentan, which is currently approved for the treatment of symptoms of pulmonary arterial hypertension (PAH) WHO Class III and IV, to a new category of patients suffering from ILD associated with SSc. Phase(s): Phase II; Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00070590
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Identification of Genes Associated with Lung Disease in Patients with Rheumatoid Arthritis Condition(s): Healthy; Pulmonary Fibrosis; Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Pulmonary fibrosis (PF) is a condition in which the lungs of a patient become scarred and fibrous. It has been known to occur in as many as 40% of patients diagnosed with rheumatoid arthritis (RA). The cause of the pulmonary fibrosis in patients with RA is unknown. Data gathered from previous research studies suggest that genetics may play a role in the development of PF in patients with rheumatoid
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arthritis. However, the actual genetic factors involved in the disease process have not been identified. The goal of this study is to identify the genetic markers in patients with pulmonary fibrosis and rheumatoid arthritis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001885 •
Idiopathic Pulmonary Fibrosis Condition(s): Pulmonary Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): Wyeth-Ayerst Research Purpose - Excerpt: The objective of the study is to evaluate the safety and efficacy of etanercept in comparison with placebo in a double-blind, parallel, randomized fashion in subjects with idiopathic pulmonary fibrosis (IPF) who failed previous therapy. The treatment period will be up to 1 year. The primary objective is evaluation of safety and efficacy. Secondary: The secondary objective is to evaluate quality of life (QoL) and pharmacokinetics (PK). Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00063869
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Lung Disease Associated with Rheumatoid Arthritis Condition(s): Pulmonary Fibrosis; Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Pulmonary fibrosis (PF) is a condition in which the lungs of a patient become scarred and fibrous. It has been known to occur in as many as 40% of patients diagnosed with rheumatoid arthritis (RA). The cause of the pulmonary fibrosis in patients with RA is unknown. Patients participating in this study will undergo a series of tests and examinations before and throughout the study. The tests include blood and urine tests, electrical measures of heart function (ECG), chest x-rays, CAT scans, nuclear medicine scans, breathing tests, exercise tests, and fiberoptic bronchoscopy. The goals of this study are to: 1. Estimate how common pulmonary fibrosis is in patients with rheumatoid arthritis, 2. Describe the natural course of pulmonary fibrosis in patients with rheumatoid arthritis, 3. Estimate the survival rate of patients with pulmonary fibrosis and rheumatoid arthritis, and 4. Learn more about the factors that contribute to the development or progression fibrotic lung disease. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001876
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Oral Pirfenidone for the Pulmonary Fibrosis of Hermansky-Pudlak Syndrome Condition(s): Albinism; Inborn Errors of Metabolism; Oculocutaneous Albinism; Platelet Storage Pool Deficiency; Pulmonary Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): National Human Genome Research Institute (NHGRI) Purpose - Excerpt: Hermansky-Pudlak Syndrome (HPS) is an inherited disease which results in decreased pigmentation (oculocutaneous albinism), bleeding problems due to a platelet abnormality (platelet storage pool defect), and storage of an abnormal fatprotein compound (lysosomal accumulation of ceroid lipofuscin). The disease can cause poor functioning of the lungs, intestine, kidneys, or heart. The most serious complication of the disease is pulmonary fibrosis and typically causes death in patients ages 40 - 50 years old. The disorder is common in Puerto Rico, where many of the clinical research studies on the disease have been conducted. Neither the full extent of the disease nor the basic cause of the disease is known. There is no known treatment for HPS. The drug Pirfenidone blocks the biochemical process of inflammation and has been reported to slow or reverse pulmonary fibrosis in animal systems. In this study researchers will select 40 patients diagnosed with pulmonary fibrosis 20 who have not received steroid therapy in the last 3 months and 20 currently taking steroids. The patients will be randomly divided into 4 groups. The patients will not know if they are taking pirfenidone or a placebo "sugar pill". 1. Group one will be patients not taking steroids who will receive pirfenidone. 2. Group two will be patients not taking steroids who will receive a placebo "sugar pill" 3. Group three will be patients taking steroids who will receive pirfenidone. 4. Group four will be patients taking steroids who will receive a placebo "sugar pill". The major outcome measurement of the therapy will be a change in the lung function (forced vital capacity). The study will be stopped if one therapy proves to be more effective than the others. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001596
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Pirfenidone for the Treatment of Patients with Pulmonary Fibrosis/Idiopathic Pulmonary Fibrosis (PF/IPF) Condition(s): Idiopathic Pulmonary Fibrosis; Pulmonary Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): InterMune Purpose - Excerpt: To assess the long-term safety and efficacy of oral pirfenidone in doses of 40 mg/kg/d for up to 152 weeks in a limited number of patients with pulmonary fibrosis/idiopathic pulmonary fibrosis (PF/IPF) * Enrollment: A limited number of patients will be enrolled from up to 20 centers; * Duration: 3 years Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00080223
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•
Safety and Tolerability Study of FG-3019 in Patients with Idiopathic Pulmonary Fibrosis Condition(s): Idiopathic Pulmonary Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): FibroGen, Inc. Purpose - Excerpt: The purpose of this study is to evaluate the safety and tolerability of FG-3019, a therapeutic antibody designed to block the pro-fibrotic activity of connective tissue growth factor (CTGF). CTGF triggers the production of collagen and fibronectin, which cause scarring and thickening of the lungs. Approximately 18 to 27 males and females, 21 to 80 years of age with a diagnosis of idiopathic pulmonary fibrosis (IPF) will be enrolled in this study. The duration of the study is approximately one month, during which patients will receive a single infusion of FG-3019. In addition, there will be two follow-up visits 6 and 12 months after receiving the study drug. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00074698
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Segmental Bronchoalveolar Lavage Condition(s): Asthma; Chronic Obstructive Airway Disease; Healthy; Lung Disease; Pulmonary Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Bronchoalveolar lavage is a diagnostic and therapeutic procedure conducted by placing a fiberoptic scope into the lung of a patient, and injecting sterile water (saline) into the lung and removing. The sterile water removed contains secretions, cells, and protein from the lower respiratory tract. This sample can be analyzed to provide more information about possible disease processes going on in the lungs. This protocol will be used to perform BAL, bronchial brushing, and bronchial wall biopsy in normal volunteers. The samples collected during the study will be used to examine biochemical processes in the lung that may contribute to lung disease Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001618
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Specimen Collection for Individuals with Lung Disease Associated with Rheumatoid Arthritis Condition(s): Pulmonary Fibrosis; Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Pulmonary fibrosis (PF) is a condition in which the lungs of a patient become scarred and fibrous. It has been known to occur in as many as 40% of patients diagnosed with rheumatoid arthritis (RA). The cause of the pulmonary fibrosis in patients with RA is unknown. Researchers hope to improve their understanding of the
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disease process involved in PF and RA by analyzing specimens collected by bronchoscopy, lung biopsy, lung transplantation, or autopsy from patients with these conditions. The purpose of this study is to collect specimens from rheumatoid arthritis patients with and without pulmonary fibrosis as well as patients with pulmonary fibrosis without associated diseases or cause (idiopathic pulmonary fibrosis). Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001884 •
The INSPIRE A Study of Interferon gamma-1b for Idiopathic Pulmonary Fibrosis (IPF) Condition(s): Idiopathic Pulmonary Fibrosis; Lung Disease; Pulmonary Fibrosis Study Status: This study is currently recruiting patients. Sponsor(s): InterMune Purpose - Excerpt: - Purpose: A phase 3, randomized, double-blind, placebo-controlled trial to determine the efficacy and safety of 200 µg of recombinant Interferon gamma-1b administered by subcutaneous (SC) injection, compared with placebo, in patients with IPF * Enrollment: 600 patients will be enrolled from approximately 70 centers in North America and Europe * Randomization: 2:1 active-to-placebo ratio * Duration: 2 years active drug or placebo (rescue therapy will be permitted for patients who meet predefined criteria) Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00075998
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An Open-label study of the safety and efficacy of subcutaneous recombinant interferon-gamma 1b (IFN-gamma 1b) in patients with Idiopathic Pulmonary Fibrosis (IPF) Condition(s): Lung Disease; Pulmonary Fibrosis Study Status: This study is no longer recruiting patients. Sponsor(s): InterMune Purpose - Excerpt: Study GIPF-004 is an open-label, multicenter study that will enroll approximately 250 patients who complete Protocol GIPF-001. The purpose of this study is to assess the safety and efficacy of continued IFN-gamma 1b therapy in this welldefined cohort of patients for up to 48 weeks. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00052052
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An Open-Label Study of the Safety of Interferon gamma-1b in Patients with IPF Condition(s): Idiopathic Pulmonary Fibrosis; Pulmonary Fibrosis; Lung Disease
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Study Status: This study is no longer recruiting patients. Sponsor(s): InterMune Purpose - Excerpt: Open-label therapy will be administered to up to 220 patients, following completion of either InterMune Protocol GIPF-002 Part B or Protocol GIPF004, to assess the long-term safety of subcutaneous Interferon gamma-1b. The study duration will be 5 years. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00076635 •
Linkage Study in Familial Pulmonary Fibrosis Condition(s): Pulmonary Fibrosis; Lung Diseases; Lung Diseases, Interstitial Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To map the gene (or genes) for familial pulmonary fibrosis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00016627
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Scleroderma Lung Study Condition(s): Lung Diseases; Pulmonary Fibrosis; Systemic Scleroderma; Scleroderma, Systemic Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To evaluate the efficacy and safety of cyclophosphamide versus placebo for the prevention and progression of symptomatic pulmonary disease in patients with systemic sclerosis. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004563
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A Randomized, Double-Blind, Three-arm, Phase 3b Study Comparing the Safety and efficacy of Interferon gamma-1b with Azatioprine, and Azathioprine Alone in Patients with IPF Receiving Prednisone Condition(s): Lung Disease; Pulmonary Fibrosis Study Status: This study is terminated. Sponsor(s): InterMune Purpose - Excerpt: Study GIPF-003 is a Phase 3b study designed to define better therapeutic use of IFN-gamma 1b in patients wtih IPF. The study will be conducted primarily in Europe and will enroll 210 patients.
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Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00052039 •
A Study of the Safety and Clinical Effects of Interferon gamma-1b in Patients with Idiopathic Pulmonary Fibrosis (IPF) Condition(s): Idiopathic Pulmonary Fibrosis Study Status: This study is completed. Sponsor(s): InterMune Purpose - Excerpt: Study GIPF-002 is a phase 2 study designed to characterize the biologic and clinical effects of IFN-g 1b. The objective of the Study is to characterize the biologic and clinical effects of IFN-g 1b administered to patients with idiopathic pulmonary fibrosis (IPF). The Study will be conducted at multiple sites and enroll 30 patients with IPF who have failed treatment with corticosteroids. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00047658
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A study of the safety and efficacy Interferon-gamma 1b in patients with Idiopathic Pulmonary Fibrosis (IPF) Condition(s): Idiopathic Pulmonary Fibrosis Study Status: This study is completed. Sponsor(s): InterMune Purpose - Excerpt: Study GIPF-001 is phase 3 study designed to determine the safety and efficacy of IFN-g 1b administered by subcutaneous injection; compared to placebo in patients with IPF who are unresponsive to steroids. 330 patients have been enrolled and were assigned to either a IFN-g 1b group or a placebo group. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00047645
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Diffuse Fibrotic Lung Disease Condition(s): Lung Diseases; Pulmonary Fibrosis; Sarcoidosis Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the effects of cyclophosphamide compared with prednisone, dapsone, or high-dose intermittent 'pulse' therapy with methylprednisolone in patients with idiopathic pulmonary fibrosis. Also, to evaluate the use of intermittent, short-term, high-dose intravenous corticosteroids in patients with sarcoidosis. There were actually four separate clinical trials.
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Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000596 •
Idiopathic Pulmonary Fibrosis: a Case-control Study Condition(s): Lung Diseases; Pulmonary Fibrosis; Lung Diseases, Interstitial Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine risk factors for idiopathic pulmonary fibrosis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005295
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Idiopathic Pulmonary Fibrosis--Pathogenesis and Staging - SCOR in Occupational and Immunological Lung Diseases Condition(s): Lung Diseases; Scleroderma, Systemic
Pulmonary
Fibrosis;
Lung
Diseases,
Interstitial;
Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To conduct cross-sectional and longitudinal studies of patients with idiopathic pulmonary fibrosis (IPF) and patients with progressive systemic sclerosis (PSS), with and without associated lung disease. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005317
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 “pulmonary 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:
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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 5. PATENTS ON PULMONARY 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 “pulmonary fibrosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on pulmonary fibrosis, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Pulmonary Fibrosis By performing a patent search focusing on pulmonary 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. 9Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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The following is an example of the type of information that you can expect to obtain from a patent search on pulmonary fibrosis: •
3-[(S)-1'-Phenylethylamino]propylaminobleomycin, method for producing same
non-toxic
salt
thereof,
and
Inventor(s): Fujii; Akio (Kamakura, JP), Fukuoka; Takeyo (Tokyo, JP), Muraoka; Yasuhiko (Kitamoto, JP), Takita; Tomohisa (Asaka, JP), Umezawa; Hamao (Tokyo, JP), Yoshioka; Osamu (Yono, JP) Assignee(s): Nippon Kayaku Kabushiki Kaisha (tokyo, Jp) Patent Number: 4,195,018 Date filed: June 15, 1978 Abstract: Novel 3-[(S)-1'-phenylethylamino]propylaminobleomycin obtained by reacting a reactive derivative of the carboxyl group of bleomycinic acid with N-[(S)-1'phenylethyl]-1,3-diaminopropane, a non-toxic salt of said novel bleomycin, and a method for producing the novel bleomycin. Because of much reduction in the side effect causing pulmonary fibrosis, the novel bleomycin is more useful than a commercial bleomycin complex which gives rise to said undesirable side effect. Excerpt(s): Bleomycins are carcinostatic antibiotic substances discovered by Umezawa, one of the present inventors, and collaborators [Journal of Antibiotics, 19A, 200 (1966)], which are water-soluble basic glycopeptides produced by Actinomycete Streptomyces verticillus and are capable of readily chelating one atom of divalent copper. In normal cultivation, 16 components of bleomycins are produced and isolated [for example, Umezawa et al., Journal of Antibiotics, 19A, 210 (1966)]. Of the bleomycins, a mixture of copper-free A.sub.1, A.sub.2, A.sub.5, B.sub.2 and demethyl A.sub.2 (hereinafter referred to as "Bleomycin complex") has been widely used in clinical fields of cancer therapy and has proved to be successful particularly in the therapy of squamous cell carcinoma as major target, skin cancer, head and neck cancer, cancer of the uterine cervix, lung cancer, and malignant lymphoma. Regarding the side effect, however, there have been reported cases of pumonary fibrosis and other undesirable occurrences. Of the side effects exhibited by bloemycins, the most fearful is pulmonary fibrosis. It is readily imaginable that the carcinostatic activity of bleomycins might be more effectively manifested in clinical fields if the above-noted side effect could be more or less reduced. Under the circumstances, the present inventors had engaged for years in the synthesis of various bleomycins and in various animal tests on their carcinostatic activity as well as their toxicity including pulmonary fibrosis as major test item. As a result, it was found that 3-[(S)-1'-phenylethylamino]propylaminobleomycin (hereinafter referred to as "NK631" including both copper-containing and copper-free forms), which is a new bleomycin obtained by reacting a reactive derivative of the carboxyl group of bleomycinic acid with N-[(S)-1'-phenylethyl]-1,3-diaminopropane, is markedly reduced in the side effect causing pulmonary fibrosis and is not deteriorated in carcinostatic activity, as compared with a commercial bleomycin complex and other known bleomycins. The present invention has been accomplished based on the above finding. Web site: http://www.delphion.com/details?pn=US04195018__
Patents
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Benzenesulfonylimine derivatives as inhibitors of IL-1 action Inventor(s): Dalton; Christopher R. (Mundelein, IL), Harrison; Boyd L. (Cincinnati, OH), Ku; George (Burlington, MA), Meikrantz; Scott B. (Carson City, NV), Stemerick; David M. (Fairfield, OH) Assignee(s): Merrell Pharmaceuticals Inc. (cincinnati, Oh) Patent Number: 5,684,017 Date filed: August 6, 1996 Abstract: The present invention relates to novel benzenesulfonylimine derivatives and their use as inhibitors of Interleukin-1 (IL-1) action. Such inhibitors are useful in the treatment of various disease states as disclosed herein including: rheumatoid arthritis, multiple sclerosis, diabetes mellitus, atherosclerosis, septic shock and pulmonary fibrosis. Excerpt(s): Y is from 1 to 3 substituents independently chosen from the group: hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halogen. f) the term "pharmaceutically acceptable salts thereof" refers to either an acid addition salt or a basic addition salt. Web site: http://www.delphion.com/details?pn=US05684017__
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Germanium-containing organic polymer and its use in the treatment of pulmonary fibrosis Inventor(s): Ikegami; Shiro (2310 Kamikoizumi, Oizumicho, Funabashi, JP), Ishida; Yukihito (2310 Kamikoizumi, Oizumicho, Fujisawa, JP), Ishikawa; Akira (2310 Kamikoizumi, Oizumicho, Tokyo, JP), Sato; Ryuichi (2310 Kamikoizumi, Oizumicho, Ora-gun,; Gunma-ken, JP), Satoh; Hiroshi (2310 Kamikoizumi, Oizumicho, Tokyo, JP), Tomisawa; Setsuo (Tokyo, JP), Toyoshima; Shigeru (Tokyo, JP) Assignee(s): Sato; Ryuichi (tokyo, Jp) Patent Number: 4,321,273 Date filed: February 29, 1980 Abstract: Germanium-containing organic polymers are obtained by polymerizing 3trichlorogermylpropionic acid obtained by reacting halogermanium-phosphoric acid complexes with acrylic acid. The polymers are markedly effective in treating pulmonary fibrosis. Excerpt(s): The present invention relates to germanium-containing organic polymers which possess important therapeutic effects as medicine. In recent years, attention has been drawn to germanium-containing organic compounds in view of their pharmacological activities, which have been disclosed in Japanese Patent Publication No. 2964/71, Japanese Patent Application Laid Open No. 61431/73, Japanese Patent Publication Nos. 21855/71 and 2498/71, etc. The germanium-containing organic compound disclosed in these publications is a low molecular weight compound represented by the formula: (GeOH.sub.2 CH.sub.2 COOH).sub.2 O.sub.3. drawing their attention to the pharmacological activities of the germanium-containing organic compound, the present inventors have found novel germanium-containing organic polymers and the process for the production thereof as well as their use as medicine. Web site: http://www.delphion.com/details?pn=US04321273__
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Heterocyclic benzenesulfonylimine derivatives as inhibitors of IL-1 action Inventor(s): Harrison; Boyd L. (Cincinnati, OH), Ku; George (Burlington, MA), Stemerick; David M. (Fairfield, OH) Assignee(s): Merrell Pharmaceuticals Inc. (cincinnati, Oh) Patent Number: 5,668,143 Date filed: July 3, 1996 Excerpt(s): The present invention relates to heterocyclic benzenesulfonylimine derivatives and their use as inhibitors of Interleukin-1 (IL-1) action. Such inhibitors are useful in the treatment of various disease states as disclosed herein including rheumatoid arthritis, multiple sclerosis, diabetes mellitus, atherosclerosis, septic shock and pulmonary fibrosis. Y is from 1 to 3 substituents chosen independently from the group: hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, and halogen. Web site: http://www.delphion.com/details?pn=US05668143__
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Matrix metalloprotease Inventor(s): Atsushi; Nishimura (Tsukuba, JP), Koji; Yoshimura (Tsukuba, JP), Yuichi; Hikichi (Tsukuba, JP) Assignee(s): Takeda Chemical Industries, Ltd. (osaka, Jp) Patent Number: 6,566,116 Date filed: July 26, 1999 Abstract: This invention relates to a novel metalloprotease having a proteolytic activity, its partial peptide or a salt either of them, a DNA coding for the protein, a recombinant vector comprising the DNA, a transformant carrying the recombinant vector, a process for producing the protein, a pharmaceutical composition comprising the DNA, an antibody against the protein, a method for screening for a compound which activates or inhibits a proteolytic activity of the protein, a kit for screening for the compound, and a compound which activates or inhibits a proteolytic activity of the protein which is identified by the screening method or the kit. The DNA coding for the protein of the present invention can be used as a therapeutic and prophylactic composition for a variety of diseases including diabetic nephropathy, glomerulonephritis, pulmonary fibrosis, hepatolienal fibrosis, hepatocirrhosis, osteopetrosis and herniated disk. Furthermore, the protein of the present invention is useful as a screening reagent for any compounds which activate or inhibit the function of the protein of the present invention. In addition, the antibody against the protein of the present invention specifically recognizes the protein of the present invention and can be used in the quantitative determination of the protein of the present invention in a test fluid. Excerpt(s): This application is based on PCT/JP97/01433, having an International filing date of Apr. 24, 1997, which claims the priority date of Apr. 24, 1996 of Japanese application number 8-104902. The extracellular matrix, which is a cell-supporting tissue composed mainly of collagens and proteoglycans, is profoundly involved in such events as cell development, inflammation, and tissue repair. The enzymes known to be associated with the degradation of extracellular matrix are (1) cathepsin D, etc. which belongs to the aspartic proteaseas, (2) cathepsin B, H, L, etc. which belong to the cysteine proteases, (3) plasmin, kallikrein, neutrophil elastase, tryptase, chymase, cathepsin G, etc. which belong to the serine proteases, and (4) metalloproteases are known. Also
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called matrix metalloproteases, these metalloproteases are known to be playing central roles in the degradation of extracellular matrix. So far, in humans, 13 kinds of matrix metalloproteases such as collagenases, gelatinases stromelysins, and membrane-type matrix metalloproteases have been cloned and their nucleotide sequences and amino acid sequences have been reported (T. Takino et al., Journal of Biological Chemistry, 270, 23013, 1995; J. M. P. Freije et al., Journal of Biological Chemistry, 269, 16766, 1994; H. Wills et al., European Journal of Biochemistry, 231, 602, 1995). All of these enzymes are zinc-dependent metalloproteases, in which the amino acid sequence of the zinc-binding domain: His-Glu-X-Gly-His-Ser-Leu-Gly-Leu-X-His-Ser is well conserved, and their activities are inhibited by o-phenanthroline. Each of these enzymes is secreted in the latent form which is inactive with a propeptide at the N-terminus of the active enzyme. A conserved domain consisting in the amino acid sequence of Met-Arg-Lys-Pro-ArgCys-Gly-Val-Pro-Asp is located near the C-terminal region of the propeptide. This domain is called "cysteine switch", and it controls a protease activity by coordinating the zinc atom at active center with cysteine in the domain. While the latent enzymes are activated upon cleavage of the propeptide, three kinds of inhibitor proteins, named TIMP, have been reported and known to performing strict control of activity. It is also known that, in vitro, the latent enzymes are activated by treatment with trypsin or aminophenyl-mercuric acetate. Web site: http://www.delphion.com/details?pn=US06566116__ •
Method for augmenting a decreased level of reduced glutathione in the lung Inventor(s): Crystal; Ronald G. (Potomac, MD) Assignee(s): The United States of America AS Represented by the Department of Health (washington, Dc) Patent Number: 5,989,521 Date filed: December 31, 1991 Abstract: The present invention relates, in general, to a method for augmenting reduced glutathione level in the lungs of patients. In particular, the present invention relates to a method for augmenting reduced glutathione level in the lungs of patients with cystic fibrosis (CF), acquired immunodeficiency syndrome (AIDS), or idiopathic pulmonary fibrosis (IPF). Excerpt(s): In the lung, reduced glutathione (GSH) is present in high concentrations in the epithelial lining fluid (ELF) of the lower respiratory tract, with normal levels in human ELF being more than 40-fold greater than that in plasma. As such, ELF GSH is a major component of the antioxidant screen that protects the pulmonary epithelium from oxidants released by inflammatory cells as well as inhaled oxidants. In addition, ELF GSH helps maintain the normal function of the immune components of the pulmonary epithelial host defense system. However, in certain conditions, such as (1) cystic fibrosis (CF), (2) acquired immunodeficiency syndrome (AIDS), and (3) idiopathic pulmonary fibrosis (IPF), there is found to be a substantial ELF GSH deficiency. Cystic fibrosis (CF), the most common lethal hereditary disorder of Caucasians, is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene (Rommens, J. M. et al. (1989) Science 245:1059-1065; Riordan, J. R. et al. (1989) Science 245:1066-1073; Kerem, B-S. et al. (1989) Science 245:1073-1080). The clinical manifestations of CF are characterized by chronic purulent bronchitis, pancreatic insufficiency, and high levels of sodium chloride in sweat (Boat, T. F. et al. (1989) In The Metabolic Basis of Inherited Diseases. C. R. Scriver et al. eds. McGraw-Hill, New York. 2649-2680). Although the
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disease manifests in several organ systems, the lethal manifestations of CF are usually related to the epithelial surface of the airways. For reasons not completely defined, mutations of the CFTR gene are associated with abnormalities in airway mucus, colonization of the airway epithelium with Pseudomonas and other bacteria, and intense local neutrophil-dominated inflammation (Boat, T. F. et al. (1989) In The Metabolic Basis of Inherited Diseases. C. R. Scriver et al. eds. McGraw-Hill, New York. 2649-2680; McElvaney, N. G. et al. (1991) Lancet. 337:392-394; Elborn, J. S., and D. J. Shale (1990) Thorax 45:970-973; Suter, S. (1989) In Pseudomonas aeruginosa Infection, Antibiotic Chemother. N. Hoiby et al. eds. Basel, Karger. 42:158-168). It is the inflammation that is responsible for the progressive derangements to the epithelium, with eventual development of bronchiectasis and loss of functioning alveoli. Web site: http://www.delphion.com/details?pn=US05989521__ •
Monospecific antibodies and assay system for detecting stromelysin cleavage products Inventor(s): Bayne; Ellen B. K. (Westfield, NJ), Hoerrner; Lori A. (Scotch Plains, NJ), Lark; Michael W. (East Windsor, NJ), Mumford; Richard A. (Red Bank, NJ) Assignee(s): Merck & Co., Inc. (rahway, Nj) Patent Number: 5,387,504 Date filed: September 30, 1992 Abstract: Monospecific antibodies are produced which are specific for fragments of the connective tissue protein aggrecan, generated by specific stromelysin cleavage. These monospecific antibodies are used in an assay system to detect polypeptide fragments of aggrecan, produced by the specific cleavage of aggrecan by stromelysin. The presence of aggrecan polypeptide fragments demonstrates stromelysin activity. Elevations of stromelysin occur in osteoarthritis, rheumatoid arthritis, atherosclerotic lesions, gout, inflammatory bowel disease (IBD), idiopathic pulmonary fibrosis (IPF), certain cancers, joint injuries, and numerous inflammatory diseases. The monospecific antibodies and the assay system are used to quantitate aggrecan polypeptide fragments as a readout of stromelysin activity and to evaluate potential stromelysin inhibitors. Excerpt(s): The present invention is directed to the development of an antiserum and assay which reflects the in vivo activity of stromelysin in certain animal models as well as in those disease states where stromelysin is thought to play a major and/or central role. In addition, this antiserum and assay allow the evaluation of specific and selective inhibitors of stromelysin in these various diseases. Over 32 million Americans have some type of musculoskeletal disease, and of these, half have osteoarthritis (OA). OA is significantly more prevalent than rheumatoid arthritis (RA). In both RA and OA, there is degradation and loss of cartilage aggrecan and collagen which ultimately results in degradation of the underlying bone. Although the end result is similar for these two diseases, the mechanisms by which these diseases begin and progress appear to be different. RA is an inflammatory disease in which various cytokines such as IL-1 and TNF.alpha. have been implicated to stimulate the synovium to proliferate and produce degradative enzymes. On the other hand, OA is a disease which seems to develop from within the cartilage, in which biochemical and biomechanical factors play a major role. For instance, patients with cruciate ligament and meniscal injuries, which destabilize the joint, tend to develop OA at an accelerated rate. In OA, there appears to be synthesis of degradative proteinases by the chondrocytes with synovial hypertrophy and inflammation occuring late in the disease. The degradative proteinase stromelysin (SLN)
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is common to both OA and RA and may be responsible for the cartilage connective tissue destruction observed in both of these diseases. The non-antibody bound radioactivity was then separated as described above. Stromelysin cleavage products such as stromelysin cleaved aggrecan fragments, are measured with a rabbit polyclonal antiserum in either a classical RIA or by classical immunolocalization techniques. The antiserum detects stromelysin-cleaved aggrecan in: (a) SLN digestion of purified rabbit, bovine and human aggrecan in vitro; and (b) cleaved aggrecan in model systems where SLN is injected intraarticularly in vivo (i.e., rabbit knee joint). As a measure of stromelysin activity the antiserum is used to quantify stromelysin-cleaved aggrecan in: (a) models in which endogenous stromelysin synthesis is stimulated by various cytokines (i.e., IL-1 and TNF.alpha.); and (b) in various human diseases such as RA and OA. Use of this antibody also allows the evaluation of SLN inhibitors in various pharmocokinetic/pharmacological animal models as well as in various human diseases, such as RA and OA. Web site: http://www.delphion.com/details?pn=US05387504__ •
Post-translational activation of TGF-.beta.sub.1 involving the TSP-1 receptor CD36 Inventor(s): Khalil; Nasreen (Winnipeg, CA) Assignee(s): Manitoba Cancer Treatment and Research Foundation (winnipeg, Ca), The University of Manitoba (winnipeg, Ca) Patent Number: 6,090,367 Date filed: November 17, 1997 Abstract: A protein called transforming growth factor-beta (TGF-.beta.) is important in causing the inflammation and progressive scar tissue in pulmonary fibrosis. The TGF.beta.sub.1 isoform is important in the pathogenesis of pulmonary fibrosis. It is usually secreted non-covalently bound to a latency associated peptide (LAP) which renders it biologically inactive. The inactive form is called latent TGF-.beta.sub.1 (L-TGF.beta.sub.1). Activation of L-TGF-.beta.sub.1 involves L-TGF-.beta.sub.1 /TSP-1 complex which interacts with the TSP-1 receptor, CD36, to process L-TGF-.beta.sub.1 to the mature form in the presence of plasmin. Synthetic or natural CD36 peptides or fragments thereof can be used to prevent activation of TGF-.beta.sub.1, in mammalian alveolar macrophages, thereby controlling the inflammation process. Excerpt(s): The present invention relates to a treatment of pulmonary fibrosis which can be caused by a variety of agents and may be associated with a number of diseases. The most common form of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). IPF is a progressive and lethal pulmonary disease occurring in between about 9 to 23 people per 100,000 and for which no cure is presently available. Although most physicians generally treat IPF and other fibrotic lung diseases with high doses of corticosteroids, a favourable response rarely occurs, and if it does occur, it is transient. Instead, the use of high dose corticosteroids leads to a variety of complications that can be lethal themselves. It has been demonstrated that a protein called transforming growth factorbeta (TGF-.beta.) is important in causing the inflammation and progressive scar tissue in pulmonary fibrosis. The presence of inflammation and scarring lead to morbidity and mortality. TGF-.beta. exists in three isoforms in mammals, designated as TGF.beta.sub.1, TGF-.beta.sub.2 and TGF-.beta.sub.3. The characteristics as well as the in vitro and in vivo biological effects are most extensively reported for TGF-.beta.sub.1. Applicants have found that the TGF-.beta.sub.1 isoform is important in the pathogenesis of pulmonary fibrosis induced by bleomycin. All cells in the body produce TGF-.beta.s
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and all cells can respond to it. However, it is usually secreted non-covalently bound to a latency associated peptide (LAP) which renders it biologically inactive. The inactive form is called latent TGF-.beta.sub.1 (L-TGF-.beta.sub.1). Applicants have found that in an animal model of pulmonary fibrosis and in samples from patients with IPF, TGF.beta.sub.1 is secreted by alveolar macrophages in an active form. As well, applicants have found indications that in advanced cases of IPF, active TGF-.beta.sub.1 is secreted by epithelial cells. Epithelial cells may be the source of TGF-.beta.sub.1 found subepithelially where there is extensive fibrous connective tissue present. The subepithelial location of TGF-.beta.sub.1 could result in expansion of the fibroblast cell population and enhanced connective tissue synthesis and therefore play a critical role in the pathogenesis of pulmonary fibrosis. Web site: http://www.delphion.com/details?pn=US06090367__ •
Protein and DNA thereof Inventor(s): Hikichi; Yuichi (Tsukuba, JP), Nishimura; Atsushi (Tsukuba, JP), Yoshimura; Koji (Tsukuba, JP) Assignee(s): Takeda Chemical Industries, Ltd. (osaka, Jp) Patent Number: 6,680,189 Date filed: May 10, 2001 Abstract: The present invention relates to a novel protein belonging to an ADAM family, a partial peptide thereof or a salt thereof, a DNA encoding the protein, a recombinant vector comprising the DNA, a transformant, a method for producing the protein, a medicine comprising the protein or the DNA, an antibody against the protein, a method/kit for screening for a compound or a salt thereof which promotes or inhibits the protease activity or the extracellular metric degrading enzyme activity (preferably, the peptidoglycan degrading enzyme activity) of the protein, a compound obtained by the screening, and a medicine comprising the compound. The present protein and a DNA encoding it can be used, for example, as an agent for treating or preventing various diseases such as disc herniation, ischialgia, glomerular nephritis, diabetic nephropathy, hepatic fibrosis, pulmonary fibrosis or osteopetrosis. In addition, the present antibody can be used for quantitating the present protein in a test solution. Further, the present protein is useful as a reagent for screening for a compound which promotes or inhibits the protease activity of the present protein. Excerpt(s): This Application is the National Stage of International Application Serial No. PCT/JP99/04766, filed Sep. 2, 1999. The present invention relates to a novel ADAM protein. An extracellular matrix is a cell-supporting tissue surrounding cells of the tissue and is composed of a fibrous protein such as collagen and elastin, a complex carbohydrate such as proteoglycan, a glycoprotein such as fibronectin and laminin, which relate to cell-adhesion, and a sugar such as hyaluronic acid. The exracellular matrix is known to have the important influence of activities of cells such as shape, metabolism, migration, proliferation and differentiation. Therefore, the extracellular matrix is known to be associated with many living body phenomena such as development, aging, inflammation, wound healing, immunity and tumor of the living body. It is known that the abnormal degradation of the extracellular matrix occurs in a variety of diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, cancer metastasis and infiltration, arteriosclerosis and corneae ulcer. There is a possibility that regulation of the enzyme activities involved in degradation of the extracellular matrix produces a therapeutic agent for these diseases.
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Web site: http://www.delphion.com/details?pn=US06680189__ •
Protein having proteinase inhibitor activity Inventor(s): Davies; Christopher (Walnut Creek, CA), Delaria; Kathy (Walnut Creek, CA), Roczniak; Steve (Lafayette, CA) Assignee(s): Bayer Corporation (berkeley, Ca) Patent Number: 6,294,648 Date filed: July 20, 1999 Abstract: BTL.009 is a novel human serine proteinase inhibitor of the Kunitz family that exhibits greater potency towards neutral serine proteinases, particularly leukocyte elastase, and chymotrypsin than towards trypsin-like proteinases. BTL.009, or variants thereof, may be employed as therapeutics in diseases such as emphysema, idiopathic pulmonary fibrosis, adult respiratory distress syndrome, cystic fibrosis, rheumatoid arthritis, organ failure, and glomerulonephritis in which uncontrolled proteolysis due to neutral serine proteinase activity results in tissue damage. Excerpt(s): This invention relates to newly identified polynucleotides, polypeptides encoded by such polynucleotides, the use of such polynucleotides and polypeptides, as well as the production of such polynucleotides and polypeptides. More particularly, the polypeptide of the present invention has been identified as a member of the Kunitz serine proteinase inhibitor family and is hereinafter referred to as BTL.009. The inflammatory response after surgeries, trauma and infection involves neutrophil activation and infiltration into the injured tissue. The activated neutrophils release the neutral serine proteinases leukocyte elastase, cathepsin G and proteinase 3, which, if not properly controlled, cause abnormal connective tissue turnover and result in severe damage to healthy tissue (1-3, 81). The uncontrolled proteolysis can lead to a myriad of diseases including emphysema, idiopathic pulmonary fibrosis, adult respiratory distress syndrome, cystic fibrosis, rheumatoid arthritis, organ failure, and glomerulonephritis. Proteins capable of inhibiting the neutral serine proteinases released by neutrophils can have therapeutic efficacy in treating inflammatory diseases. In patients suffering from hyperdynamic septic shock, plasma levels of the serine proteinase inhibitors antithrombin III, alpha 2-macroglobulin and inter-alpha-trypsin inhibitor, as well as those of various clotting, complement and other plasma factors, are significantly decreased (5). In an experimental endotoxemia model, the reduction in the plasma levels of these factors was considerably diminished by the intravenous injection of a soybean-derived leukocyte elastase and cathepsin G inhibitor, indicating that these neutral proteinases are at least partially responsible for the proteolysis of the plasma factors. In addition, the survival rate in the rat lethal peritonitis model (cecal ligation and puncture-induced septic shock model) was improved by treatment with the second domain of human urinary trypsin inhibitor (2), which has been shown to inhibit leukocyte elastase and cathepsin G (6, 7). Web site: http://www.delphion.com/details?pn=US06294648__
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Regulated angiogenesis genes and polypeptides Inventor(s): Jay; Gilbert (North Bethesda, MD), Li; Xuan (Silver Spring, MD), Sun; Zairen (Rockville, MD) Assignee(s): Origene Technologies, Inc. (rockville, Md) Patent Number: 6,657,054 Date filed: June 10, 2002 Abstract: The present invention relates to all facets of novel polynucleotides, the polypeptides they encode, antibodies and specific binding partners thereto, and their applications to research, diagnosis, drug discovery, therapy, clinical medicine, forensic science and medicine, etc. The polynucleotides are modulated during angiogeneis and are therefore useful in variety of ways, including, but not limited to, as molecular markers, as drug targets, and for detecting, diagnosing, staging, monitoring, prognosticating, preventing or treating, determining predisposition to, etc., diseases and conditions, determining predisposition to, etc., diseases and conditions, such as abnormal, insufficient, excessive, etc., angiogenesis, inflammatory diseases, rheumatoid arthritis, osteoarthritis, asthma, pulmonary fibrosis, age-related macular degeneration (ARMD), diabetic retinopathy, macular degeneration, and retinopathy of prematurity (ROP), endometriosis, cancer, Coats' disease, peripheral retinal neovascularization, neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, etc. Excerpt(s): Angiogenesis, the process of blood vessel formation, is a key event in many physiological processes that underlie normal and diseased tissue function. During ontogeny, angiogenesis is necessary to establish to the network of blood vessels required for normal cell, tissue and organ development and maintenance. In the adult organism, the production of new blood vessels is needed for organ homeostasis, e.g., in the cycling of the female endometrium, for blood vessel maturation during wound healing, and other processes involved in the maintenance of organism integrity. It also is important in regenerative medicine, including, e.g., in promoting tissue repair, tissue engineering, and the growth of new tissues, inside and outside the body. Not all angiogenesis is beneficial. Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumor enlargement and metastasis. Web site: http://www.delphion.com/details?pn=US06657054__
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Substituted ureas as cell adhesion inhibitors Inventor(s): DeLaszlo; Stephen E. (Rumson, NJ), Hagmann; William K. (Westfield, NJ), Kamenecka; Theodore M. (Atlantic Highlands, NJ) Assignee(s): Merck & Co., Inc. (rahway, Nj) Patent Number: 6,353,099 Date filed: August 17, 2000 Abstract: Compounds of Formula I are antagonists of VLA-4 and/or.alpha.sub.4.beta.sub.7, and as such are useful in the inhibition or prevention of
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cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of AIDS-related dementia, allergic conjunctivitis, allergic rhinitis, Alzheimer's disease, asthma, atherosclerosis, autologous bone marrow transplantation, certain types of toxic and immune-based nephritis, contact dermal hypersensitivity, inflammatory bowel disease including ulcerative colitis and Crohn's disease, inflammatory lung diseases, inflammatory sequelae of viral infections, meningitis, multiple sclerosis, multiple myeloma, myocarditis, organ transplantation, psoriasis, pulmonary fibrosis, restenosis, retinitis, rheumatoid arthritis, septic arthritis, stroke, tumor metastasis, uveititis, and type I diabetes. Excerpt(s): The compounds of the present invention are antagonists of the VLA-4 integrin ("very late antigen-4"; CD49d/CD29; or.alpha.sub.4.beta.sub.1), the.alpha.4.beta.7 integrin (LPAM-1 and.alpha.sub.4.beta.sub.p), and/or the.alpha.9.beta.1 integrin, thereby blocking the binding of VLA-4 to its various ligands, such as VCAM-1 and regions of fibronectin,.alpha.4.beta.7 to its various ligands, such as MadCAM-1, VCAM-1 and fibronectin, and /or.alpha.9.beta.1 to its various ligands, such as tenascin, osteopontin and VCAM-1. Thus, these antagonists are useful in inhibiting cell adhesion processes including cell activation, migration, proliferation and differentiation. These antagonists are useful in the treatment, prevention and suppression of diseases mediated by VLA-4,.alpha.4.beta.7-, and/or.alpha.9.beta.1binding and cell adhesion and activation, such as AIDS-related dementia, allergic conjunctivitis, allergic rhinitis, Alzheimer's disease, aortic stenosis, asthma, atherosclerosis, autologous bone marrow transplantation, certain types of toxic and immune-based nephritis, contact dermal hypersensitivity, inflammatory bowel disease including ulcerative colitis and Crohn's disease, inflammatory lung diseases, inflammatory sequelae of viral infections, meningitis, multiple sclerosis, myocarditis, organ transplantation, psoriasis, restenosis, retinitis, rheumatoid arthritis, septic arthritis, stroke, tumor metastasis, type I diabetes, vascular occlusion following angioplasty. The present invention relates to substituted urea derivatives which are useful for the inhibition and prevention of leukocyte adhesion and leukocyte adhesionmediated pathologies. This invention also relates to compositions containing such compounds and methods of treatment using such compounds. Many physiological processes require that cells come into close contact with other cells and/or extracellular matrix. Such adhesion events may be required for cell activation, migration, proliferation and differentiation. Cell-cell and cell-matrix interactions are mediated through several families of cell adhesion molecules (CAMs) including the selectins, integrins, cadherins and immunoglobulins. CAMs play an essential role in both normal and pathophysiological processes. Therefore, the targetting of specific and relevant CAMs in certain disease conditions without interfering with normal cellular functions is essential for an effective and safe therapeutic agent that inhibits cell-cell and cell-matrix interactions. Web site: http://www.delphion.com/details?pn=US06353099__ •
Use of intratracheally administered hyaluronic acid to ameliorate emphysema Inventor(s): Cantor; Jerome O. (5900 Arlington Ave., Apt. 4H, Riverdale, NY 10471) Assignee(s): None Reported Patent Number: 5,633,003 Date filed: March 31, 1994
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Abstract: The subject invention is directed to the treatment of respiratory disorders by intratracheal administration of an effective amount of hyaluronic acid. Respiratory disorders include emphysema, chronic bronchitis, asthma, pulmonary edema, acute respiratory distress syndrome, bronchopulmonary dysplasia, pulmonary fibrosis, and pulmonary atelectasis. The treatment is intended for a variety of mammals, such as premature neonates to adult humans. Administration of hyaluronic acid may be performed by aerosol, which can be generated by a nebulizer, or by instillation. The hyaluronic acid may be administered alone, or with a carrier such as saline solution, DMSO, an alcohol or water. It may be isolated from a natural source such as a bovine or rooster. The effective daily amount of hyaluronic acid is from about 10.mu.g/kg to about 1 mg/kg of body weight. Excerpt(s): Throughout this application various publications are referenced by numbers. The full citations are listed at the end of the specification immediately preceeding the claims. The proteinase-antiproteinase concept of emphysema has served to focus research on the role of elastases, with the hope that inhibiting the activity of these enzymes will prevent lung injury (1-4). Such a treatment strategy assumes, however, that emphysema is caused by a specific type of biochemical derangement, as in the case of alpha-1-antiproteinase deficiency (5). If the disease represents a more general response of the lung to a variety of insults (with elastases playing a variable role), then enzyme inhibition may have only limited efficacy. In attempting to address the issue of whether emphysema is a specific or multifactorial disease process, a series of experiments were previously performed by this laboratory involving both the induction and modification of experimental emphysema with agents other than elastases. It was found that elastase-induced emphysema is greatly enhanced by exposing the lungs to a normally nontoxic concentration of oxygen (60 percent) (6). Similarly, it was possible to produce air-space enlargement with a nonelastolytic enzyme, hyaluronidase, by the addition of 60 percent oxygen (7). The experiments using hyaluronidase and 60 percent oxygen showed that loss of lung elastin occurred only when both agents were given concomitantly, suggesting the possibility that hyaluronidase may facilitate the breakdown of elastic fibers by making them more accessible to injury. Web site: http://www.delphion.com/details?pn=US05633003__
Patent Applications on Pulmonary 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 pulmonary fibrosis:
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This has been a common practice outside the United States prior to December 2000.
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Antagonists of MCP-1 function and methods of use thereof Inventor(s): Anuskiewicz, Steven E.; (San Bruno, CA), Inagaki, Hideaki; (Anjoh-shi, JP), Ishiwata, Yoshiro; (Aichi-gun, JP), Jomori, Takahito; (Nagoya-shi, JP), Kakigami, Takuji; (Inabe-gun, JP), Laborde, Edgardo; (Foster City, CA), Matsumoto, Yukiharu; (Gifu-shi, JP), Matsushima, Kouji; (Matsudo-shi, JP), Meng, Fanying; (San Francisco, CA), Peterson, Brian T.; (San Francisco, CA), Robinson, Louise; (San Carlos, CA), Villar, Hugo O.; (La Jolla, CA), Yokochi, Shoji; (Inabe-gun, JP) Correspondence: Heller Ehrman White & Mcauliffe Llp; 275 Middlefield Road; Menlo Park; CA; 94025-3506; US Patent Application Number: 20030105085 Date filed: February 27, 2002 Abstract: Compounds which are antagonists of MCP-1 function and are useful in the prevention or treatment of chronic or acute inflammatory or autoimmune diseases, especially those associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease, Crohn's disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, and transplant rejection; pharmaceutical compositions comprising these compounds; and the use of these compounds and compositions in the prevention or treatment of such diseases. Excerpt(s): This application claims the priority under 35 USC 119(e) of U.S. Provisional Application No. 60/272,792, filed Mar. 1, 2001, which is incorporated herein by reference. The present invention relates to compounds which are antagonists of MCP-1 function and are useful in the prevention or treatment of chronic or acute inflammatory or autoimmune diseases, especially those associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease, Crohn's disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, and transplant rejection; and to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases. The migration of leukocytes from blood vessels into diseased tissues is an important process in the initiation of normal inflammatory responses to certain stimuli or insults to the immune system. However, this process is also involved in the onset and progression of life-threatening inflammatory and autoimmune diseases; blocking leukocyte recruitment in these disease states, therefore, can be an effective therapeutic strategy. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Anti fibrotic agent containing sphingosine 1-phosphate receptor agonist or sphingosine 1-phospate as active ingredient Inventor(s): Kishikawa, Katsuya; (Mishima-gun, JP), Matsumoto, Shigeru; (Mishimagun, JP) Correspondence: Sughrue Mion, Pllc; 2100 Pennsylvania Avenue, N.W.; Suite 800; Washington; DC; 20037; US Patent Application Number: 20040063667 Date filed: September 15, 2003
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Abstract: An anti fibrotic agent, comprising a sphingosine 1-phosphate (S1P) receptor agonist or sphingosine 1-phosphate (S1P) as an active ingredient. Since an S1P receptor agonist, particularly S1P, has activity of inhibiting fibrosis in various organs, it is useful in preventing and/or treating diseases caused by fibrosis in organs, such as pulmonary fibrosis, interstitial pneumonia, chronic hepatitis, hepatic cirrhosis, chronic renal failure, renal glomerulosclerosis, etc. Excerpt(s): Sphingolipid as one of the cell membrane-constituting lipid-soluble components contains two kinds, sphingomyelin and glycolipid. They are converted into ceramides enzymatically via sphingomyelinase and endoglycanase, and then metabolized into sphingosine by a ceramidase. Furthermore, the sphingosine is then converted into sphingosine 1-phosphate (hereinafter referred to as "S1P") by a sphingosine kinase. Studies on such intracellular metabolism of sphingolipid have been carried out since 1960's, but until now, S1P has been recognized only as one of the intermediate metabolic products in the sphingolipid metabolism. However, S1P is focused because its physiological activities are being revealed recently. For example, the followings are known as the activities possessed by S1P. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Attenuation of fibroblast proliferation Inventor(s): Cauchon, Elizabeth; (Ile Perrot, CA), Denholm, Elizabeth M.; (Pointe Claire, CA), Silver, Paul J.; (Spring City, PA) Correspondence: Patrea L. Pabst; Arnall Golden & Gregory, Llp; 2800 One Atlantic Center; 1201 West Peachtree Street; Atlanta; GA; 30309-3450; US Patent Application Number: 20020102249 Date filed: December 1, 2000 Abstract: Highly purified and specific glycosaminoglycan degrading enzymes, chondroitinase B and chondroitinase AC, are used to treat fibroproliferative diseases. The enzymatic removal of chondroitin sulfate B (dermatan sulfate), and to a lesser extent, chondroitin sulfate A or C, from cell surfaces effectively decreases growth factor receptors on the cells and thereby decreases the cell proliferative response to such growth factors. In addition, removal of chondroitin sulfates reduces secretion of collagen, one of the major extracellular matrix components. Through the combined inhibition of fibroblast proliferation and collagen synthesis, treatment with chondroitinase B or chondroitinase AC decreases the size of fibrous tissue found in psoriasis, scleroderma, keloids, pulmonary fibrosis and surgical adhesions. Excerpt(s): The present invention is a method and composition using chondroitinase B and chondroitinase AC, glycosaminoglycan degrading enzymes, to inhibit the formation of fibrotic tissue. This application claims priority to U.S. Ser. No. 60/168,518, filed Dec. 2, 1999. Proteoglycans on the cell surface and in the extracellular matrix contain variable glycosaminoglycan chains, which include heparan sulfate and chondroitin sulfates A, B, or C. While some proteoglycans contain only one type of glycosaminoglycan, others contain a mixture of heparan and chondroitin sulfates (Jackson et. al., Physiol. Rev. 71:481-530,1991). Extracellular proteoglycans form a structural framework for cells and tissues, and together with cell-associated proteoglycans, have major functions in regulating cell adhesion, migration, and proliferation. The functions of proteoglycans and their component parts have been extensively studied, with much of the emphasis on the roles of heparin and heparan sulfate on cell metabolism (Kjellen, L., and Lindahl, U.
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(1991) Ann. Rev. Biochem. 60:443-475; Vlodavsky, et al. (1995) Thrombosis Haemostasis 74:534-540; Yayon, et al. (1991) Cell 64:841-848)). Much less is known about the biological activities of proteoglycans containing chondroitin sulfate glycosaminoglycans, and in particular, their effects on cell proliferation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Compounds and methods Inventor(s): Bondinell, William E.; (Collegeville, PA), Neeb, Michael J.; (Collegeville, PA) Correspondence: Smithkline Beecham Corporation; Corporate Intellectual Property-us, Uw2220; P. O. Box 1539; King OF Prussia; PA; 19406-0939; US Patent Application Number: 20040038982 Date filed: February 5, 2003 Abstract: This invention relates to substituted heterocyclic compounds which are modulators, agonists or antagonists, of the CCR5 receptor. In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5, including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis, or idiopathic pulmonary fibrosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, treating and/or preventing rejection of transplanted organs, and inflammatory bowel disease, all in mammals, by the use of substituted heterocyclic compounds which are CCR5 receptor antagonists. Furthermore, since CD8+ T cells have been implicated in COPD, CCR5 may play a role in their recruitment and therefore antagonists to CCR5 could provide potential therapeutic in the treatment of COPD. Also, since CCR5 is a coreceptor for the entry of HIV into cells, selective receptor modulators may be useful in the treatment of HIV infection. Excerpt(s): This invention relates to substituted heterocyclic compounds which are modulators, agonists or antagonists, of the CC chemokine receptor CC-CKR5 now designated as CCR5 (Nature Medicine 1996, 2, 1174-8). In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5. T cells are not only key regulators of the immune response to infectious agents but are believed critical for the initiation and maintenance of the inflammatory reaction in a variety of chronic diseases. Increased numbers or enhanced activation state of T cells, especially CD4+ T cells, have been demonstrated in the synovium of individuals with rheumatoid arthritis (M. J. Elliott and R. N. Maini, Int. Arch. Allergy Immunol. 104: 112-1125, 1994), in the bronchial mucosa of asthmatics (C. J. Corrigan and A. B. Kay, Immunol. Today 13:501506, 1992), in the lesions of multiple sclerosis (R. Martin and H. F. McFarland, Crit. Rev. Clin. Lab. Sci. 32: 121-182, 1995), in psoriatic lesions (J. L. Jones, J. Berth-Jone, A. Fletcher and P. E. Hutchinson, J. Pathol. 174: 77-82, 1994) and in the fatty streaks of atherosclerosis (R. Ross, Annu. Rev. Physiol. 57: 791-804, 1995). T cells, as well as other inflammatory cells, will migrate into tissues in response to the production of a variety of chemotactic factors. Among these factors are a superfamily of 8-12 kDa proteins known as the chemokines. These proteins share structural features such as the presence of 3-4 conserved cysteine residues. RANTES, which stands for Regulated upon Activation Normal T cell Expressed and Secreted, is an 8 kDa protein member of CC branch of the chemokine family. These proteins recruit and activate immune and inflammatory cells through an interaction with G-protein coupled receptors. The CC branch is defined by the absence of an intervening amino acid residue between the first two cysteine residues and members of this family predominately elicit the migration of mononuclear cells,
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eosinophils and basophils (M. Baggiolini, B. Dewald, and B. Moser, Adv. Immunol. 55: 97-179, 1994; and J. J. Oppenheim, C. O. C. Zachariae, N. Mukaida, and K. Matsushima, Annu. Rev. Immunol. 9: 617-648, 1991). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Copper lowering treatment of inflammatory and fibrotic diseases Inventor(s): Brewer, George J.; (Ann Arbor, MI) Correspondence: Thomas J. Bordner; Medlen & Carroll, Llp; Suite 350; 101 Howard Street; San Francisco; CA; 94105; US Patent Application Number: 20040009237 Date filed: May 23, 2003 Abstract: The present invention relates generally to the field of prophylaxis and therapy for inflammatory and/or fibrotic diseases which include responses to injuries. In particular, the present invention is related to agents that can bind or complex copper such as thiomolybdate, and to the use of these agents in the prevention and treatment of inflammatory and/or fibrotic diseases. Exemplary thiomolybdates include mono-, di-, tri- and tetrathiomolybdate; these agents are administered to patients to prevent and/or treat inflammatory and/or fibrotic diseases, such as pulmonary disease including pulmonary fibrosis and acute respiratory distress syndrome, liver disease including liver cirrhosis and hepatitis C, kidney disease including renal interstitial fibrosis, scleroderma, cystic fibrosis, pancreatic fibrosis, keloid, secondary fibrosis in the gastrointestinal tract, hypertrophic bum scars, myocardial fibrosis, Alzheimer's disease, retinal detachment inflammation and/or fibrosis resulting after surgery, and graft versus host and host versus graft rejections. Excerpt(s): The present invention claims priority to U.S. No. 60/382,993 filed on May 24, 2002, the disclosure of which is herein incorporated by reference in its entirety. The present invention relates generally to the field of prophylaxis and therapy for inflammatory and fibrotic diseases. In particular, the present invention is related to agents that can bind or complex copper, and to the use of these agents in the prevention and treatment of inflammatory and fibrotic diseases. Many diseases begin with inflammation, which if excessive, may overwhelm and kill the patient, or if the patient survives, often leads to a disabling fibrosis, which ultimately may also kill the patient. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Differentially-expressed genes and polypeptides in angiogenesis Inventor(s): Jay, Gilbert; (North Bethesda, MD), Sun, Zairen; (Rockville, MD) Correspondence: Origene Technologies, Incorporated; 6 Taft Court; Suite 100; Rockville; MD; 20850; US Patent Application Number: 20030148334 Date filed: October 11, 2002 Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/328,395, filed Oct. 12, 2002, which is hereby incorporated by reference in its entirety. The present invention relates to all facets of polynucleotides, the polypeptides they encode, antibodies and specific binding partners thereto, and their applications to
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research, diagnosis, drug discovery, therapy, clinical medicine, forensic science and medicine, etc. The polynucleotides are expressed during angiogenesis and are therefore useful in variety of ways, including, but not limited to, as molecular markers, as drug targets, and for detecting, diagnosing, staging, monitoring, prognosticating, preventing or treating, determining predisposition to, etc., diseases and conditions, especially relating to the vascular system. The identification of specific genes, and groups of genes, expressed in pathways physiologically relevant to angiogenesis permits the definition of functional and disease pathways, and the delineation of targets in these pathways which are useful in diagnostic, therapeutic, and clinical applications. The present invention also relates to methods of using the polynucleotides and related products (proteins, antibodies, etc.) in business and computer-related methods, e.g., advertising, displaying, offering, selling, etc., such products for sale, commercial use, licensing, etc. Angiogenesis, the process of blood vessel formation, is a key event in many physiological processes that underlie normal and diseased tissue function. During ontogeny, angiogenesis is necessary to establish to the network of blood vessels required for normal cell, tissue and organ development and maintenance. In the adult organism, the production of new blood vessels is needed for organ homeostasis, e.g., in the cycling of the female endometrium, for blood vessel maturation during wound healing, and other processes involved in the maintenance of organism integrity. It also is important in regenerative medicine, including, e.g., in promoting tissue repair, tissue engineering, and the growth of new tissues, inside and outside the body. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Interferon gamma polypeptide variants Inventor(s): Jensen, Anne Dam; (Copenhagen, DK) Correspondence: Donald J. Pochopien, ESQ.; Mcandrews, Held & Malloy, LTD.; 34th Floor; 500 West Madison Street; Chicago; IL; 60661; US Patent Application Number: 20020192183 Date filed: April 4, 2002 Excerpt(s): The present invention relates to novel interferon gamma polypeptide variants having interferon gamma (IFNG) activity, methods for their preparation, pharmaceutical compositions comprising the polypeptide variants and their use in the treatment of diseases, in particular for the treatment of interstitial pulmonary diseases, such as idiopathic pulmonary fibrosis. Interferon gamma (IFNG) is a cytokine produced by T-lymphocytes and natural killer cells and exists as a homodimer of two noncovalently bound polypeptide subunits. The mature form of each dimer comprises 143 amino acid residues (shown in SEQ ID NO:17), the precursor form thereof includes 166 amino acid residues (shown in SEQ ID NO: 18). Each subunit has two potential Nglycosylation sites (Aggarwal et al., Human Cytokines, Blackwell Scientific Publications, 1992) at positions 25 and 97. Depending on the degree of glycosylation the molecular weight of IFNG in dimer form is 34-50 kDa (Farrar et al., Ann. Rev. Immunol, 1993, 11:571-611). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Lectins as anti-fibrotic agents Inventor(s): Cantor, Jerome Owen; (Brooklyn, NY), Shteyngart, Bronislava; (Brooklyn, NY) Correspondence: Jerome O. Cantor, MD; 242 92nd Street; Brooklyn; NY; 11209; US Patent Application Number: 20030216300 Date filed: May 12, 2003 Abstract: The subject invention is directed to the treatment of tissue fibrosis by administration of an effective amount of lectin. Fibrosis herein refers to the accumulation of extracellular matrix constituents that occurs following trauma, inflammation, tissue repair, immunological reactions, cellular hyperplasia, and neoplasia. Examples of tissue fibrosis include, but are not limited to, pulmonary fibrosis, cirrhosis of the liver, skin scars and keloids, adhesions, fibromatosis, atherosclerosis, and amyloidosis. The treatment is intended for a variety of mammals, including humans. Excerpt(s): Lectins bind to carbohydrate moieties, e.g. acetylglucosamine, that are ubiquitous in the mammalian extracellular matrix. This suggests the possibility that lectins may be used to coat the matrix and limit further binding of collagen, elastin, and other connective tissue components to carbohydrate groups. The aggregation of large amounts of matrix constituents, as occurs in fibrosis, may therefore be subject to limitation by the introduction of lectins. This hypothesis was tested in our laboratory. Elastic fiber matrix prepared from cultured rat lung mesothelial cells (1,2) was first treated with tomato lectin (lycopersicon esculentum), then covered with hyaluronan (HA), which normally protects the matrix from degradation by elastases. It was found that lectin treatment abolished the protective effect of HA and facilitated breakdown of the elastic fiber matrix by elastase. Since the binding of HA to the elastic fibers is analogous to fibrosis in that it involves deposition of new matrix material (HA) over existing matrix, the addition of lectin may provide a means of counteracting this process and preventing the formation of scar tissue. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Methods for treating pulmonary fibrosis Inventor(s): Uhal, Bruce D.; (East Lansing, MI) Correspondence: Marshall, Gerstein & Borun; 6300 Sears Tower; 233 South Wacker; Chicago; IL; 60606-6357; US Patent Application Number: 20030113330 Date filed: January 6, 2003 Abstract: The present invention relates to uses of non-thiol ACE inhibitors, angiotensin II antagonists, angiotensin II receptor antagonists, endonuclease inhibitors, and caspaseinhibitors to treat pulmonary fibrosis and/or inhibit pulmonary epithelial cell apoptosis, including pulmonary fibrosis associated with amiodarone product toxicity. Excerpt(s): This application claims priority of U.S. Serial No. 60/164,052 filed Nov. 8, 1999, the entire disclosure of which is incorporated by reference herein. The present invention relates generally to novel therapeutic methods for treating pulmonary fibrosis using compounds that inhibit apoptosis of cells mediated by the reninangiotensin-aldosterone system. Intact alveolar epithelium is critical in maintaining
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many lung functions including gas exchange, water balance, surfactant synthesis and local immunomodulation. Damage to the human lung can result from either bloodborne or inhaled toxicants or by inflammation of extrapulmonary origin, such as that associated with sepsis, although injury by inhalation is the most common mechanism. Studies have documented and detailed the lung injuries induced by a variety of mineral dusts, see, e.g., Miller et al., Environ Health Perspect. 85:15-23 (1990), oxidant gases, see, e.g., Evans et al., Arch. Environ. Health 24:180-188 (1972), and cytotoxic drugs, see, e.g., Thrall et al., Am. J. Pathol. 95:117-130 (1979). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Novel proteins, their production and use Inventor(s): Atsushi, Nishimura; (Tsukuba, JP), Koji, Yoshimura; (Tsukuba, JP), Yuichi, Hikichi; (Tsukuba, JP) Correspondence: Edwards & Angell, Llp; P.O. Box 9169; Boston; MA; 02209; US Patent Application Number: 20030099631 Date filed: September 19, 2002 Abstract: This invention relates to a novel metalloprotease having a proteolytic activity, its partial peptide or a salt either of them, a DNA coding for the protein, a recombinant vector comprising the DNA, a transformant carrying the recombinant vector, a process for producing the protein, a pharmaceutical composition comprising the DNA, an antibody against the protein, a method for screening for a compound which activates or inhibits a proteolytic activity of the protein, a kit for screening for the compound, and a compound which activates or inhibits a proteolytic activity of the protein which is identified by the screening method or the kit. The DNA coding for the protein of the present invention can be used as a therapeutic and prophylactic composition for a variety of diseases including diabetic nephropathy, glomerulonephritis, pulmonary fibrosis, hepatolienal fibrosis, hepatocirrhosis, osteopetrosis and herniated disk. Furthermore, the protein of the present invention is useful as a screening reagent for any compounds which activate or inhibit the function of the protein of the present invention. In addition, the antibody against the protein of the present invention specifically recognizes the protein of the present invention and can be used in the quantitative determination of the protein of the present invention in a test fluid. Excerpt(s): The present invention relates to a novel matrix metalloprotease and a DNA coding for the metalloprotease. The extracellular matrix, which is a cell-supporting tissue composed mainly of collagens and proteoglycans, is profoundly involved in such events as cell development, inflammation, and tissue repair. The enzymes known to be associated with the degradation of extracellular matrix are (1) cathepsin D, etc. which belongs to the aspartic proteaseas, (2) cathepsin B, H, L, etc. which belong to the cysteine proteases, (3) plasmin, kallikrein, neutrophil elastase, tryptase, chymase, cathepsin G, etc. which belong to the serine proteases, and (4) metalloproteases are known. Also called matrix metalloproteases, these metalloproteases are known to be playing central roles in the degradation of extracellular matrix. So far, in humans, 13 kinds of matrix metalloproteases such as collagenases, gelatinases stromelysins, and membrane-type matrix metalloproteases have been cloned and their nucleotide sequences and amino acid sequences have been reported (T. Takino et al., Journal of Biological Chemistry, 270, 23013, 1995; J. M. P. Freije et al., Journal of Biological Chemistry, 269, 16766, 1994; H. Wills et al., European Journal of Biochemistry, 231, 602, 1995). All of these enzymes are zinc-dependent metalloproteases, in which the amino acid sequence of the zinc-binding
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domain: His-Glu-X-Gly-His-Ser-Leu-Gly-Leu-X-His-Ser is well conserved, and their activities are inhibited by o-phenanthroline. Each of these enzymes is secreted in the latent form which is inactive with a propeptide at the N-terminus of the active enzyme. A conserved domain consisting in the amino acid sequence of Met-Arg-Lys-Pro-ArgCys-Gly-Val-- Pro-Asp is located near the C-terminal region of the propeptide. This domain is called "cysteine switch", and it controls a protease activity by coordinating the zinc atom at active center with cysteine in the domain. While the latent enzymes are activated upon cleavage of the propeptide, three kinds of inhibitor proteins, named TIMP, have been reported and known to performing strict control of activity. It is also known that, in vitro, the latent enzymes are activated by treatment with trypsin or aminophenyl-mercuric acetate. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Recombinant adenoviral vectors and their utility in the treatment of various types of fibrosis: hepatic, renal, pulmonary, as well as hypertrophic scars Inventor(s): Aguilar Cordova, Estuardo; (Col. Prado Coapa, MX), Armendariz Borunda, Juan; (Prado Coapa, MX) Correspondence: Pennie & Edmonds Llp; 1667 K Street NW; Suite 1000; Washington; DC; 20006 Patent Application Number: 20030003077 Date filed: March 18, 2002 Abstract: The use of gene therapy for the treatment of different kinds of fibrosis in human beings is disclosed. The purpose is the use of "therapeutic2 genes specifically directed to target organs to revert and/or prevent the development of the fibrosis process.The potential application of gene therapy to patients with fibrosis and/or cirrhosis will depend to a large extent on the successful delivery of genes which encode for therapeutic proteins to livers with severe fibrosis and that these genes which encode for proteins human MMP-8 active and latent, MMP-1, MMP-2, MMP-9 and MMP-13; human uPA wild type and/or modified (or its truncated version), the truncated receptor for TGF-.beta. type II and Smad-7 can be directed by adenovirus and/or other recombinant vectors that cannot transduce (infect) others organs. The recombinant adenoviruses (AdR) are vectors highly efficient for the transduction of therapeutic genes to diverse target cells. We have proved that they can carry genes to cirrhotic livers.The delivery of therapeutic genes through such adenoviral vectors and other recombinant vectors could also be performed using cationic and anionic liposomes (DOTMA).Therefore, we propose the use of this patent to be applied in the same manner to:Renal fibrosisPulmonary fibrosisHypertrophic and keloid scars (skin fibrosis), andOther kinds of fibrosis. Excerpt(s): The present invention relates to the creation of RECOMBINANT ADENOVIRAL vectors bearing exogenous genes that encode for therapeutic proteins useful in the treatment of HEPATIC cirrhosis and generalized FIBROSIS, such as renal FIBROSIS, pulmonary FIBROSIS, HYPERTROPHIC scars and keloid of the skin, and/or in other target organs susceptible to suffer from it. It also relates to a mechanism of tissue-specific recognition of the affected cells by means of delivery of therapeutic genes to cirrhotic organs. Moreover, the invention provides an effective way for the treatment of fibrosis through the employment of recombinant adenoviral vectors which are claimed here, as well as the process to prepare these vectors, the pharmaceutical composition that contains them, and their therapeutic uses in the treatment of several
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fibrosis, which has great commercial expectancy in the pharmaceutical industry and also presents an important alternative as gene therapy for the treatment of chronicdegenerative diseases characterized by fibrosis, with great therapeutic application in the field of Medicine. Hepatic cirrhosis is a disease resulting from hepatic chronic damage. Damage might be toxic (chronic ingestion of alcohol), infectious (viral hepatitis, mainly by hepatitis B and/or C virus), immunological, (primary biliary cirrhosis), by biliary obstruction, (secondary biliary cirrhosis), metabolic (Wilson's disease). All forms of cirrhosis have characteristics in common: synthesis and excessive deposition of proteins of extracellular matrix (ECM), mainly collagen I and to a lesser extent collagens IV and III), and consequently the formation of nodules of hepatocytes, abnormal vascularization and portal hypertension (Antoni P P, Ishak K G, Nayak Nc, Poulsen H E, Sheuer P J, Sobin L H. These physiopathological processes lead to an alteration in the blood supply and in consequence in the nutrition of hepatic cells. Regardless of the ethiological agent and morphologic differences, all forms of cirrhosis have as a common end, hepatic failure causing the patient's death. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Substituted cyclic amidine derivatives as inhibitors of cell adhesion Inventor(s): Doherty, George A.; (Princeton, NJ), Hagmann, William K.; (Westfield, NJ), Shah, Shrenik; (Metuchen, NJ) Correspondence: Merck And CO Inc; P O Box 2000; Rahway; NJ; 070650907 Patent Application Number: 20020010199 Date filed: May 21, 2001 Abstract: Compounds of Formula I are antagonists of VLA-4 and/or.alpha.sub.4.beta.sub.7, and as such are useful in the inhibition or prevention of cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of AIDS-related dementia, allergic conjunctivitis, allergic rhinitis, Alzheimer's disease, asthma, atherosclerosis, autologous bone marrow transplantation, certain types of toxic and immune-based nephritis, contact dermal hypersensitivity, inflammatory bowel disease including ulcerative colitis and Crohn's disease, inflammatory lung diseases, inflammatory sequelae of viral infections, meningitis, multiple sclerosis, multiple myeloma, myocarditis, organ transplantation, psoriasis, pulmonary fibrosis, restenosis, retinitis, rheumatoid arthritis, septic arthritis, stroke, tumor metastasis, uveititis, and type I diabetes. Excerpt(s): This application claims priority from provisional application No. 60/206,183 filed on May 22, 2000, which is hereby incorporated by reference in its entirety. The compounds of the present invention are antagonists of the VLA-4 integrin ("very late antigen-4"; CD49d/CD29; or.alpha.sub.4.beta.sub.1- ) and/or the.alpha.4.beta.7 integrin (LPAM-1 and.alpha.sub.4.beta.sub.- p), thereby blocking the binding of VLA-4 to its various ligands, such as VCAM-1 and regions of fibronectin, and.alpha.4.beta.7 to its various ligands, such as MadCAM-1, VCAM-1 and fibronectin. Thus, these antagonists are useful in inhibiting cell adhesion processes including cell activation, migration, proliferation and differentiation. These antagonists are useful in the treatment, prevention and suppression of diseases mediated by VLA-4- and/or.alpha.4.beta.7binding and cell adhesion and activation, such as AIDS-related dementia, allergic conjunctivitis, allergic rhinitis, Alzheimer's disease, aortic stenosis, asthma, atherosclerosis, autologous bone marrow transplantation, certain types of toxic and
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immune-based nephritis, contact dermal hypersensitivity, inflammatory bowel disease including ulcerative colitis and Crohn's disease, inflammatory lung diseases, inflammatory sequelae of viral infections, meningitis, multiple sclerosis, myocarditis, organ transplantation, psoriasis, restenosis, retinitis, rheumatoid arthritis, septic arthritis, stroke, tumor metastasis, type I diabetes, and vascular occlusion following angioplasty. The present invention relates to susbstituted cyclic amine derivatives which are useful for the inhibition and prevention of leukocyte adhesion and leukocyte adhesion-mediated pathologies. This invention also relates to compositions containing such compounds and methods of treatment using such compounds. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) Inventor(s): Crandall, David LeRoy; (Doylestown, PA), Elokdah, Hassan Mahmoud; (Yardley, PA), Jennings, Lee D.; (Chestnut Ridge, NY), Li, David Zenan; (Princeton, NJ), McFarlane, Geraldine Ruth; (Monmouth Junction, NJ) Correspondence: Wyeth; 5 Giralda Farms; Madison; NJ; 07940; US Patent Application Number: 20030125371 Date filed: June 18, 2002 Abstract: This invention provides compounds of the formula: 1wherein: X is a chemical bond, --CH.sub.2-- or --C(O)--; R.sub.1 is alkyl, cycloalkyl, --CH.sub.2-cycloalkyl, pyridinyl, --CH.sub.2-pyridinyl, phenyl or benzyl; R.sub.2 is H, alkyl, cycloalkyl, -CH.sub.2-cycloalkyl, or perfluoroalkyl; R.sub.3 is H, halo, alkyl, perfluoroalkyl, alkoxy, cycloalkyl, --CH.sub.2-cycloalkyl, --NH.sub.2, or --NO.sub.2; R.sub.4 is optionally substituted phenyl, benzyl, benzyloxy, pyridinyl, or --CH.sub.2-pyridinyl, or the salt or ester forms thereof, as well as methods for using the compounds as inhibitors of plasminogen activator inhibitor-1 (PAI-1) and as therapeutic compositions for treating conditions resulting from fibrinolytic disorders such as deep vein thrombosis and coronary heart disease, and pulmonary fibrosis. Excerpt(s): This invention relates to the composition and utility of substituted indole derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) and as therapeutic compositions for treating conditions resulting from fibrinolytic disorders such as deep vein thrombosis and coronary heart disease, and pulmonary fibrosis. Plasminogen activator inhibitor-1 (PAI-1) is a major regulatory component of the plasminogenplasmin system. PAI-1 is the principal physiologic inhibitor of both tissue type plasminogen activator (t-PA) and urokinase type plasminogen activator (u-PA). Elevated plasma levels of PAI-1 have been associated with thrombotic events as indicated by animal experiments (Krishnamurti, Blood, 69, 798 (1987); Reilly, Arteriosclerosis and Thrombosis, 11, 1276 (1991); Carmeliet, Journal of Clinical Investigation, 92, 2756 (1993)) and clinical studies (Rocha, Fibrinolysis, 8, 294, 1994; Aznar, Haemostasis 24, 243 (1994)). Antibody neutralization of PAI-1 activity resulted in promotion of endogenous thrombolysis and reperfusion (Biemond, Circulation, 91, 1175 (1995); Levi, Circulation 85, 305, (1992)). Elevated levels of PAI-1 have also been implicated in diseases of women such as polycystic ovary syndrome (Nordt, Journal of clinical Endocrinology and Metabolism, 85, 4, 1563 (2000)) and bone loss induced by estrogen deficiency (Daci, Journal of Bone and Mineral Research, 15, 8, 1510 (2000)). Accordingly, agents that inhibit PAI-1 would be of utility in treating conditions originating from fibrinolytic disorder such as deep vein thrombosis, coronary heart
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disease, pulmonary fibrosis, polycystic ovary syndrome, etc. A is a five-membered, or six-membered ring heterocycle. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Substituted naphthyl benzofuran derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) Inventor(s): Crandall, David LeRoy; (Doylestown, PA), Elokdah, Hassan Mahmoud; (Yardley, PA), Mayer, Scott Christian; (Bridgewater, NJ), McFarlane, Geraldine Ruth; (Monmouth Junction, NJ) Correspondence: Wyeth; 5 Giralda Farms; Madison; NJ; 07940; US Patent Application Number: 20030018067 Date filed: June 18, 2002 Abstract: This invention provides compounds which act as inhibitors of plasminogen activator inhibitor-1 (PAI-1) of the formula: 1wherein: R, R.sub.1, R.sub.2, and R.sub.3 are H, alkyl, cycloalkyl, --CH.sub.2-(cycloalkyl), alkanoyl, halo, hydroxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, perfluoroalkyl, alkoxy, amino, -NH(alkyl), --N(alkyl).sub.2, or perfluoroalkoxy; R.sub.4 is H, alkyl, perflouroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl, alkenyl-aryl, aryl, -CH.sub.2R.sub.5, --CH(OH)R.sub.5, --C(O)R.sub.5, --CH(SH)R.sub.5, or --C(S)R.sub.5; R.sub.5 is H, alkyl, perflouroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl, alkenyl-aryl; R.sub.6 is H, alkyl, cycloalkyl, --CH.sub.2-cycloalkyl, alkylaryl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; n is an integer of 06; A is COOH, or an acid mimic; or a pharmaceutically acceptable salt or ester form thereof, as well as pharmaceutical compositions and methods using these compounds to treat or prevent conditions resulting from fibrinolytic disorders such as deep vein thrombosis and coronary heart disease, and pulmonary fibrosis. Excerpt(s): This invention relates to the composition and the utility of substituted naphthyl benzofuran derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI1) and as therapeutic compositions for treating conditions resulting from fibrinolytic disorders such as deep vein thrombosis and coronary heart disease, and pulmonary fibrosis. Plasminogen activator inhibitor-1 (PAI-1) is a major regulatory component of the plasminogen-plasmin system. PAI-1 is the principal physiologic inhibitor of both tissue type plasminogen activator (t-PA) and urokinase type plasminogen activator (uPA). Elevated plasma levels of PAI-1 have been associated with thrombotic events as indicated by animal experiments (Krishnamurti, Blood, 69, 798 (1987); Reilly, Arteriosclerosis and Thrombosis, 11, 1276 (1991); Carmeliet, Journal of Clinical Investigation, 92, 2756 (1993)) and clinical studies (Rocha, Fibrinolysis, 8, 294, 1994; Aznar, Haemostasis 24, 243 (1994)). Antibody neutralization of PAI-1 activity resulted in promotion of endogenous thrombolysis and reperfusion (Biemond, Circulation, 91, 1175 (1995); Levi, Circulation 85, 305, (1992)). Elevated levels of PAI-1 have also been implicated in diseases of women such as polycystic ovary syndrome (Nordt, Journal of clinical Endocrinology and Metabolism, 85, 4, 1563 (2000)) and bone loss induced by estrogen deficiency (Daci, Journal of Bone and Mineral Research, 15, 8, 1510 (2000)). Accordingly, agents that inhibit PAI-1 would be of utility in treating conditions originating from fibrinolytic disorder such as deep vein thrombosis, coronary heart disease, pulmonary fibrosis, polycystic ovary syndrome, etc. U.S. Pat. No. 6,110,963 claims benzofuran derivatives useful in the treatment of hyperglycemia.
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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Surfactant prevention of lung complications from cancer chemotherapy Inventor(s): Al-Mondhiry, Hamid A.; (Harrisburg, PA), Floros, Joanna; (Hershey, PA), Huang, Weixiong; (Hershey, PA), Phelps, David S.; (Hershey, PA), Wang, Guirong; (Hershey, PA) Correspondence: Mckee, Voorhees & Sease, P.L.C.; Attn: Pennsylvania State University; 801 Grand Avenue, Suite 3200; Des Moines; IA; 50309-2721; US Patent Application Number: 20030144248 Date filed: December 12, 2002 Abstract: A means and method for treating pulmonary fibrosis in animals is described. The compositions include surfactant lipids in a pharmaceutically acceptable carrier. Surfactant lipids have been found to suppress the synergistic effect of bleomycin and SP-A in enhancing proinflammatory cytokine production. Surfactant lipids are also effective in the prevention and treatment of pulmonary fibrosis resulting from exposure to inflammatory agents affecting cytokine production. Excerpt(s): This application claims priority to U.S. Provisional Application Serial No. 60/339,695 filed Dec. 12, 2001. This invention relates to the use of surfactant lipids for a variety of therapeutic uses, including the treatment of pulmonary inflammation and fibrosis. Pulmonary fibrosis (PF) is a complicated, chronic illness characterized by abnormal formation of fiberlike scar tissue in the lungs. Most patients with PF first have alveolitis, or inflammation of the lung, which drives the scarring process. If the disease progresses, the lungs eventually thicken and become stiff, which prevents oxygen from getting from the air sacs into nearby blood vessels that deliver oxygen to the body, thus making it more difficult for the person to breathe. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
•
Treatment and diagnosis of macrophage mediated disease Inventor(s): Low, Philip S.; (West Lafavette, IN), Turk, Mary Jo; (New York, NY) Correspondence: Barnes & Thornburg; 11 South Meridian Street; Indianapolis; IN; 46204; US Patent Application Number: 20020192157 Date filed: May 2, 2002 Abstract: The invention relates to a method of treating or monitoring/diagnosing a disease state mediated by activated macrophages. The method comprises the step of administering to a patient suffering from a macrophage mediated disease state an effective amount of a composition comprising a conjugate or complex of the general formulaA.sub.b-Xwhere the group A.sub.b comprises a ligand capable of binding to activated macrophages, and when the conjugate is being used for treatment of the disease state, the group X comprises an immunogen, a cytotoxin, or a compound capable of altering macrophage function, and when the conjugate is being used for monitoring/diagnosing the disease state, X comprises an imaging agent. The method is useful for treating a patient suffering from a disease selected from the group consisting of rheumatoid arthritis, ulcerative colitis, Crohn's disease, inflammation, infections,
Patents
osteomyelitis, atherosclerosis, organ sarcoidosis, and systemic sclerosis.
transplant
rejection,
pulmonary
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Excerpt(s): This application claims priority under 35 U.S.C.sctn.119(e) to U.S. Provisional Application Serial No. 60/288,208, filed on May 2, 2001. This invention relates to methods for treating and monitoring disease states mediated by activated macrophages. More particularly, ligands that bind to activated macrophages are complexed with an imaging agent, or an immunogen, a cytotoxin or an agent for altering macrophage function for administration to a diseased host for diagnosis and/or treatment of macrophage mediated disease. The mammalian immune system provides a means for the recognition and elimination of foreign pathogens. While the immune system normally provides a line of defense against foreign pathogens, there are many instances where the immune response itself is involved in the progression of disease. Exemplary of diseases caused or worsened by the host's own immune response are autoimmune diseases such as multiple sclerosis, lupus erythematosus, psoriasis, pulmonary fibrosis, and rheumatoid arthritis and diseases in which the immune response contributes to pathogenesis such as atherosclerosis, inflammatory diseases, osteomyelitis, ulcerative colitis, Crohn's disease, and graft versus host disease often resulting in organ transplant rejection. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Treatment of idiopathic pulmonary fibrosis using IP-10 Inventor(s): Kunkel, Steven L.; (Ann Arbor, MI), Strieter, Robert M.; (Ann Arbor, MI) Correspondence: Shelley P.M. Fussey; Williams, Morgan & Amerson, P.C.; Suite 250; 7676 Hillmont; Houston; TX; 77040; US Patent Application Number: 20030031645 Date filed: March 21, 2002 Abstract: Disclosed are various discoveries concerning the angiogenic and angiostatic properties of the CXC chemokines, including the finding that the ELR motif controls the ability of these molecules to induce angiogenesis. Aspects of the invention include, for example, the identification of IP-10, MIG and certain IL-8 analogues as angiostatic agents, and their use in inhibiting angiogenesis in various systems. Excerpt(s): The present invention relates generally to the field of cytokines. More particularly, it concerns CXC chemokines, CXC chemokine analogues, and methods of using such chemokines, for example, in modulating angiogenic and angiostatic responses. Cytokines are, generally, small protein or polypeptide-based molecules that modulate the activity of certain cell types following binding to cell surface receptors. The CXC (a) chemokines are one group of cytokines, so named due to the conserved Cys Xaa Cys sequence element located towards their N-terminus. The CXC chemokine family includes interleukin-8 (IL-8);.gamma.-interferon-inducible protein-10 (IP-10); Platelet Factor 4 (PF4); the growth related oncogene (GRO) peptides GRO.alpha., GRO.beta. and GRO.gamma.; monokine induced by gamma-interferon (MIG); epithelial neutrophil activating protein-78 (ENA-78); granulocyte chemotactic protein-2 (GCP-2); and the NH.sub.2-terminal truncated forms of platelet basic protein (PBP), namely connective tissue activating protein-III (CTAP-III),.beta.-thromboglobulin (.beta.TG) and neutrophil activating peptide-2 (NAP-2). IL-8 is a peptide of approximately 8 kD, and is about 72 amino acids in length, with this length varying according to the posttranslational processing in different cell types (Yoshimura et al., 1989; Strieter et al.,
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1989b). The IL-8 gene was initially identified by analyzing the genes transcribed by human blood mononuclear cells stimulated with Staphylococcal enterotoxin A (Schmid and Weissman, 1987). IL-8 production is induced by tumor necrosis factor and by interleukin-1 (Strieter et al., 1989a; 1989b; 1990a). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Treatment with small peptides to effect antifibrotic activity Inventor(s): Clagett, James; (Snohomish, WA) Correspondence: Edwards & Angell, Llp; P.O. Box 9169; Boston; MA; 02209; US Patent Application Number: 20020072499 Date filed: September 21, 2001 Abstract: Methods for treating treating fibrosis in a mammal are described. An antifibrotic effective amount of a peptide having the formula f-Met-Leu-X where X is selected from the group consisting of Tyr, Tyr-Phe, Phe-Phe and Phe-Tyr is administered to the mammal. The fibrosis may be due to pathological changes resulting, e.g., from pulmonary fibrosis, atherosclerosis, cirrhosis, glomerulosclerosis, chronic pancreatitus, coronary artery disease (such as caused by infection by bacterium Chlamydia pneumoniae), trauma or surgical procedures. Examples of surgical procedures that cause fibrosis are post-operative fibrosis peri-neurally in the dura or nerve roots following spinal surgery, tenolysis of injured or repaired tendons with adhesions, neurolysis of damaged or repaired peripheral nerves with adhesions, postoperative adhesions from gynecologic and abdominal surgeries, reparative surgery of the vas deferens or fallopian tubes for reversal of male or female sterilization, and surgical repair of other tubular structures such as urethra, intestine or esophagus. Excerpt(s): This invention claims priority of provisional application Ser. No. 60/125,514 filed Mar. 22, 1999 which is a Continuation of PCT/US00/07411 filed Mar. 20, 2000. This invention relates to methods for treating mammals with small peptides to effect antifibrotic activity and thereby inhibit, prevent or even reverse fibrolysis in the mammal. More particularly, such treatment of mammals exhibiting fibrous lesions in arterial or airway lumens provides lumen remodeling as demonstrated by reduction in fibrosis. Endothelial dysfunction that results from the injury leads to compensatory responses that alter the normal homeostatic properties of the endothelium. Thus, the different forms of injury increase the adhesiveness of the endothelium with respect to leukocytes or platelets, as well as its permeability. The injury also induces the endothelium to have procoagulant instead of anticoagulant properties and to form vasoactive molecules, cytokines, and growth factors. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
•
USE OF AEROSOLIZED CYCLOSPORINE FOR PREVENTION AND TREATMENT OF PULMONARY DISEASE Inventor(s): IACONO, ALDO T.; (PITTSBURGH, PA) Correspondence: Baker & Botts; 30 Rockefeller Plaza; New York; NY; 10112 Patent Application Number: 20020006901 Date filed: February 5, 1999
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Excerpt(s): The present invention relates to methods and compositions for prevention of graft rejection in lung transplant recipients and for treatment of subjects with pulmonary disorders. Specifically, the methods and compositions of the invention provide a means for inhibiting immune response mediated inflammatory processes in the lungs. The method of the invention comprises the administration of aerosolized cyclosporine for prevention of acute and/or chronic refractory rejection in lung transplant patients. The invention is based on the observation that when aerosolized cyclosporine is administered shortly after lung transplantation, the preparation is well tolerated and the rate of acute rejection is substantially reduced, compared to controls that receive conventional oral or intravenous immunosuppression only. The invention further provides for the use of aerosolized cyclosporine to treat subjects having immunologically mediated inflammatory pulmonary disorders including, but not limited to, asthma, cystic fibrosis, idiopathic pulmonary fibrosis, chronic bronchitis and allergic rhinitis. The present invention, by enabling a method for the use of aerosolized cyclosporine for inhibiting pulmonary inflammation leading to prevention of graft rejection and treatment of pulmonary disorders, provides a safer and less toxic treatment than those methods that utilize systemic administration of cyclosporine. The long-term success of lung transplantation is currently limited by the high incidence of transplant-related lung disease (Glanville, A. R., et al., 1987, Ann Intern Med 107:300306; Trulock, E. P., 1993, Chest 103:1566-1576; Kesten, S., 1995, 152: 1321-1324; Paradis, I. et al., 1993, 14:751-763). This complication is related to the transplant recipients' ongoing immune response against donor major histocompatability antigens. Such an immune response generally leads to persistent acute rejection of the lung allograft which is a predominant risk factor for the subsequent development of chronic rejection and permanent allograft dysfunction and failure resulting in excessive morbidity and mortality. This is a tragic consequence of lung transplantation and for this reason, is a leading area of research in this field. Although the rates of short-term survival after lung transplantation have improved compared to most other solid organ transplants, the therapeutic benefit of lung transplantation is still limited by poor longer-term outcomes principally due to chronic rejection of the transplanted lung. Patients, whose lung allografts are in acute and/or chronic rejection, are currently treated by a variety of potent immunosuppressive agents, such as azathioprine, tacrolimus, mycophenolate mofetil and cyclosporine, generally given by the intravenous or oral route, that profoundly inhibit the T cell response to donor antigen within the transplanted allograft. Unfortunately, these immunosuppressive agents diminish the patient's ability to mount an effective response to viral, fungal and bacterial pathogens thereby predisposing the patient to life threatening opportunistic infections and other toxic events such as kidney toxicity. Despite usage of conventional systemic (oral or intravenous) immunosuppressive drugs, about 50% of the treated patients develop refractory chronic rejection, characterized histologically by bronchiolitis obliterans, followed by a progressive decline in pulmonary function and eventually respiratory failure and death. 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 pulmonary 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
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steps: Under “Issued Patents,” click “Quick Search.” Then, type “pulmonary 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 pulmonary fibrosis. You can also use this procedure to view pending patent applications concerning pulmonary 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 6. BOOKS ON PULMONARY FIBROSIS Overview This chapter provides bibliographic book references relating to pulmonary fibrosis. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on pulmonary 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: 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 “pulmonary fibrosis” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “pulmonary fibrosis” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “pulmonary fibrosis” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
Basic and Clinical Aspects of Pulmonary Fibrosis by Tamotsu Takishima (Editor); ISBN: 0849389275; http://www.amazon.com/exec/obidos/ASIN/0849389275/icongroupinterna
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Idiopathic Pulmonary Fibrosis (Lung Biology in Health and Disease) by Joseph P., III Lynch (Editor); ISBN: 0824740734; http://www.amazon.com/exec/obidos/ASIN/0824740734/icongroupinterna
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Pulmonary Fibrosis by Sem Hin Phan, Roger S. Thrall (Editor); ISBN: 0824788516; http://www.amazon.com/exec/obidos/ASIN/0824788516/icongroupinterna
•
The Official Patient's Sourcebook on Idiopathic Pulmonary Fibrosis by James N. Parker; ISBN: 0597831653; http://www.amazon.com/exec/obidos/ASIN/0597831653/icongroupinterna
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Chapters on Pulmonary Fibrosis In order to find chapters that specifically relate to pulmonary fibrosis, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and pulmonary 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 and language you prefer, and the format option “Book Chapter.” Type “pulmonary fibrosis” (or synonyms) into the “For these words:” box.
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CHAPTER 7. PERIODICALS AND NEWS ON PULMONARY FIBROSIS Overview In this chapter, we suggest a number of news sources and present various periodicals that cover pulmonary fibrosis.
News Services and Press Releases One of the simplest ways of tracking press releases on pulmonary 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 “pulmonary 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 pulmonary 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 “pulmonary fibrosis” (or synonyms). The following was recently listed in this archive for pulmonary fibrosis: •
FDA grants InterMune's Actimmune fast track designation for pulmonary fibrosis Source: Reuters Medical News Date: January 07, 2002
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•
Lung biopsy may not be needed for idiopathic pulmonary fibrosis diagnosis Source: Reuters Industry Breifing Date: August 17, 2001
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Dual factors help guide transplant referral in idiopathic pulmonary fibrosis Source: Reuters Medical News Date: August 15, 2001
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Conservative management helpful in pulmonary fibrosis in infants Source: Reuters Medical News Date: August 24, 2000
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Interferon gamma-1b effective in idiopathic pulmonary fibrosis Source: Reuters Medical News Date: October 21, 1999
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Integrin plays a key role in pulmonary fibrosis process Source: Reuters Medical News Date: February 05, 1999
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Mold, Dust In Workplace Linked To Idiopathic Pulmonary Fibrosis Source: Reuters Medical News Date: April 17, 1998
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Extensive Testing Does Not Help Predict Course Of Pulmonary Fibrosis Source: Reuters Medical News Date: February 06, 1997
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Plant Extract Reduces Pulmonary Fibrosis In Experimental Studies Source: Reuters Medical News Date: November 04, 1996
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Risk Of Pulmonary Fibrosis After Radiotherapy Increased With Concurrent Tamoxifen Therapy Source: Reuters Medical News Date: July 15, 1996
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Pulmonary fibrosis linked to coronary artery disease Source: Reuters Medical News Date: March 12, 2004
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Bone marrow stem cells tied to pulmonary fibrosis Source: Reuters Industry Breifing Date: January 30, 2004
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Interferon gamma-1b does not delay progression of idiopathic pulmonary fibrosis Source: Reuters Medical News Date: January 09, 2004
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Prostaglandin therapy might help in pulmonary fibrosis Source: Reuters Industry Breifing Date: December 19, 2003
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InterMune starts pulmonary fibrosis drug trial Source: Reuters Industry Breifing Date: December 16, 2003
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Diabetes mellitus may increase the risk of idiopathic pulmonary fibrosis Source: Reuters Medical News Date: July 01, 2003
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•
InterMune reports positive phase II data for pulmonary fibrosis trial Source: Reuters Medical News Date: May 09, 2003
•
InterMune reports positive data for phase II pulmonary fibrosis trial Source: Reuters Industry Breifing Date: May 09, 2003 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 “pulmonary 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 “pulmonary fibrosis” (or synonyms). If you know the name of a company that is relevant to pulmonary 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 “pulmonary fibrosis” (or synonyms).
Academic Periodicals covering Pulmonary Fibrosis Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to pulmonary fibrosis. In addition to these sources, you can search for articles covering pulmonary 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 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 8. 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 pulmonary 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 non-profit 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).
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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. 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 pulmonary 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 “pulmonary 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
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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 pulmonary fibrosis: •
interferon Gamma-1B (trade name: Actimmune) http://www.rarediseases.org/nord/search/nodd_full?code=1304
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.
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APPENDICES
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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 Institute11: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
11
These publications are typically written by one or more of the various NIH Institutes.
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•
National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm
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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
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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
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National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html
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National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm
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Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp
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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 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:13 •
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
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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
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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
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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/
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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
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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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/
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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
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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
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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
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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
12
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). 13 See http://www.nlm.nih.gov/databases/databases.html.
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Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
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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 NLM Gateway14 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.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “pulmonary 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 16012 87 869 19 238 17225
HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 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.18 Simply search by “pulmonary fibrosis” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
14
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
15
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). 16 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 17 18
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.
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Coffee Break: Tutorials for Biologists19 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 used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.20 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.21 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/.
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Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
The Genome Project and Pulmonary Fibrosis In the following section, we will discuss databases and references which relate to the Genome Project and pulmonary 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).22 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. 19 Adapted 20
from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
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. 21 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. 22 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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To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “pulmonary 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 pulmonary fibrosis: •
Pulmonary Fibrosis, Idiopathic Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=178500 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 “pulmonary fibrosis” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database23 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 Database24 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 “pulmonary 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).
23
Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 24 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 pulmonary 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 Internetbased 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 pulmonary 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 pulmonary 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 “pulmonary fibrosis”:
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COPD http://www.nlm.nih.gov/medlineplus/copdchronicobstructivepulmonarydisease.t ml Cystic Fibrosis http://www.nlm.nih.gov/medlineplus/cysticfibrosis.html Pulmonary Fibrosis http://www.nlm.nih.gov/medlineplus/pulmonaryfibrosis.html Pulmonary Hypertension http://www.nlm.nih.gov/medlineplus/pulmonaryhypertension.html Respiratory Diseases http://www.nlm.nih.gov/medlineplus/respiratorydiseases.html
Within the health topic page dedicated to pulmonary fibrosis, the following was listed: •
General/Overviews Facts about Pulmonary Fibrosis and Interstitial Lung Disease Source: American Lung Association http://www.lungusa.org/diseases/pulmfibrosis.html Let's Talk about Idiopathic Pulmonary Fibrosis: Questions and Answers for Patients and Caregivers http://www.coalitionforpf.org/pdfs/patientbro.pdf
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Diagnosis/Symptoms Blood Gas Tests Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/blood_gases/test.html Bronchoscopy: Pulmonary Branch Protocols Source: National Institutes of Health, Clinical Center http://www.cc.nih.gov/ccc/patient_education/pepubs/bronchoscopy.pdf Radiography -- Chest (Chest X-ray) Source: American College of Radiology, Radiological Society of North America http://www.radiologyinfo.org/content/chest_radiography.htm Spirometry Testing Source: National Jewish Medical and Research Center http://www.nationaljewish.org/medfacts/spirometry.html Symptoms and Diagnosis: Idiopathic Pulmonary Fibrosis Source: Coalition for Pulmonary Fibrosis http://www.coalitionforpf.org/patient/symptoms.asp Understanding PFT's (Pulmonary Function Testing) Source: Alpha 1 Association http://www.alpha1.org/what/lunginfo_pfts.htm
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•
Treatment Treatment: Idiopathic Pulmonary Fibrosis Source: Coalition for Pulmonary Fibrosis http://www.coalitionforpf.org/patient/treatment.asp
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From the National Institutes of Health Facts about Idiopathic Pulmonary Fibrosis Source: National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/health/public/lung/other/idiopath.htm
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Organizations American Lung Association http://www.lungusa.org/ National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/
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Research IPF Research Source: Coalition for Pulmonary Fibrosis http://www.coalitionforpf.org/patient/ipfresearch.asp
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 pulmonary 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: •
Hermansky-Pudlak Syndrome Source: National Organization for Albinism and Hypopigmentation (NOAH). 200x. 4 p. Contact: Available online from National Organization for Albinism and Hypopigmentation (NOAH). Website: www.albinism.org. Summary: This fact sheet provides information to health professionals and individuals with albinism about Hermansky Pudlack Syndrome (HPS), a type of albinism in which patients have bleeding problems, lung disease, and inflammation of the intestines. This
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condition occurs world-wide. The severity and onset of HPS varies and its course is unpredictable. HPS is difficult to diagnose, but should be suspected in any child with albinism who shows easy bruising or unusual bleeding. A test that examines blood platelets is used to diagnose HPS. In HPS the platelets contain few or no dense bodies. Some people with HPS may have less of a blood-clotting substance called von Willebrand factor. Many people who have HPS have pulmonary fibrosis and/or inflammatory bowel disease. The National Guideline Clearinghouse™ The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site located at http://www.guideline.gov/ by using the keyword “pulmonary fibrosis” (or synonyms). The following was recently posted: •
AACE/AAES medical/surgical guidelines for clinical practice: management of thyroid carcinoma Source: American Association of Clinical Endocrinologists - Medical Specialty Society; 1997 (updated 2001 May-Jun); 19 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2848&nbr=2074&a mp;string=pulmonary+AND+fibrosis
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Acute pain management Source: University of Iowa Gerontological Nursing Interventions Research Center, Research Dissemination Core - Academic Institution; 1997 (revised 1999 April 6); 38 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1888&nbr=1114&a mp;string=pulmonary+AND+fibrosis
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American Association of Clinical Endocrinologists medical guidelines for the clinical use of dietary supplements and nutraceuticals Source: American Association of Clinical Endocrinologists - Medical Specialty Society; 2003 Sep-October; 54 pages http://www.guideline.gov/summary/summary.aspx?doc_id=4265&nbr=3265&a mp;string=pulmonary+AND+fibrosis
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American Gastroenterological Association medical position statement: guidelines for the evaluation of food allergies Source: American Gastroenterological Association - Medical Specialty Society; 2000 November 12 (reviewed 2001); 3 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3059&nbr=2285&a mp;string=pulmonary+AND+fibrosis
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Bland aerosol administration: 2003 revision and update Source: American Association for Respiratory Care - Professional Association; 1993 December (revised 2003); 5 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3752&nbr=2978&a mp;string=pulmonary+AND+fibrosis
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Body plethysmography: 2001 revision and update Source: American Association for Respiratory Care - Professional Association; 2001 May; 8 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2843&nbr=2069&a mp;string=pulmonary+AND+fibrosis
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Chemotherapy and biotherapy: guidelines and recommendations for practice Source: Oncology Nursing Society - Professional Association; 2001; 226 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3209&nbr=2435&a mp;string=pulmonary+AND+fibrosis
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Clinical practice guideline for the management of rheumatoid arthritis Source: Advanced Research Techniques in the Health Services - Private For Profit Research Organization; 2001; 170 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3683&nbr=2909&a mp;string=pulmonary+AND+fibrosis
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Deep venous thrombosis Source: Finnish Medical Society Duodecim - Professional Association; 2001 April 30 (revised 2002 Apr 20); Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3384&nbr=2610&a mp;string=pulmonary+AND+fibrosis
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Evidence-based clinical practice guideline of community-acquired pneumonia in children 60 days to 17 years of age Source: Cincinnati Children's Hospital Medical Center - Hospital/Medical Center; 2000 July; 11 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2654&nbr=1880&a mp;string=pulmonary+AND+fibrosis
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Global initiative for asthma. Global strategy for asthma management and prevention Source: National Heart, Lung, and Blood Institute (U.S.) - Federal Government Agency [U.S.]; 1995 January (revised 2002); 176 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3203&nbr=2429&a mp;string=pulmonary+AND+fibrosis
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Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease Source: National Heart, Lung, and Blood Institute (U.S.) - Federal Government Agency [U.S.]; 2001; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=2779&nbr=2005&a mp;string=pulmonary+AND+fibrosis
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Guidelines for referral to pediatric surgical specialists Source: American Academy of Pediatrics - Medical Specialty Society; 2002 July; 5 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3420&nbr=2646&a mp;string=pulmonary+AND+fibrosis
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Guidelines for the diagnosis and treatment of chronic heart failure Source: European Society of Cardiology - Medical Specialty Society; 2001 September; 34 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2976&nbr=2202&a mp;string=pulmonary+AND+fibrosis
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Intravenous immunoglobulin preparations Source: University HealthSystem Consortium - Private Nonprofit Organization; 1999 March; 216 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1976&nbr=1202&a mp;string=pulmonary+AND+fibrosis
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Management of chronic kidney disease and pre-ESRD in the primary care setting Source: Department of Defense - Federal Government Agency [U.S.]; 2000 November; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3099&nbr=2325&a mp;string=pulmonary+AND+fibrosis
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Palliative treatment of cancer Source: Finnish Medical Society Duodecim - Professional Association; 2001 December 27 (revised 2003 May 30); Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=4374&nbr=3296&a mp;string=pulmonary+AND+fibrosis
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Preoperative evaluation Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1997 September (revised 2002 Mar); 27 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3357&nbr=2583&a mp;string=pulmonary+AND+fibrosis
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Procedure guideline for gallium scintigraphy in inflammation Source: Society of Nuclear Medicine, Inc - Medical Specialty Society; 1999 February; 21 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1349&nbr=607&am p;string=pulmonary+AND+fibrosis
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Pulmonary rehabilitation Source: American Association for Respiratory Care - Professional Association; 2002; 9 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3211&nbr=2437&a mp;string=pulmonary+AND+fibrosis
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Reduction of the influenza burden in children Source: American Academy of Pediatrics - Medical Specialty Society; 2002 December; 7 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3527&nbr=2753&a mp;string=pulmonary+AND+fibrosis
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Rhinitis Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1998 August (revised 2003 May); 34 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3875&nbr=3084&a mp;string=pulmonary+AND+fibrosis
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Selection of an oxygen delivery device for neonatal and pediatric patients: 2002 revision and update Source: American Association for Respiratory Care - Professional Association; 1996 July (revised 2002 Jun); 10 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3249&nbr=2475&a mp;string=pulmonary+AND+fibrosis
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Single-breath carbon monoxide diffusing capacity, 1999 update Source: American Association for Respiratory Care - Professional Association; 1999 January; 9 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1767&nbr=993&am p;string=pulmonary+AND+fibrosis
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The diagnosis and treatment of adult asthma Source: New Zealand Guidelines Group - Private Nonprofit Organization; 2002 September; 101 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3462&nbr=2688&a mp;string=pulmonary+AND+fibrosis
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The management of priapism Source: American Urological Association, Inc. - Medical Specialty Society; 2003; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3741&nbr=2967&a mp;string=pulmonary+AND+fibrosis
•
Use of antibiotics in paediatric care Source: Singapore Ministry of Health - National Government Agency [Non-U.S.]; 2002 March; 109 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3436&nbr=2662&a mp;string=pulmonary+AND+fibrosis
•
Using live, attenuated influenza vaccine for prevention and control of influenza: supplemental recommendations of the Advisory Committee on Immunization Practices (ACIP) Source: Centers for Disease Control and Prevention - Federal Government Agency [U.S.]; 2003 September 26; 8 pages http://www.guideline.gov/summary/summary.aspx?doc_id=4154&nbr=3182&a mp;string=pulmonary+AND+fibrosis
•
VHA/DOD clinical practice guideline for the management of chronic obstructive pulmonary disease. Source: Department of Defense - Federal Government Agency [U.S.]; 1999 August; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=2584&nbr=1810&a mp;string=pulmonary+AND+fibrosis 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 pulmonary 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
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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. 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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WebMDHealth: http://my.webmd.com/health_topics
Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to pulmonary fibrosis. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with pulmonary 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 pulmonary 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. 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 “pulmonary fibrosis” (or a synonym), and you will receive information on all relevant organizations listed in the database.
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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 “pulmonary 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 “pulmonary 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 “pulmonary fibrosis” (or a synonym) into the search box, and click “Submit Query.”
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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.25
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
25
Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.
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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)26: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
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Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
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Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html
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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
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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
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California: Gateway Health Library (Sutter Gould Medical Foundation)
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California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
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California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
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California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
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California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
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Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
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Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
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Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
26
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
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•
Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml
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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
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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html
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Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm
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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp
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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/
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Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm
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Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html
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Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/
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Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm
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Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/
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Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/
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Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/
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Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm
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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/
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•
Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp
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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
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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/
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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
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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
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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330
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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)
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National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
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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/
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•
Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
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New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
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•
South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
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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).
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
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PULMONARY 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] Ablation: The removal of an organ by surgery. [NIH] Abscess: A localized, circumscribed collection of pus. [NIH] 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] 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] Acetylglucosamine: The N-acetyl derivative of glucosamine. [NIH] Acetylglucosaminidase: 2-Acetamido-2-deoxy-beta-D-glucoside acetamidodeoxyglucohydrolase. Catalyzes the hydrolysis of terminal, non-reducing 2-acetamido-2-deoxy-betaglucose residues in chitobiose and higher analogs as well as in glycoproteins. Has been used widely in structural studies on bacterial cell walls and in the study of diseases such as mucolipidosis and various inflammatory disorders of muscle and connective tissue. [NIH] Acquired Immunodeficiency Syndrome: An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive Tlymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect criteria for AIDS as defined by the CDC in 1993. [NIH] Actin: Essential component of the cell skeleton. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [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] 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] Adhesions: Pathological processes consisting of the union of the opposing surfaces of a
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wound. [NIH] Adoptive Transfer: Form of passive immunization where previously sensitized immunologic agents (cells or serum) are transferred to non-immune recipients. When transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy (immunotherapy, adoptive). [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] 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]
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] 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] Air Pollutants: Substances which pollute the air. [NIH] Air Sacs: Thin-walled sacs or spaces which function as a part of the respiratory system in birds, fishes, insects, and mammals. [NIH] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Albinism: General term for a number of inherited defects of amino acid metabolism in which there is a deficiency or absence of pigment in the eyes, skin, or hair. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldosterone: (11 beta)-11,21-Dihydroxy-3,20-dioxopregn-4-en-18-al. A hormone secreted by
Dictionary 195
the adrenal cortex that functions in the regulation of electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] 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] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allergic Rhinitis: Inflammation of the nasal mucous membrane associated with hay fever; fits may be provoked by substances in the working environment. [NIH] Allium: A genus of liliaceous herbs containing onions (Allium cepa), garlic (Allium sativum), and others; many produce pungent, often bacteriostatic and physiologically active compounds and are used as food, condiment, and medicament, the latter in traditional medicine. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Alloys: A mixture of metallic elements or compounds with other metallic or metalloid elements in varying proportions. [NIH] Allylamine: Possesses an unusual and selective cytotoxicity for vascular smooth muscle cells in dogs and rats. Useful for experiments dealing with arterial injury, myocardial fibrosis or cardiac decompensation. [NIH] Alopecia: Absence of hair from areas where it is normally present. [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-Defensins: Defensins found in azurophilic granules of neutrophils and in the secretory granules of intestinal paneth cells. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. 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] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Alveolitis: Inflammation of an alveolus. Called also odontobothritis. [EU] Amenorrhea: Absence of menstruation. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU]
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Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] 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-terminal: The end of a protein or polypeptide chain that contains a free amino group (-NH2). [NIH] Amiodarone: An antianginal and antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting Na,K-activated myocardial adenosine triphosphatase. There is a resulting decrease in heart rate and in vascular resistance. [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] 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] 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, 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] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgenic: Producing masculine characteristics. [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]
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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] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anionic: Pertaining to or containing an anion. [EU] 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]
Anovulation: Suspension or cessation of ovulation in animals and humans. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antianginal: Counteracting angina or anginal conditions. [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] Antigen: Any substance which is capable, under appropriate conditions, of inducing a
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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 causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] 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] Antiproliferative: Counteracting a process of proliferation. [EU] Antiserum: The blood serum obtained from an animal after it has been immunized with a particular antigen. It will contain antibodies which are specific for that antigen as well as antibodies specific for any other antigen with which the animal has previously been immunized. [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Aphakia: Absence of crystalline lens totally or partially from field of vision, from any cause except after cataract extraction. Aphakia is mainly congenital or as result of lens dislocation and subluxation. [NIH] Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [NIH]
Apnea: A transient absence of spontaneous respiration. [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] Aqueous: Having to do with water. [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
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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] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Archaea: One of the three domains of life (the others being bacteria and Eucarya), formerly called Archaebacteria under the taxon Bacteria, but now considered separate and distinct. They are characterized by: 1) the presence of characteristic tRNAs and ribosomal RNAs; 2) the absence of peptidoglycan cell walls; 3) the presence of ether-linked lipids built from branched-chain subunits; and 4) their occurrence in unusual habitats. While archaea resemble bacteria in morphology and genomic organization, they resemble eukarya in their method of genomic replication. The domain contains at least three kingdoms: crenarchaeota, euryarchaeota, and korarchaeota. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatic: Having a spicy odour. [EU] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Articular: Of or pertaining to a joint. [EU] Asbestos: Fibrous incombustible mineral composed of magnesium and calcium silicates with or without other elements. It is relatively inert chemically and used in thermal insulation and fireproofing. Inhalation of dust causes asbestosis and later lung and gastrointestinal neoplasms. [NIH] Asbestosis: A lung disorder caused by constant inhalation of asbestos particles. [NIH] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a
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neurotransmitter. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] 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] Atopic: Pertaining to an atopen or to atopy; allergic. [EU] 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] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmune Hepatitis: A liver disease caused when the body's immune system destroys liver cells for no known reason. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autologous bone marrow transplantation: A procedure in which bone marrow is removed from a person, stored, and then given back to the person after intensive treatment. [NIH] Autopsy: Postmortem examination of the body. [NIH] Backcross: A cross between a hybrid and either one of its parents. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls,
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multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [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] Bacteriuria: The presence of bacteria in the urine with or without consequent urinary tract infection. Since bacteriuria is a clinical entity, the term does not preclude the use of urine/microbiology for technical discussions on the isolation and segregation of bacteria in the urine. [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] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] 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]
Berylliosis: A lung disease caused by exposure to metallic beryllium or its soluble salts. [NIH]
Beryllium: An element with the atomic symbol Be, atomic number 4, and atomic weight 9.01218. Short exposure to this element can lead to a type of poisoning known as berylliosis. [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] 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
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fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassays: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [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] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] 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] Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH] Bladder: The organ that stores urine. [NIH] Bleomycin: A complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [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
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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] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]
Bodily Secretions: Endogenous substances produced through the activity of intact cells of glands, tissues, or organs. They do not include hormones or enzymes. [NIH] Body Fluids: Liquid components of living organisms. [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 Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [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] 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] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Broad Ligament: A broad fold of peritoneum that extends from the side of the uterus to the wall of the pelvis. [NIH] Bromocriptine: A semisynthetic ergot alkaloid that is a dopamine D2 agonist. It suppresses prolactin secretion and is used to treat amenorrhea, galactorrhea, and female infertility, and has been proposed for Parkinson disease. [NIH]
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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] Bronchioles: The tiny branches of air tubes in the lungs. [NIH] Bronchiolitis: Inflammation of the bronchioles. [NIH] Bronchiolitis Obliterans: Inflammation of the bronchioles with obstruction by fibrous granulation tissue or bronchial exudate. It may follow inhalation of irritating gases or foreign bodies and it complicates pneumonia. [NIH] Bronchiolitis Obliterans Organizing Pneumonia: Inflammation of the bronchioles. [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 the lung. It is used to assess biochemical and inflammatory changes in and effects of therapy on the interstitial lung tissue. [NIH] Bronchoconstriction: Diminution of the caliber of a bronchus physiologically or as a result of pharmacological intervention. [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] Cadherins: A group of functionally related glycoproteins responsible for the calciumdependent cell-to-cell adhesion mechanism. They are divided into subclasses E-, P-, and Ncadherins, which are distinct in immunological specificity and tissue distribution. They promote cell adhesion via a homophilic mechanism. These compounds play a role in the construction of tissues and of the whole animal body. [NIH] Cadmium: An element with atomic symbol Cd, atomic number 48, and atomic weight 114. It is a metal and ingestion will lead to cadmium poisoning. [NIH] Cadmium Poisoning: Poisoning occurring after exposure to cadmium compounds or fumes. It may cause gastrointestinal syndromes, anemia, or pneumonitis. [NIH] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [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
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functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually composed of mineral salts. Also called stones. [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] 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] Carboplatin: An organoplatinum compound that possesses antineoplastic activity. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]
Carcinostatic: Pertaining to slowing or stopping the growth of cancer. [NIH] Cardiac: Having to do with the heart. [NIH] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [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] 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] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule, especially an opacity impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU]
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Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [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 Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Adhesion Molecules: Surface ligands, usually glycoproteins, that mediate cell-to-cell adhesion. Their functions include the assembly and interconnection of various vertebrate systems, as well as maintenance of tissue integration, wound healing, morphogenic movements, cellular migrations, and metastasis. [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 Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [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, 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] Centromere: The clear constricted portion of the chromosome at which the chromatids are joined and by which the chromosome is attached to the spindle during cell division. [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH]
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Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] 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] Ceroid: A naturally occurring lipid pigment with histochemical characteristics similar to lipofuscin. It accumulates in various tissues in certain experimental and pathological conditions. [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] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [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] Chemotaxis: The movement of cells or organisms toward or away from a substance in response to its concentration gradient. [NIH] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapy: Treatment with anticancer drugs. [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] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [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] Chondrocytes: Polymorphic cells that form cartilage. [NIH] Chondroitin sulfate: The major glycosaminoglycan (a type of sugar molecule) in cartilage. [NIH]
Chorioretinitis: Inflammation of the choroid in which the sensory retina becomes edematous and opaque. The inflammatory cells and exudate may burst through the sensory retina to cloud the vitreous body. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH]
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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] Chromium: A trace element that plays a role in glucose metabolism. It has the atomic symbol Cr, atomic number 24, and atomic weight 52. According to the Fourth Annual Report on Carcinogens (NTP85-002,1985), chromium and some of its compounds have been listed as known carcinogens. [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] Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [NIH] 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] 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] Cicatrix: The formation of new tissue in the process of wound healing. [NIH] Cicatrix, Hypertrophic: An elevated scar, resembling a keloid, but which does not spread into surrounding tissues. It is formed by enlargement and overgrowth of cicatricial tissue and regresses spontaneously. [NIH] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] C-kit receptor: A protein on the surface of some cells that binds to stem cell factor (a substance that causes certain types of cells to grow). Altered forms of this receptor may be associated with some types of cancer. [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] 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] Clot Retraction: Retraction of a clot resulting from contraction of platelet pseudopods attached to fibrin strands that is dependent on the contractile protein thrombosthenin. Used as a measure of platelet function. [NIH]
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Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] 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] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [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] Collagenases: Enzymes that catalyze the degradation of collagen by acting on the peptide bonds. EC 3.4.24.-. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [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 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,
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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] 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] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [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 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] Concomitant: Accompanying; accessory; joined with another. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Conjunctivitis: Inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. [EU] Conjunctivitis, Allergic: Conjunctivitis due to hypersensitivity to various allergens. [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] 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 Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU]
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Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Contractile Proteins: Proteins which participate in contractile processes. They include muscle proteins as well as those found in other cells and tissues. In the latter, these proteins participate in localized contractile events in the cytoplasm, in motile activity, and in cell aggregation phenomena. [NIH] Contractility: Capacity for becoming short in response to a suitable stimulus. [EU] 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] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [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] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneal Ulcer: Loss of epithelial tissue from the surface of the cornea due to progressive erosion and necrosis of the tissue; usually caused by bacterial, fungal, or viral infection. [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 heart disease: A type of heart disease caused by narrowing of the coronary
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arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Critical Care: Health care provided to a critically ill patient during a medical emergency or crisis. [NIH] Cryoglobulinemia: A condition characterized by the presence of abnormal or abnormal quantities of cryoglobulins in the blood. They are precipitated into the microvasculature on exposure to cold and cause restricted blood flow in exposed areas. [NIH] 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] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Curcumin: A dye obtained from tumeric, the powdered root of Curcuma longa Linn. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes. [NIH] Cutaneous: Having to do with the skin. [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] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH]
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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] Cytoprotection: The process by which chemical compounds provide protection to cells against harmful agents. [NIH] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Danazol: A synthetic steroid with antigonadotropic and anti-estrogenic activities that acts as an anterior pituitary suppressant by inhibiting the pituitary output of gonadotropins. It possesses some androgenic properties. Danazol has been used in the treatment of endometriosis and some benign breast disorders. [NIH] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [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] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [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] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]
Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal
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of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Dermal: Pertaining to or coming from the skin. [NIH] Dermatitis: Any inflammation of the skin. [NIH] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] Desmosine: 4-(4-Amino-4-carboxybutyl)-1-(5-amino-5-carboxypentyl)-3,5-bis(3-amino-3carboxypropyl)pyridinium. A rare amino acid found in elastin, formed by condensation of four molecules of lysine into a pyridinium ring. [NIH] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Retinopathy: Retinopathy associated with diabetes mellitus, which may be of the background type, progressively characterized by microaneurysms, interretinal punctuate macular edema, or of the proliferative type, characterized by neovascularization of the retina and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [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]
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] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [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] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Dimethyl Sulfoxide: A highly polar organic liquid, that is used widely as a chemical solvent. Because of its ability to penetrate biological membranes, it is used as a vehicle for topical application of pharmaceuticals. It is also used to protect tissue during cryopreservation. Dimethyl sulfoxide shows a range of pharmacological activity including
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analgesia and anti-inflammation. [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] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disease Susceptibility: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the individual more than usually susceptible to certain diseases. [NIH] Disparity: Failure of the two retinal images of an object to fall on corresponding retinal points. [NIH] Dissection: Cutting up of an organism for study. [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 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] Diurnal: Occurring during the day. [EU] Domesticated: Species in which the evolutionary process has been influenced by humans to meet their needs. [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] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] 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 Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] 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
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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] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [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] Ectopic: Pertaining to or characterized by ectopia. [EU] 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] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [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] Ejection fraction: A measure of ventricular contractility, equal to normally 65 8 per cent; lower values indicate ventricular dysfunction. [EU] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Electroconvulsive Therapy: Electrically induced convulsions primarily used in the treatment of severe affective disorders and schizophrenia. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Emaciation: Clinical manifestation of excessive leanness usually caused by disease or a lack of nutrition. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Endarterectomy:
Surgical
excision,
performed
under
general
anesthesia,
of
the
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atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [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] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]
Endometriosis: A condition in which tissue more or less perfectly resembling the uterine mucous membrane (the endometrium) and containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity. [NIH] Endometrium: The layer of tissue that lines the uterus. [NIH] Endoscopy: Endoscopic examination, therapy or surgery performed on interior parts of the body. [NIH] 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] Endotoxemia: A condition characterized by the presence of endotoxins in the blood. If endotoxemia is the result of gram-negative rod-shaped bacteria, shock may occur. [NIH] 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] 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]
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]
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH]
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Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] Eosinophilic: A condition found primarily in grinding workers caused by a reaction of the pulmonary tissue, in particular the eosinophilic cells, to dust that has entered the lung. [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] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermoid carcinoma: A type of cancer in which the cells are flat and look like fish scales. Also called squamous cell carcinoma. [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]
Epitope Mapping: Methods used for studying the interactions of antibodies with specific regions of protein antigens. Important applications of epitope mapping are found within the area of immunochemistry. [NIH] Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Ergot: Cataract due to ergot poisoning caused by eating of rye cereals contaminated by a fungus. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Esophageal Manometry: A test to measure muscle tone inthe esophagus. [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] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH]
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Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [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] Exhaustion: The feeling of weariness of mind and body. [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] Expiration: The act of breathing out, or expelling air from the lungs. [EU] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [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] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from 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] Fallopian tube: The oviduct, a muscular tube about 10 cm long, lying in the upper border of the broad ligament. [NIH]
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Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [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] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibronectins: Glycoproteins found on the surfaces of cells, particularly in fibrillar structures. The proteins are lost or reduced when these cells undergo viral or chemical transformation. They are highly susceptible to proteolysis and are substrates for activated blood coagulation factor VIII. The forms present in plasma are called cold-insoluble globulins. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fibrotic tissue: Inflamed tissue that has become scarred. [NIH] Fine-needle aspiration: The removal of tissue or fluid with a needle for examination under a microscope. Also called needle biopsy. [NIH] Flatus: Gas passed through the rectum. [NIH] Fluoroscopy: Production of an image when X-rays strike a fluorescent screen. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Founder Effect: The principle that when a small subgroup of a larger population establishes itself as a separate and isolated entity, its gene pool carries only a fraction of the genetic diversity of the parental population. This may result in an increased frequency of certain diseases in the subgroup, especially those diseases known to be autosomal recessive. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH]
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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] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallium: A rare, metallic element designated by the symbol, Ga, atomic number 31, and atomic weight 69.72. [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] Gamma-interferon: Interferon produced by T-lymphocytes in response to various mitogens and antigens. Gamma interferon appears to have potent antineoplastic, immunoregulatory and antiviral activity. [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] 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] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [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 Neoplasms: Tumors or cancer of the gastrointestinal system. [NIH] Gastrointestinal tract: The stomach and intestines. [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 pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gelatinases: A class of enzymes that catalyzes the degradation of gelatin by acting on the peptide bonds. EC 3.4.24.-. [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]
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Gene Deletion: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus. [NIH] Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Expression Profiling: The determination of the pattern of genes expressed i.e., transcribed, under specific circumstances or in a specific cell. [NIH] Gene Products, rev: Trans-acting nuclear proteins whose functional expression are required for HIV viral replication. Specifically, the rev gene products are required for processing and translation of the HIV gag and env mRNAs, and thus rev regulates the expression of the viral structural proteins. rev can also regulate viral regulatory proteins. A cis-acting antirepression sequence (CAR) in env, also known as the rev-responsive element (RRE), is responsive to the rev gene product. rev is short for regulator of virion. [NIH] Gene Targeting: The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genes, env: DNA sequences that form the coding region for the viral envelope (env) proteins in retroviruses. The env genes contain a cis-acting RNA target sequence for the rev protein (= gene products, rev), termed the rev-responsive element (RRE). [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 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 Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [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] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germanium: A rare metal element with a blue-gray appearance and atomic symbol Ge, atomic number 32, and atomic weight 72.59. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of
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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] 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] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]
Glomeruli: Plural of glomerulus. [NIH] Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [NIH] Glomerulosclerosis: Scarring of the glomeruli. It may result from diabetes mellitus (diabetic glomerulosclerosis) or from deposits in parts of the glomerulus (focal segmental glomerulosclerosis). The most common signs of glomerulosclerosis are proteinuria and kidney failure. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [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] 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] 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] Glycols: A generic grouping for dihydric alcohols with the hydroxy groups (-OH) located on different carbon atoms. They are viscous liquids with high boiling points for their molecular weights. [NIH] Glycopeptides: Proteins which contain carbohydrate groups attached covalently to the polypeptide chain. The protein moiety is the predominant group with the carbohydrate making up only a small percentage of the total weight. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycan: A type of long, unbranched polysaccharide molecule. Glycosaminoglycans are major structural components of cartilage and are also found in the cornea of the eye. [NIH]
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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] Gout: Hereditary metabolic disorder characterized by recurrent acute arthritis, hyperuricemia and deposition of sodium urate in and around the joints, sometimes with formation of uric acid calculi. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [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] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [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] Granulation Tissue: A vascular connective tissue formed on the surface of a healing wound, ulcer, or inflamed tissue. It consists of new capillaries and an infiltrate containing lymphoid cells, macrophages, and plasma cells. [NIH] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Granuloma: A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. [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] Guinea Pigs: A common name used for the family Caviidae. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. [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]
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Hay Fever: A seasonal variety of allergic rhinitis, marked by acute conjunctivitis with lacrimation and itching, regarded as an allergic condition triggered by specific allergens. [NIH]
Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heartburn: Substernal pain or burning sensation, usually associated with regurgitation of gastric juice into the esophagus. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [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] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Heparan Sulfate Proteoglycan: A substance released by astrocytes, which is critical in stopping nervous fibers in their tracks. [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, 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] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatitis A: Hepatitis caused by hepatovirus. It can be transmitted through fecal contamination of food or water. [NIH]
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Hepatitis, Chronic: A collective term for a clinical and pathological syndrome which has several causes and is characterized by varying degrees of hepatocellular necrosis and inflammation. Specific forms of chronic hepatitis include autoimmune hepatitis, chronic hepatitis B, chronic hepatitis C, chronic hepatitis D, indeterminate chronic viral hepatitis, cryptogenic chronic hepatitis, and drug-related chronic hepatitis. [NIH] Hepatocellular: Pertaining to or affecting liver cells. [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] Hepatotoxicity: How much damage a medicine or other substance does to the liver. [NIH] Hepatovirus: A genus of Picornaviridae causing infectious hepatitis naturally in humans and experimentally in other primates. It is transmitted through fecal contamination of food or water. [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] Herniated: Protrusion of a degenerated or fragmented intervertebral disc into the intervertebral foramen compressing the nerve root. [NIH] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes Zoster: Acute vesicular inflammation. [NIH] Heterochromatin: The portion of chromosome material that remains condensed and is transcriptionally inactive during interphase. [NIH] Heterodimers: Zippered pair of nonidentical proteins. [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]
Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histocompatibility: The degree of antigenic similarity between the tissues of different individuals, which determines the acceptance or rejection of allografts. [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] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [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] 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
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help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Hyaluronidase: An enzyme that splits hyaluronic acid and thus lowers the viscosity of the acid and facilitates the spreading of fluids through tissues either advantageously or disadvantageously. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [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] Hydration: Combining with water. [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 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] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydroxides: Inorganic compounds that contain the OH- group. [NIH] Hydroxyl Radical: The univalent radical OH that is present in hydroxides, alcohols, phenols, glycols. [NIH] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hypercalcemia: Abnormally high level of calcium in the blood. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperoxia: An abnormal increase in the amount of oxygen in the tissues and organs. [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] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH]
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Hypertension, Pulmonary: Increased pressure within the pulmonary circulation, usually secondary to cardiac or pulmonary disease. [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] Hyperuricemia: A buildup of uric acid (a byproduct of metabolism) in the blood; a side effect of some anticancer drugs. [NIH] Hypotension: Abnormally low blood pressure. [NIH] 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] Hypoxic: Having too little oxygen. [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] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
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 microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
of
foreign
Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunochemistry: Field of chemistry that pertains to immunological phenomena and the study of chemical reactions related to antigen stimulation of tissues. It includes physicochemical interactions between antigens and antibodies. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunogen: A substance that is capable of causing antibody formation. [NIH] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [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] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about
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in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [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] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] 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] Incompetence: Physical or mental inadequacy or insufficiency. [EU] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Indolent: A type of cancer that grows slowly. [NIH] 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] 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]
Infertility: The diminished or absent ability to conceive or produce an offspring while
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sterility is the complete inability to conceive or produce an offspring. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] 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]
Influenza: An acute viral infection involving the respiratory tract. It is marked by inflammation of the nasal mucosa, the pharynx, and conjunctiva, and by headache and severe, often generalized, myalgia. [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] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Instillation: . [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] Integrins: A family of transmembrane glycoproteins consisting of noncovalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement, and other cells, while their intracellular domains interact with the cytoskeleton. The integrins consist of at least three identified families: the cytoadhesin receptors, the leukocyte adhesion receptors, and the very-late-antigen receptors. Each family contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and oncogenic transformation. [NIH] Intensive Care: Advanced and highly specialized care provided to medical or surgical
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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]
Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon Alfa-2b: A recombinant alfa interferon consisting of 165 amino acid residues with arginine in position 23 and histidine in position 34. It is used extensively as an antiviral and antineoplastic agent. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interindividual: Occurring between two or more individuals. [EU] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-4: Soluble factor produced by activated T-lymphocytes that causes proliferation and differentiation of B-cells. Interleukin-4 induces the expression of class II major histocompatibility complex and Fc receptors on B-cells. It also acts on T-lymphocytes, mast cell lines, and several other hematopoietic lineage cells including granulocyte, megakaryocyte, and erythroid precursors, as well as macrophages. [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] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] 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] Interphase: The interval between two successive cell divisions during which the chromosomes are not individually distinguishable and DNA replication occurs. [NIH]
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Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intervertebral: Situated between two contiguous vertebrae. [EU] Intestinal: Having to do with the intestines. [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] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] 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] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] 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] Irradiation: The use of high-energy radiation from x-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 from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [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] Keloid: A sharply elevated, irregularly shaped, progressively enlarging scar resulting from formation of excessive amounts of collagen in the dermis during connective tissue repair. It is differentiated from a hypertrophic scar (cicatrix, hypertrophic) in that the former does not spread to surrounding tissues. [NIH] Keratinocyte growth factor: A substance that stimulates the growth of epithelial cells that line the surface of the mouth and intestinal tract. [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] 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.
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Also called nephropathy. [NIH] Killer Cells: Lymphocyte-like effector cells which mediate antibody-dependent cell cytotoxicity. They kill antibody-coated target cells which they bind with their Fc receptors. [NIH]
Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lacrimal: Pertaining to the tears. [EU] Lacrimal gland: The small almond-shaped structure that produces tears; located just above the outer corner of the eye. [NIH] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] 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] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Latent period: A seemingly inactive period, as that between exposure of tissue to an injurious agent and the manifestation of response, or that between the instant of stimulation and the beginning of response. [EU] Lavage: A cleaning of the stomach and colon. Uses a special drink and enemas. [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] Leflunomide: An anticancer drug that works by inhibiting a cancer cell growth factor. Also called SU101. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species. [NIH] Lethal: Deadly, fatal. [EU] 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]
Leukemia: Cancer of blood-forming tissue. [NIH] Leukocyte Elastase: An enzyme that catalyzes the hydrolysis of proteins, including elastin. It cleaves preferentially bonds at the carboxyl side of Ala and Val, with greater specificity for Ala. EC 3.4.21.37. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils,
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and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [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] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipofuscin: A naturally occurring lipid pigment with histochemical characteristics similar to ceroid. It accumulates in various normal tissues and apparently increases in quantity with age. [NIH] Liposomes: Artificial, single or multilaminar vesicles (made from lecithins or other lipids) that are used for the delivery of a variety of biological molecules or molecular complexes to cells, for example, drug delivery and gene transfer. They are also used to study membranes and membrane proteins. [NIH] 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] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [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] 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] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [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] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [NIH]
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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] 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]
Lucida: An instrument, invented by Wollaton, consisting essentially of a prism or a mirror through which an object can be viewed so as to appear on a plane surface seen in direct view and on which the outline of the object may be traced. [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 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] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphocyte Count: A count of the number of lymphocytes in the blood. [NIH] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphokine: A soluble protein produced by some types of white blood cell that stimulates other white blood cells to kill foreign invaders. [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] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Macula: A stain, spot, or thickening. Often used alone to refer to the macula retinae. [EU] Macula Lutea: An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the superior pole of the eye and slightly below the level of the optic disk. [NIH] Macular Degeneration: Degenerative changes in the macula lutea of the retina. [NIH] 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] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined
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(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] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]
Mammary: Pertaining to the mamma, or breast. [EU] Mammogram: An x-ray of the breast. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mannans: Polysaccharides consisting of mannose units. [NIH] Matrilysin: The smallest member of the matrix metalloproteinases. It plays a role in tumor progression. EC 3.4.24.23. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [NIH]
Meat Products: Articles of food which are derived by a process of manufacture from any portion of carcasses of any animal used for food (e.g., head cheese, sausage, scrapple). [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] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] 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] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [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]
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Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [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] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] 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] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesothelial: It lines the peritonealla and pleural cavities. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metalloporphyrins: Porphyrins which are combined with a metal ion. The metal is bound equally to all four nitrogen atoms of the pyrrole rings. They possess characteristic absorption spectra which can be utilized for identification or quantitative estimation of porphyrins and porphyrin-bound compounds. [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] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] Methylprednisolone: (6 alpha,11 beta)-11,17,21-Trihydroxy-6-methylpregna-1,4-diene-3,2dione. A prednisolone derivative which has pharmacological actions similar to prednisolone. [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] 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]
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Microcalcifications: Tiny deposits of calcium in the breast that cannot be felt but can be detected on a mammogram. A cluster of these very small specks of calcium may indicate that cancer is present. [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] 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] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Mineralocorticoids: A group of corticosteroids primarily associated with the regulation of water and electrolyte balance. This is accomplished through the effect on ion transport in renal tubules, resulting in retention of sodium and loss of potassium. Mineralocorticoid secretion is itself regulated by plasma volume, serum potassium, and angiotensin II. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [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] 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] 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] 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] Morphology: The science of the form and structure of organisms (plants, animals, and other
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forms of life). [NIH] Motility: The ability to move spontaneously. [EU] 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] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] 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]
Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [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] Muscle Proteins: The protein constituents of muscle, the major ones being ACTINS and MYOSIN. More than a dozen accessary proteins exist including troponin, tropomyosin, and dystrophin. [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] Myalgia: Pain in a muscle or muscles. [EU] Mycophenolate mofetil: A drug that is being studied for its effectiveness in preventing graft-versus-host disease and autoimmune disorders. [NIH] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelodysplastic syndrome: Disease in which the bone marrow does not function normally. Also called preleukemia or smoldering leukemia. [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration,
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sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]
Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myopia: That error of refraction in which rays of light entering the eye parallel to the optic axis are brought to a focus in front of the retina, as a result of the eyeball being too long from front to back (axial m.) or of an increased strength in refractive power of the media of the eye (index m.). Called also nearsightedness, because the near point is less distant than it is in emmetropia with an equal amplitude of accommodation. [EU] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] Natural killer cells: NK cells. A type of white blood cell that contains granules with enzymes that can kill tumor cells or microbial cells. Also called large granular lymphocytes (LGL). [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] Nebulizer: A device used to turn liquid into a fine spray. [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] Needle biopsy: The removal of tissue or fluid with a needle for examination under a microscope. Also called fine-needle aspiration. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neonatology: A subspecialty of pediatrics concerned with the newborn infant. [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] Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] 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] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers
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or strands. [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] Neuroretinitis: Inflammation of the optic nerve head and adjacent retina. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutralization: An act or process of neutralizing. [EU] 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] Neutrophil Activation: The process in which the neutrophil is stimulated by diverse substances, resulting in degranulation and/or generation of reactive oxygen products, and culminating in the destruction of invading pathogens. The stimulatory substances, including opsonized particles, immune complexes, and chemotactic factors, bind to specific cellsurface receptors on the neutrophil. [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] Non-small cell lung cancer: A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal 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] 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] Nuclear Medicine: A specialty field of radiology concerned with diagnostic, therapeutic, and investigative use of radioactive compounds in a pharmaceutical form. [NIH]
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Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with nucleoproteins which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. [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] Nucleoproteins: Proteins conjugated with nucleic acids. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Occupational Exposure: The exposure to potentially harmful chemical, physical, or biological agents that occurs as a result of one's occupation. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Oligomenorrhea: Abnormally infrequent menstruation. [NIH] Omeprazole: A highly effective inhibitor of gastric acid secretion used in the therapy of gastric ulcers and Zollinger-Ellison syndrome. The drug inhibits the H(+)-K(+)-ATPase (H(+)-K(+)-exchanging ATPase) in a pH-dependent manner. This ATPase is considered the proton pump in the secretory membrane of the parietal cell. [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 environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Disk: The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. [NIH]
Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the
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suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [NIH] Ossification: The formation of bone or of a bony substance; the conversion of fibrous tissue or of cartilage into bone or a bony substance. [EU] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Osteomyelitis: Inflammation of bone caused by a pyogenic organism. It may remain localized or may spread through the bone to involve the marrow, cortex, cancellous tissue, and periosteum. [EU] Osteopetrosis: Excessive formation of dense trabecular bone leading to pathological fractures, osteitis, splenomegaly with infarct, anemia, and extramedullary hemopoiesis. [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] Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily. [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] Overexpress: An excess of a particular protein on the surface of a cell. [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]
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 metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, cell respiration, or aerobic metabolism. [NIH]
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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] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] P53 gene: A tumor suppressor gene that normally inhibits the growth of tumors. This gene is altered in many types of cancer. [NIH] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Paediatric: Of or relating to the care and medical treatment of children; belonging to or concerned with paediatrics. [EU] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] 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 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] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic 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] Paneth Cells: Epithelial cells found in the basal part of the intestinal glands (crypts of Lieberkuhn). Paneth cells synthesize and secrete lysozyme and cryptdins. [NIH] Paraneoplastic syndrome: A group of symptoms that may develop when substances released by some cancer cells disrupt the normal function of surrounding cells and tissue. [NIH]
Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Parathyroid Glands: Two small paired endocrine glands in the region of the thyroid gland. They secrete parathyroid hormone and are concerned with the metabolism of calcium and phosphorus. [NIH] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the
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parietal bone, as the parietal lobe. [EU] Parietal Lobe: Upper central part of the cerebral hemisphere. [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] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [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] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]
Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Pelvic: Pertaining to the pelvis. [EU] Penicillamine: 3-Mercapto-D-valine. The most characteristic degradation product of the penicillin antibiotics. It is used as an antirheumatic and as a chelating agent in Wilson's disease. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] 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] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [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] 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] 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 blood: Blood circulating throughout the body. [NIH]
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Peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [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] Peritonitis: Inflammation of the peritoneum; a condition marked by exudations in the peritoneum of serum, fibrin, cells, and pus. It is attended by abdominal pain and tenderness, constipation, vomiting, and moderate fever. [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] 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] 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] 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] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [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] 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] Phosphorylate: Attached to a phosphate group. [NIH] Phosphorylated: Attached to a phosphate group. [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] Photosensitivity: An abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280400 mm. There are two main types : photoallergy and photoxicity. [EU] 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]
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Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigmentation: Coloration or discoloration of a part by a pigment. [NIH] Pigments: Any normal or abnormal coloring matter in plants, animals, or micro-organisms. [NIH]
Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [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] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [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] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [NIH] Platelet Activating Factor: A phospholipid derivative formed by platelets, basophils, neutrophils, monocytes, and macrophages. It is a potent platelet aggregating agent and inducer of systemic anaphylactic symptoms, including hypotension, thrombocytopenia, neutropenia, and bronchoconstriction. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, 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-Derived Growth Factor: Mitogenic peptide growth hormone carried in the alphagranules of platelets. It is released when platelets adhere to traumatized tissues. Connective tissue cells near the traumatized region respond by initiating the process of replication. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH]
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Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]
Plethysmography: Recording of change in the size of a part as modified by the circulation in it. [NIH] Pleura: The thin serous membrane enveloping the lungs and lining the thoracic cavity. [NIH] Pleural: A circumscribed area of hyaline whorled fibrous tissue which appears on the surface of the parietal pleura, on the fibrous part of the diaphragm or on the pleura in the interlobar fissures. [NIH] Pneumoconiosis: Condition characterized by permanent deposition of substantial amounts of particulate matter in the lungs, usually of occupational or environmental origin, and by the tissue reaction to its presence. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Pneumonitis: A disease caused by inhaling a wide variety of substances such as dusts and molds. Also called "farmer's disease". [NIH] Pneumothorax: Accumulation of air or gas in the space between the lung and chest wall, resulting in partial or complete collapse of the lung. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polyarthritis: An inflammation of several joints together. [EU] 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] Polycystic Ovary Syndrome: Clinical symptom complex characterized by oligomenorrhea or amenorrhea, anovulation, and regularly associated with bilateral polycystic ovaries. [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] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same
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population. [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [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]
Porphyria Cutanea Tarda: A form of hepatic porphyria (porphyria, hepatic) characterized by photosensitivity resulting in bullae that rupture easily to form shallow ulcers. This condition occurs in two forms: a sporadic, nonfamilial form that begins in middle age and has normal amounts of uroporphyrinogen decarboxylase with diminished activity in the liver; and a familial form in which there is an autosomal dominant inherited deficiency of uroporphyrinogen decarboxylase in the liver and red blood cells. [NIH] Porphyria, Hepatic: Porphyria in which the liver is the site where excess formation of porphyrin or its precursors is found. Acute intermittent porphyria and porphyria cutanea tarda are types of hepatic porphyria. [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] Portal Hypertension: High blood pressure in the portal vein. This vein carries blood into the liver. Portal hypertension is caused by a blood clot. This is a common complication of cirrhosis. [NIH] Portal Vein: A short thick vein formed by union of the superior mesenteric vein and the splenic vein. [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] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] 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] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [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
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convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] 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] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Preleukemia: Conditions in which the abnormalities in the peripheral blood or bone marrow represent the early manifestations of acute leukemia, but in which the changes are not of sufficient magnitude or specificity to permit a diagnosis of acute leukemia by the usual clinical criteria. [NIH] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Priapism: Persistent abnormal erection of the penis, usually without sexual desire, and accompanied by pain and tenderness. It is seen in diseases and injuries of the spinal cord, and may be caused by vesical calculus and certain injuries to the penis. [EU] Primary Biliary Cirrhosis: A chronic liver disease. Slowly destroys the bile ducts in the liver. This prevents release of bile. Long-term irritation of the liver may cause scarring and cirrhosis in later stages of the disease. [NIH] Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [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] Procollagen: A biosynthetic precursor of collagen containing additional amino acid sequences at the amino-terminal ends of the three polypeptide chains. Protocollagen, a precursor of procollagen consists of procollagen peptide chains in which proline and lysine have not yet been hydroxylated. [NIH] Progeny: The offspring produced in any generation. [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
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severity. [EU] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [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] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Promotor: In an operon, a nucleotide sequence located at the operator end which contains all the signals for the correct initiation of genetic transcription by the RNA polymerase holoenzyme and determines the maximal rate of RNA synthesis. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prone Position: The posture of an individual lying face down. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] 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] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [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]
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Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] 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] 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] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteoglycan: A molecule that contains both protein and glycosaminoglycans, which are a type of polysaccharide. Proteoglycans are found in cartilage and other connective tissues. [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] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]
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] Proton Pump: Integral membrane proteins that transport protons across a membrane against a concentration gradient. This transport is driven by hydrolysis of ATP by H(+)transporting ATP synthase. [NIH] Proton Pump Inhibitors: Medicines that stop the stomach's acid pump. Examples are omeprazole (oh-MEH-prah-zol) (Prilosec) and lansoprazole (lan-SOH-prah-zol) (Prevacid). [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] Proxy: A person authorized to decide or act for another person, for example, a person having durable power of attorney. [NIH] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and
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treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [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] Pulmonary: Relating to the lungs. [NIH] Pulmonary Circulation: The circulation of blood through 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] Pulmonary Fibrosis: Chronic inflammation and progressive fibrosis of the pulmonary alveolar walls, with steadily progressive dyspnea, resulting finally in death from oxygen lack or right heart failure. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulmonary Sarcoidosis: A disease of unknown etiology characterized by tuberclelike, granulomatous nodules which may affect the skin, the lungs, the lymph nodes, the bones of the distal extremities, the conjunctiva, the lacrimal gland, the retina and the uveal tract. [NIH] Pulmonary Ventilation: The total volume of gas per minute inspired or expired measured in liters per minute. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [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] Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Pyogenic: Producing pus; pyopoietic (= liquid inflammation product made up of cells and a thin fluid called liquor puris). [EU] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [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] 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
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substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radioactivity: The quality of emitting or the emission of corpuscular or electromagnetic radiations consequent to nuclear disintegration, a natural property of all chemical elements of atomic number above 83, and possible of induction in all other known elements. [EU] Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [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] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [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] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] 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] 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
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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] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [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] Refractory: Not readily yielding to treatment. [EU] 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] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] 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
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about. [NIH] Response Elements: Nucleotide sequences, usually upstream, which are recognized by specific regulatory transcription factors, thereby causing gene response to various regulatory agents. These elements may be found in both promotor and enhancer regions. [NIH]
Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [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] Retinal Detachment: Separation of the inner layers of the retina (neural retina) from the pigment epithelium. Retinal detachment occurs more commonly in men than in women, in eyes with degenerative myopia, in aging and in aphakia. It may occur after an uncomplicated cataract extraction, but it is seen more often if vitreous humor has been lost during surgery. (Dorland, 27th ed; Newell, Ophthalmology: Principles and Concepts, 7th ed, p310-12). [NIH] Retinal Neovascularization: Formation of new blood vessels originating from the retinal veins and extending along the inner (vitreal) surface of the retina. [NIH] Retinal Vein: Central retinal vein and its tributaries. It runs a short course within the optic nerve and then leaves and empties into the superior ophthalmic vein or cavernous sinus. [NIH]
Retinitis: Inflammation of the retina. It is rarely limited to the retina, but is commonly associated with diseases of the choroid (chorioretinitis) and of the optic nerve (neuroretinitis). The disease may be confined to one eye, but since it is generally dependent on a constitutional factor, it is almost always bilateral. It may be acute in course, but as a rule it lasts many weeks or even several months. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [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] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild
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type in previously mutated cells, tissues, or organisms. [NIH] Rheumatic Diseases: Disorders of connective tissue, especially the joints and related structures, characterized by inflammation, degeneration, or metabolic derangement. [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] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Ribavirin: 1-beta-D-Ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. A nucleoside antimetabolite antiviral agent that blocks nucleic acid synthesis and is used against both RNA and DNA viruses. [NIH] Ribonuclease: RNA-digesting enzyme. [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] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [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] 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]
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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] Screening: Checking for disease when there are no symptoms. [NIH] Scrotum: In males, the external sac that contains the testicles. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [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] Sediment: A precipitate, especially one that is formed spontaneously. [EU] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [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] Selective estrogen receptor modulator: SERM. A drug that acts like estrogen on some tissues, but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are SERMs. [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] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Septum: A dividing wall or partition; a general term for such a structure. The term is often
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used alone to refer to the septal area or to the septum pellucidum. [EU] Septum Pellucidum: A triangular double membrane separating the anterior horns of the lateral ventricles of the brain. It is situated in the median plane and bounded by the corpus callosum and the body and columns of the fornix. [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] Serine Endopeptidases: Any member of the group of endopeptidases containing at the active site a serine residue involved in catalysis. EC 3.4.21. [NIH] Serine Proteinase Inhibitors: Exogenous or endogenous compounds which inhibit serine endopeptidases. [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 Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Shedding: Release of infectious particles (e. g., bacteria, viruses) into the environment, for example by sneezing, by fecal excretion, or from an open lesion. [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. [NIH]
Shunt: A surgically created diversion of fluid (e.g., blood or cerebrospinal fluid) from one area of the body to another area of the body. [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] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Silicosis: A type of pneumoconiosis caused by inhalation of particles of silica, quartz, ganister or slate. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH]
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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] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sleep apnea: A serious, potentially life-threatening breathing disorder characterized by repeated cessation of breathing due to either collapse of the upper airway during sleep or absence of respiratory effort. [NIH] Small cell lung cancer: A type of lung cancer in which the cells appear small and round when viewed under the microscope. Also called oat cell lung cancer. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smoking Cessation: Discontinuation of the habit of smoking, the inhaling and exhaling of tobacco smoke. [NIH] Smoldering leukemia: Disease in which the bone marrow does not function normally. Also called preleukemia or myelodysplastic syndrome. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]
Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [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] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] 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] 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
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a disease. [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] 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] Splenomegaly: Enlargement of the spleen. [NIH] Spondylitis: Inflammation of the vertebrae. [EU] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Sputum: The material expelled from the respiratory passages by coughing or clearing the throat. [NIH] Squamous: Scaly, or platelike. [EU] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cells: Flat cells that look like fish scales under a microscope. These cells cover internal and external surfaces of the body. [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]
Steady state: Dynamic equilibrium. [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] Stellate: Star shaped. [NIH] Stem Cell Factor: Hematopoietic growth factor and the ligand of the c-kit receptor CD117 (proto-oncogene protein C-kit). It is expressed during embryogenesis and provides a key signal in multiple aspects of mast-cell differentiation and function. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stenosis: Narrowing or stricture of a duct or canal. [EU] Sterile: Unable to produce children. [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
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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] Steroid therapy: Treatment with corticosteroid drugs to reduce swelling, pain, and other symptoms of inflammation. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]
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] 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] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [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]
Sulfates: Inorganic salts of sulfuric acid. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Sulfuric acid: A strong acid that, when concentrated is extemely corrosive to the skin and mucous membranes. It is used in making fertilizers, dyes, electroplating, and industrial explosives. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH]
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Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [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] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] 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 Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [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] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Synovial: Of pertaining to, or secreting synovia. [EU] Systemic: Affecting the entire body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tacrolimus: A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. [NIH] Tamoxifen: A first generation selective estrogen receptor modulator (SERM). It acts as an agonist for bone tissue and cholesterol metabolism but is an estrogen antagonist in mammary and uterine. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH]
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Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetany: 1. Hyperexcitability of nerves and muscles due to decrease in concentration of extracellular ionized calcium, which may be associated with such conditions as parathyroid hypofunction, vitamin D deficiency, and alkalosis or result from ingestion of alkaline salts; it is characterized by carpopedal spasm, muscular twitching and cramps, laryngospasm with inspiratory stridor, hyperreflexia and choreiform movements. 2. Tetanus. [EU] 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] 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] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] 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] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]
Thymidine Kinase: An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC 2.7.1.21. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are
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concerned in regulating the metabolic rate of the body. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [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] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [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] Toxicokinetics: Study of the absorption, distribution, metabolism, and excretion of test substances. [NIH] 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] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] 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] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [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
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compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transforming Growth Factor alpha: Factor isolated in a variety of tissues including epithelium, and maternal decidua. It is closely related to epidermal growth factor and binds to the EGF receptor. TGF-alpha acts synergistically with TGF-beta in inducing phenotypic transformation, but its physiological role is unknown. [NIH] Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGFbeta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. [NIH]
Transgenes: Genes that are introduced into an organism using gene transfer techniques. [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] 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] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Tropoelastin: A salt-soluble precursor of elastin. Lysyl oxidase is instrumental in converting it to elastin in connective tissue. [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] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [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 marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body.
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Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [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] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [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] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] 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] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Univalent: Pertaining to an unpaired chromosome during the zygotene stage of prophase to first metaphase in meiosis. [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] Urease: An enzyme that catalyzes the conversion of urea and water to carbon dioxide and ammonia. EC 3.5.1.5. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Urinalysis: Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH]
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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] Urokinase: A drug that dissolves blood clots or prevents them from forming. [NIH] Uroporphyrinogen Decarboxylase: One of the enzymes active in heme biosynthesis. It catalyzes the decarboxylation of uroporphyrinogen III to coproporphyrinogen III by the conversion of four acetic acid groups to four methyl groups. EC 4.1.1.37. [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] Uveal tract: The middle coat of the eyeball, consisting of the choroid in the back of the eye and the ciliary body and iris in the front of the eye. [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] Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [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] 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] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilators: Any nerve or agent which induces dilatation of the 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] Venous Thrombosis: The formation or presence of a thrombus within a vein. [NIH] 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]
Dictionary 269
Ventilator: A breathing machine that is used to treat respiratory failure by promoting ventilation; also called a respirator. [NIH] 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] Ventricular Dysfunction: A condition in which the ventricles of the heart exhibit a decreased functionality. [NIH] 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] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Vinorelbine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [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] 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] 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] 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] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Hemorrhage: Hemorrhage into the vitreous body. [NIH] Vitreous Humor: The transparent, colorless mass of gel that lies behind the lens and in front of the retina and fills the center of the eyeball. [NIH] 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] 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]
Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH]
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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] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [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]
271
INDEX 1 1-phosphate, 139, 140, 193 A Abdomen, 193, 203, 207, 232, 234, 244, 246, 261, 262 Abdominal, 152, 193, 244, 246, 267 Abdominal Pain, 193, 246, 267 Aberrant, 12, 29, 64, 139, 193 Ablation, 20, 22, 193 Abscess, 193, 258 Acceptor, 193, 234, 243, 264, 266 Acetylcholine, 193, 241 Acetylglucosamine, 144, 193 Acetylglucosaminidase, 67, 193 Acquired Immunodeficiency Syndrome, 131, 193 Actin, 43, 50, 193 Adaptability, 193, 206 Adenocarcinoma, 193, 241 Adenosine, 193, 196, 246 Adenovirus, 13, 30, 73, 146, 193 Adhesions, 140, 144, 152, 193 Adoptive Transfer, 7, 31, 33, 194 Adrenal Cortex, 194, 195, 212, 250 Adrenal Glands, 194, 196 Adrenergic, 15, 194, 215, 218 Adverse Effect, 5, 21, 29, 194, 259 Aerobic, 194, 219, 238, 243 Aerosol, 138, 179, 194 Affinity, 9, 10, 194, 200, 260 Agonist, 15, 45, 139, 140, 194, 203, 215, 263 Air Pollutants, 29, 194 Air Sacs, 150, 194, 195 Airway, 6, 16, 18, 20, 31, 38, 40, 42, 47, 54, 55, 61, 71, 97, 121, 132, 152, 194, 260 Albinism, 117, 120, 177, 194 Albumin, 194, 243 Aldosterone, 144, 194 Algorithms, 29, 195, 202 Alkaloid, 195, 203, 209 Alleles, 26, 195 Allergen, 6, 195 Allergic Rhinitis, 153, 195, 225 Allium, 195 Allogeneic, 195, 224 Allograft, 38, 153, 195 Alloys, 195, 209 Allylamine, 195
Alopecia, 195, 212 Alpha Particles, 195, 253 Alpha-1, 49, 97, 138, 195 Alpha-Defensins, 103, 195 Alternative medicine, 159, 195 Alveoli, 11, 53, 132, 195, 268 Alveolitis, 36, 48, 73, 83, 88, 90, 91, 97, 102, 107, 150, 195 Amenorrhea, 195, 203, 248 Amine, 148, 195 Amino Acid Sequence, 131, 145, 196, 197, 219, 222, 250 Amino-terminal, 11, 196, 250 Amiodarone, 65, 112, 144, 196 Ammonia, 195, 196, 263, 267 Amyloidosis, 144, 196 Anabolic, 18, 196, 214 Anaesthesia, 196, 229 Anal, 27, 196 Analog, 196, 221 Analogous, 144, 196, 265 Analytes, 176, 196 Anaphylatoxins, 196, 210 Anatomical, 196, 200, 207, 211, 214, 229, 258 Androgenic, 196, 213 Androgens, 194, 196, 212 Anemia, 173, 197, 204, 209, 239, 243 Anesthesia, 85, 86, 194, 197, 216 Aneurysm, 197, 268 Angiogenesis, 12, 48, 57, 58, 72, 97, 136, 142, 143, 151, 197, 236 Angioplasty, 137, 148, 197, 239 Angiotensinogen, 197, 255 Animal model, 9, 14, 17, 18, 23, 25, 33, 36, 40, 49, 59, 132, 134, 197 Anionic, 146, 197 Anions, 194, 197, 232, 263 Annealing, 197, 248 Anovulation, 197, 248 Antagonism, 10, 35, 197 Antianginal, 196, 197 Antiarrhythmic, 196, 197 Antibacterial, 197, 260 Antibiotic, 128, 132, 197, 245, 260 Anticoagulant, 152, 197, 252
Pulmonary fibrosis
Antigen, 17, 33, 137, 147, 153, 194, 197, 198, 209, 213, 223, 226, 227, 228, 229, 230, 236 Antigen-Antibody Complex, 198, 209 Antigen-presenting cell, 198, 213 Anti-infective, 198, 227 Anti-inflammatory, 17, 58, 82, 198, 212, 223, 250 Anti-Inflammatory Agents, 198, 212 Antimetabolite, 198, 237, 257 Antineoplastic, 198, 202, 205, 212, 221, 231, 237, 269 Antioxidant, 28, 37, 112, 131, 198, 243, 244 Antiproliferative, 35, 198 Antiserum, 132, 198 Antiviral, 22, 198, 221, 231, 245, 257 Anus, 196, 198, 203, 209, 254 Aphakia, 198, 256 Aplastic anemia, 4, 198 Apnea, 5, 47, 198 Apoptosis, 11, 22, 35, 37, 38, 39, 43, 45, 50, 54, 58, 79, 81, 94, 144, 198, 205 Aqueous, 198, 201, 213, 227, 233 Arachidonate 15-Lipoxygenase, 198, 234 Arachidonate Lipoxygenases, 199, 234 Arachidonic Acid, 198, 199, 234, 251 Archaea, 199, 237 Arginine, 196, 199, 231, 241, 266 Aromatic, 199, 208, 246 Arterial, 118, 152, 195, 199, 211, 227, 252, 263 Arteries, 199, 203, 211, 212, 237, 253 Arterioles, 199, 203, 205, 238, 268 Arteriolosclerosis, 199 Arteriosclerosis, 134, 148, 149, 199 Artery, 62, 66, 152, 158, 197, 199, 202, 212, 217, 239, 245, 253, 255, 269 Articular, 18, 199, 243 Asbestos, 30, 80, 199 Asbestosis, 66, 86, 95, 199 Aspartic, 130, 145, 199 Aspartic Acid, 199 Assay, 25, 132, 200 Astrocytes, 200, 225 Asymptomatic, 200, 244 Ataxia, 172, 173, 200, 264 Atelectasis, 138, 200 Atopic, 141, 200 Atrial, 196, 200, 211, 266 Atrioventricular, 200, 211 Atrium, 200, 211, 266, 269 Atrophy, 172, 200
272
Attenuation, 84, 112, 140, 200 Autoantibodies, 26, 89, 94, 96, 200 Autoantigens, 200 Autodigestion, 200, 244 Autoimmune disease, 8, 139, 141, 151, 200, 239 Autoimmune Hepatitis, 200, 226 Autologous, 137, 147, 200 Autologous bone marrow transplantation, 137, 147, 200 Autopsy, 63, 122, 200 B Backcross, 27, 200 Bacteriophage, 201, 247, 265 Bacteriostatic, 195, 201 Bacterium, 152, 201 Bacteriuria, 201, 267 Basal Ganglia, 200, 201 Basal Ganglia Diseases, 200, 201 Base, 13, 19, 50, 201, 213, 222, 232, 248, 263, 267 Basement Membrane, 37, 201, 219, 233 Basophils, 142, 201, 224, 233, 247 Benign, 15, 199, 201, 213, 225, 240, 254 Berylliosis, 201 Beryllium, 25, 34, 201 Beta-Thromboglobulin, 201, 231 Bilateral, 66, 201, 248, 256 Bile, 201, 202, 221, 234, 250, 262 Bile Acids, 201, 202, 221, 262 Bile duct, 202, 250 Biliary, 147, 202, 205, 244 Biliary Tract, 202, 205, 244 Binding Sites, 9, 202 Bioassays, 60, 202 Biochemical, 7, 15, 34, 67, 104, 120, 121, 132, 138, 195, 198, 202, 204, 224, 233, 243 Biological response modifier, 202, 231 Biological therapy, 43, 202, 224 Biomarkers, 16, 27, 29, 35, 202 Biopsy, 15, 33, 34, 48, 109, 121, 122, 158, 202 Biotechnology, 61, 63, 159, 169, 171, 172, 173, 202 Biotransformation, 202 Bladder, 202, 210, 239, 251, 267, 268 Blood Coagulation, 202, 205, 220, 264 Blood Platelets, 178, 202, 236, 264 Blood pressure, 202, 205, 227, 228, 238, 249, 253, 260 Blot, 106, 203 Bodily Secretions, 4, 203
273
Body Fluids, 202, 203, 216, 260, 266 Bone Marrow, 5, 8, 36, 63, 96, 106, 108, 109, 198, 200, 203, 212, 222, 224, 228, 235, 236, 239, 250, 260, 262 Bone Marrow Cells, 203, 236 Bone Marrow Transplantation, 8, 108, 109, 203 Bone scan, 203, 257 Boron, 203, 212 Bowel, 196, 203, 214, 230, 232, 246, 262, 267 Bowel Movement, 203, 214, 262 Brachytherapy, 203, 231, 232, 253, 270 Bradykinin, 203, 241 Branch, 26, 141, 176, 189, 203, 245, 260, 264 Breakdown, 138, 144, 203, 214, 221, 242 Breeding, 27, 31, 203 Broad Ligament, 203, 219 Bromocriptine, 113, 203 Bronchi, 204, 218, 265 Bronchial, 15, 48, 121, 141, 204 Bronchiectasis, 51, 52, 97, 132, 204 Bronchioles, 71, 195, 204 Bronchiolitis, 18, 35, 38, 67, 69, 153, 204 Bronchiolitis Obliterans, 18, 35, 67, 153, 204 Bronchiolitis Obliterans Organizing Pneumonia, 35, 204 Bronchitis, 40, 131, 138, 153, 204, 208 Bronchoalveolar Lavage Fluid, 47, 73, 74, 75, 84, 87, 91, 94, 97, 99, 204 Bronchoconstriction, 204, 247 Bronchopulmonary, 20, 36, 53, 138, 204 Bronchopulmonary Dysplasia, 20, 36, 53, 138, 204 Bronchoscopy, 15, 48, 119, 122, 176, 204 Buccal, 204, 235 C Cadherins, 137, 204 Cadmium, 112, 204 Cadmium Poisoning, 204 Calcification, 100, 199, 204 Calcium, 199, 204, 209, 227, 236, 238, 240, 244, 252, 259, 264 Calculi, 205, 224 Capillary, 44, 203, 205, 269 Carbohydrate, 44, 134, 144, 205, 212, 223, 224, 249 Carbon Dioxide, 205, 221, 255, 267 Carboplatin, 80, 205 Carcinogen, 54, 205 Carcinogenic, 205, 230, 242, 251, 262
Carcinoma, 79, 88, 178, 205, 241 Carcinostatic, 128, 205 Cardiac, 13, 14, 195, 197, 205, 211, 218, 228, 240, 262 Cardiopulmonary, 13, 14, 205 Cardiovascular, 34, 38, 48, 84, 106, 205, 219, 234 Cardiovascular disease, 34, 205 Carotene, 205, 256 Case report, 99, 205, 208 Case series, 205, 208 Caspase, 39, 144, 205 Cataract, 45, 198, 205, 218, 256 Catheterization, 197, 206, 239 Cause of Death, 51, 206 Cell, 7, 8, 9, 10, 11, 14, 15, 17, 18, 21, 22, 23, 24, 30, 33, 34, 35, 36, 38, 40, 41, 42, 43, 44, 45, 46, 47, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 64, 67, 72, 76, 78, 79, 81, 95, 96, 100, 101, 106, 107, 112, 113, 130, 134, 136, 137, 140, 141, 143, 144, 145, 147, 151, 153, 172, 173, 193, 194, 196, 198, 199, 200, 201, 202, 204, 205, 206, 208, 210, 211, 213, 214, 216, 217, 219, 221, 222, 223, 224, 226, 227, 228, 230, 231, 232, 233, 236, 238, 239, 240, 241, 242, 243, 246, 247, 249, 251, 254, 255, 259, 260, 261, 262, 263, 264, 265, 266, 267, 269 Cell Adhesion, 136, 137, 140, 147, 204, 206, 230 Cell Adhesion Molecules, 137, 206 Cell Death, 22, 38, 198, 206, 223 Cell Differentiation, 206, 259, 261 Cell Division, 58, 172, 201, 206, 224, 231, 238, 247 Cell membrane, 140, 206, 214, 246 Cell motility, 206, 226 Cell proliferation, 7, 11, 34, 38, 57, 141, 199, 206, 231, 259 Cell Respiration, 206, 238, 243, 255 Cell Survival, 43, 206, 224 Cellulose, 206, 221, 247 Central Nervous System, 193, 206, 225, 234, 239, 243 Centromere, 26, 89, 206 Ceramide, 8, 206 Cerebellar, 200, 206, 255 Cerebral, 200, 201, 206, 207, 211, 218, 219, 245 Cerebral Cortex, 200, 206, 219 Cerebrospinal, 207, 259
Pulmonary fibrosis
Cerebrospinal fluid, 207, 259 Cerebrovascular, 201, 205, 207, 264 Cerebrum, 206, 207, 266 Ceroid, 117, 120, 207, 234 Cervix, 128, 207 Character, 207, 213 Chemokines, 11, 17, 18, 47, 61, 72, 90, 141, 151, 207 Chemotactic Factors, 97, 141, 207, 210, 241 Chemotaxis, 17, 21, 207 Chemotherapeutic agent, 51, 207 Chemotherapy, 80, 93, 104, 108, 150, 179, 207 Chest wall, 92, 207, 248 Chin, 113, 207, 237 Chlorophyll, 207, 221 Cholesterol, 201, 207, 212, 262, 263 Chondrocytes, 132, 207, 220 Chondroitin sulfate, 140, 207 Chorioretinitis, 207, 256 Choroid, 207, 256, 268 Chromatin, 198, 208 Chromium, 54, 208 Chromosomal, 27, 208, 247 Chromosome, 206, 208, 226, 234, 267 Chronic Disease, 141, 208 Chronic Obstructive Pulmonary Disease, 24, 78, 105, 180, 182, 208 Chronic renal, 140, 208, 248, 267 Chymotrypsin, 135, 208 Cicatrix, 208, 232 Cicatrix, Hypertrophic, 208, 232 Ciliary, 15, 208, 268 Cirrhosis, 16, 33, 140, 144, 146, 152, 208, 249, 250 CIS, 40, 208, 222, 256 C-kit receptor, 208, 261 Clinical Medicine, 89, 136, 143, 208, 250 Clinical study, 63, 208, 211 Clinical trial, 6, 19, 43, 117, 124, 125, 169, 208, 211, 212, 215, 239, 252, 254 Cloning, 27, 202, 208 Clot Retraction, 208, 247 Coagulation, 202, 209, 225, 264 Cobalt, 77, 209 Cofactor, 209, 241, 252, 264 Colchicine, 71, 95, 113, 209 Colitis, 85, 209 Collagen, 10, 13, 16, 19, 22, 23, 29, 30, 31, 32, 39, 45, 46, 50, 57, 58, 70, 73, 75, 77, 85, 86, 88, 93, 109, 121, 132, 134, 140,
274
144, 147, 196, 201, 209, 219, 220, 221, 232, 236, 247, 250, 251 Collagenases, 131, 145, 209 Collapse, 15, 203, 209, 248, 260 Colon, 84, 172, 209, 230, 233, 267 Combinatorial, 43, 209 Compassionate, 99, 209 Complement, 72, 135, 196, 209, 222, 230, 236 Complementation, 25, 210 Compliance, 26, 210 Computational Biology, 13, 169, 171, 210 Computed tomography, 102, 104, 210, 257 Computerized tomography, 210 Concomitant, 17, 49, 61, 210 Cones, 210, 256 Congestive heart failure, 26, 210 Conjugated, 210, 242 Conjunctiva, 210, 230, 253 Conjunctivitis, 137, 147, 210, 225 Conjunctivitis, Allergic, 137, 147, 210 Connective Tissue Cells, 210 Consciousness, 210, 213, 215, 253 Constipation, 210, 246 Constitutional, 210, 256 Constriction, 211, 232, 268 Constriction, Pathologic, 211, 268 Contamination, 211, 225, 226 Contractile Proteins, 55, 211 Contractility, 211, 216 Contraindications, ii, 211 Control group, 211, 250 Controlled clinical trial, 71, 211 Convulsions, 211, 216 Coordination, 211, 239 Cor, 87, 211 Cor pulmonale, 87, 211 Cornea, 211, 223 Corneal Ulcer, 4, 211 Coronary, 62, 66, 148, 149, 152, 158, 205, 211, 212, 237 Coronary heart disease, 148, 149, 205, 211 Coronary Thrombosis, 212, 237 Cortex, 212, 243, 255 Corticosteroid, 72, 92, 212, 250, 262 Cortisone, 212, 250 Creatinine, 26, 212, 267 Cryoglobulinemia, 4, 212 Cues, 16, 212 Cultured cells, 53, 212 Curative, 212, 264 Curcumin, 45, 212
275
Cutaneous, 212, 235, 246 Cyclic, 147, 148, 212, 224, 241, 249, 251 Cyclophosphamide, 72, 123, 124, 212 Cyclosporine, 5, 87, 153, 212 Cytokine, 7, 9, 13, 29, 30, 34, 41, 42, 43, 53, 54, 59, 60, 73, 78, 81, 93, 143, 150, 213, 231 Cytomegalovirus, 213, 221 Cytomegalovirus Infections, 213, 221 Cytoplasm, 198, 201, 206, 211, 213, 218, 257 Cytoprotection, 37, 213 Cytoskeleton, 43, 213, 230 Cytotoxic, 5, 54, 145, 213, 228, 254, 259 D Danazol, 79, 213 Deamination, 213, 267 Decidua, 213, 266 Defense Mechanisms, 213, 230 Degenerative, 8, 147, 213, 225, 235, 243, 256 Deletion, 39, 46, 198, 213, 222 Dementia, 137, 147, 193, 213 Denaturation, 213, 248 Dendrites, 213 Dendritic, 6, 213, 236 Dendritic cell, 6, 213 Density, 21, 51, 213, 242 Depolarization, 213, 259 Dermal, 137, 147, 148, 214 Dermatitis, 141, 214 Dermis, 214, 232, 263 Desmosine, 17, 214 Deuterium, 214, 227 Diabetes Mellitus, 129, 130, 214, 223, 225 Diabetic Retinopathy, 45, 57, 136, 214 Diagnostic procedure, 127, 159, 214 Dialyzer, 214, 225 Diastolic, 214, 227 Dietary Fats, 112, 214 Digestion, 133, 201, 203, 214, 232, 234, 244, 262 Digestive system, 126, 214, 239 Digestive tract, 214, 260, 261 Dihydrotestosterone, 214, 255 Dilatation, 197, 204, 214, 250, 268 Dilatation, Pathologic, 214, 268 Dilation, 203, 214, 268 Dimethyl, 112, 214 Dimethyl Sulfoxide, 112, 214 Diploid, 210, 215, 247
Direct, iii, 16, 17, 32, 41, 52, 60, 75, 208, 215, 235, 255, 263 Discrete, 56, 215 Disease Progression, 26, 42, 56, 215 Disease Susceptibility, 107, 215 Disparity, 60, 215 Dissection, 25, 27, 215 Dissociation, 194, 215 Distal, 12, 22, 215, 221, 252, 253 Diurnal, 28, 215 Domesticated, 215, 224 Dopamine, 203, 215, 241, 246 Double-blind, 119, 122, 215 Drive, ii, vi, 5, 59, 111, 215 Drug Interactions, 162, 215 Drug Tolerance, 215, 265 Duct, 206, 216, 219, 257, 261, 263, 268 Duodenum, 201, 208, 216, 244, 262 Dura mater, 216, 237, 244 Dyes, 201, 216, 262 Dysplasia, 173, 216 Dyspnea, 35, 36, 76, 216, 253 Dystrophy, 172, 216 E Ectopic, 136, 216 Edema, 214, 216, 239, 267 Effector, 6, 17, 20, 22, 30, 37, 39, 43, 61, 193, 209, 216, 233 Effector cell, 43, 216, 233 Efficacy, 5, 35, 43, 49, 118, 119, 120, 122, 123, 124, 135, 138, 216 Ejection fraction, 26, 216 Elastic, 52, 138, 144, 216, 263 Elasticity, 45, 199, 216 Elastin, 17, 52, 134, 138, 144, 209, 214, 216, 219, 233, 266 Electroconvulsive Therapy, 85, 216 Electrolyte, 15, 195, 212, 216, 238, 249, 260, 267 Emaciation, 193, 216 Embryo, 206, 216, 229 Embryogenesis, 216, 261 Emphysema, 12, 14, 16, 23, 37, 40, 52, 69, 104, 135, 137, 138, 208, 216 Endarterectomy, 197, 216 Endemic, 217, 261 Endogenous, 16, 28, 32, 43, 53, 133, 148, 149, 200, 203, 215, 217, 243, 259, 265 Endometrial, 217 Endometriosis, 136, 213, 217 Endometrium, 136, 143, 213, 217 Endoscopy, 5, 217
Pulmonary fibrosis
Endothelial cell, 13, 36, 106, 217, 220, 231, 264 Endothelium, 37, 152, 217, 241, 247 Endothelium, Lymphatic, 217 Endothelium, Vascular, 217 Endothelium-derived, 217, 241 Endotoxemia, 135, 217 Endotoxin, 23, 217, 267 End-stage renal, 208, 217, 248 Enhancer, 217, 256 Enteropeptidase, 217, 266 Environmental Exposure, 21, 70, 217, 242 Environmental Health, 168, 170, 217 Enzymatic, 34, 140, 196, 205, 210, 217, 220, 248, 256 Eosinophil, 6, 52, 59, 78, 91, 218 Eosinophilic, 218 Epidemic, 218, 261 Epidemiological, 54, 218 Epidermal, 218, 232, 236, 266 Epidermoid carcinoma, 218, 261 Epinephrine, 194, 215, 218, 241, 267 Epithelial, 10, 11, 28, 30, 31, 33, 39, 40, 43, 52, 53, 54, 55, 63, 71, 84, 87, 95, 106, 108, 131, 134, 144, 151, 193, 211, 213, 218, 226, 232, 233, 244 Epithelial Cells, 11, 33, 39, 40, 52, 53, 54, 55, 71, 95, 108, 134, 218, 226, 232, 233 Epithelium, 9, 10, 11, 17, 37, 103, 131, 144, 201, 217, 218, 256, 266 Epitope, 36, 67, 218 Epitope Mapping, 67, 218 Erectile, 45, 218, 245 Erection, 218, 250 Ergot, 203, 218 Erythrocytes, 197, 203, 218, 254 Esophageal, 3, 5, 218 Esophageal Manometry, 5, 218 Esophagus, 3, 152, 214, 218, 221, 225, 235, 246, 255, 262 Essential Tremor, 172, 218 Estrogen, 148, 149, 218, 251, 258, 263 Eukaryotic Cells, 218, 229 Evoke, 219, 262 Exercise Test, 119, 219 Exhaustion, 197, 219 Exocrine, 219, 244 Exogenous, 11, 28, 32, 33, 53, 56, 58, 60, 146, 202, 217, 219, 222, 259 Exon, 15, 219 Expiration, 219, 255, 269 Extensor, 219, 252
276
External-beam radiation, 219, 232, 253, 270 Extracellular Matrix Proteins, 23, 219, 236 Extracellular Space, 219 Extraction, 198, 219, 256 Exudate, 204, 207, 219 Eye Infections, 193, 219 F Fallopian tube, 152, 219 Family Planning, 169, 220 Fat, 117, 120, 199, 203, 205, 206, 211, 212, 220, 234, 239, 257, 260, 263, 266 Fatigue, 220, 225 Fatty acids, 194, 220, 234, 251 Fibrin, 32, 39, 44, 46, 202, 208, 220, 246, 247, 264 Fibrinogen, 46, 220, 247, 264 Fibrinolysis, 40, 148, 149, 220 Fibrinolytic, 148, 149, 220 Fibroblast Growth Factor, 21, 34, 67, 220 Fibronectins, 219, 220 Fibrotic tissue, 140, 220 Fine-needle aspiration, 220, 240 Flatus, 220, 221 Fluoroscopy, 15, 220 Fold, 39, 131, 203, 220 Foramen, 207, 220, 226 Founder Effect, 97, 220 Free Radicals, 198, 215, 220, 240 Fungi, 219, 221, 237, 238, 270 Fungus, 61, 218, 221 G Gallbladder, 193, 202, 214, 221 Gallium, 82, 83, 181, 221 Gamma Rays, 221, 253, 254 Gamma-interferon, 151, 221 Ganciclovir, 22, 221 Gas, 12, 83, 145, 176, 196, 205, 220, 221, 227, 241, 248, 253, 255, 268 Gas exchange, 12, 83, 145, 221, 255, 268 Gastric, 3, 200, 221, 225, 242 Gastrin, 83, 221, 226 Gastroesophageal Reflux, 3, 5, 90, 221 Gastrointestinal, 5, 142, 199, 203, 204, 218, 221, 234, 262, 267 Gastrointestinal Neoplasms, 199, 221 Gastrointestinal tract, 142, 221, 234, 267 Gelatin, 221, 223, 264 Gelatinases, 131, 145, 221 Gene Deletion, 25, 53, 222 Gene Expression Profiling, 12, 222 Gene Products, rev, 222
277
Gene Targeting, 56, 222 Gene Therapy, 8, 146, 147, 193, 222 Genes, env, 25, 222 Genetic Code, 222, 242 Genetic Engineering, 202, 208, 222 Genetic Markers, 8, 119, 222 Genetic testing, 222, 248 Genetics, 7, 8, 12, 26, 68, 76, 105, 118, 222 Genotype, 27, 222, 246 Germ Cells, 222, 243 Germanium, 129, 222 Gestation, 222, 245 Giant Cells, 223, 257 Gland, 4, 194, 212, 223, 235, 244, 245, 247, 251, 258, 262, 263, 264 Glomerular, 134, 223 Glomeruli, 223 Glomerulonephritis, 4, 82, 96, 130, 135, 145, 223 Glomerulosclerosis, 57, 140, 152, 223 Glomerulus, 223, 240 Glucocorticoid, 84, 223, 250 Glucose, 172, 193, 206, 208, 214, 223, 225, 230, 257 Glucose Intolerance, 214, 223 Glucuronic Acid, 223, 225 Glycine, 196, 223, 241, 259 Glycols, 223, 227 Glycopeptides, 128, 223 Glycoprotein, 37, 134, 220, 223, 224, 233, 239, 264, 267 Glycosaminoglycan, 140, 207, 223 Glycosylation, 143, 224 Gonadal, 224, 262 Gout, 132, 209, 224 Governing Board, 224, 249 Gp120, 224, 245 Graft, 18, 91, 109, 142, 151, 153, 224, 227, 229, 239 Graft Rejection, 142, 153, 224, 229 Graft-versus-host disease, 109, 224, 239 Gram-negative, 217, 224 Granulation Tissue, 32, 60, 204, 224 Granulocyte, 84, 151, 224, 231 Granuloma, 25, 34, 51, 224 Growth factors, 10, 11, 21, 29, 34, 35, 38, 39, 41, 43, 51, 57, 58, 60, 62, 140, 152, 224 Guanylate Cyclase, 224, 241 Guinea Pigs, 26, 224 H Haplotypes, 15, 224 Haptens, 194, 224
Hay Fever, 195, 225 Headache, 225, 230 Heart attack, 205, 225 Heart failure, 13, 180, 211, 225, 253 Heartburn, 3, 225 Heme, 107, 225, 244, 249, 268 Hemodialysis, 4, 214, 225 Hemoglobin, 197, 218, 225, 249 Hemoglobinopathies, 222, 225 Hemoglobinuria, 172, 225 Hemorrhage, 225, 240, 262, 269 Hemostasis, 44, 225, 230 Heparan Sulfate Proteoglycan, 47, 225 Heparin, 107, 140, 225 Hepatic, 134, 140, 146, 147, 194, 225, 234, 249 Hepatitis, 4, 33, 140, 142, 147, 225, 226, 269 Hepatitis A, 34, 225 Hepatitis, Chronic, 4, 226 Hepatocellular, 4, 226 Hepatocyte, 10, 73, 75, 85, 94, 226 Hepatocyte Growth Factor, 10, 73, 75, 94, 226 Hepatotoxicity, 5, 226 Hepatovirus, 225, 226 Hereditary, 49, 131, 224, 226, 256 Heredity, 221, 222, 226 Herniated, 130, 145, 226 Herpes, 22, 226 Herpes Zoster, 226 Heterochromatin, 89, 226 Heterodimers, 52, 226, 230, 266 Heterogeneity, 14, 27, 42, 86, 194, 226 Histidine, 226, 231 Histocompatibility, 20, 226 Histology, 37, 102, 226 Homeostasis, 15, 18, 28, 35, 136, 143, 226 Homodimer, 143, 226, 266 Homogeneous, 26, 199, 226 Homologous, 195, 222, 226, 263 Hormonal, 200, 212, 226 Host, 21, 25, 27, 28, 33, 37, 47, 51, 54, 57, 131, 142, 151, 201, 227, 228, 229, 234, 269 Humoral, 224, 227 Hyaluronidase, 138, 227 Hybrid, 200, 227 Hybridization, 37, 227 Hybridomas, 227, 231 Hydration, 50, 227 Hydrogen Peroxide, 37, 227, 234, 263 Hydrolysis, 193, 199, 202, 227, 233, 246, 252, 266
Pulmonary fibrosis
Hydroxides, 227 Hydroxyl Radical, 37, 227 Hydroxylysine, 209, 227 Hydroxyproline, 196, 209, 227 Hypercalcemia, 8, 227 Hyperglycemia, 149, 227 Hyperoxia, 13, 14, 37, 227 Hyperplasia, 10, 61, 144, 227 Hypersensitivity, 17, 32, 34, 91, 137, 147, 148, 195, 210, 218, 227, 234, 257 Hypertension, 24, 27, 47, 118, 176, 199, 205, 225, 227, 228, 249, 267 Hypertension, Pulmonary, 27, 228 Hypertrophy, 132, 211, 227, 228, 266 Hyperuricemia, 224, 228 Hypotension, 211, 228, 247 Hypoxemia, 105, 228 Hypoxia, 24, 47, 228, 264 Hypoxic, 24, 47, 228 I Id, 114, 172, 178, 179, 180, 181, 182, 183, 188, 190, 228 Immune function, 228, 266 Immune response, 34, 61, 141, 151, 153, 198, 200, 212, 224, 228, 229, 236, 262, 269 Immunity, 27, 43, 56, 66, 134, 193, 228 Immunization, 182, 194, 228, 229 Immunochemistry, 218, 228 Immunodeficiency, 172, 193, 228 Immunogen, 150, 151, 228 Immunoglobulin, 180, 197, 228, 238 Immunohistochemistry, 30, 55, 228 Immunologic, 32, 37, 194, 207, 228, 254 Immunology, 18, 27, 37, 40, 41, 59, 74, 86, 94, 97, 104, 194, 228 Immunosuppressant, 228, 237 Immunosuppressive, 5, 21, 74, 153, 212, 223, 228, 229, 263 Immunosuppressive Agents, 22, 153, 228 Immunosuppressive therapy, 74, 229 Immunotherapy, 194, 202, 229 Impairment, 5, 33, 103, 200, 219, 229, 237 Implant radiation, 229, 231, 232, 253, 270 Impotence, 218, 229 In situ, 30, 36, 37, 81, 229 In Situ Hybridization, 30, 81, 229 Incision, 229, 232 Incompetence, 221, 229 Incubation, 229, 233 Incubation period, 229, 233 Indicative, 155, 229, 245, 268 Indolent, 39, 229
278
Induction, 6, 24, 25, 31, 32, 38, 43, 51, 55, 60, 80, 104, 112, 138, 196, 229, 251, 254 Infancy, 65, 229 Infarction, 201, 212, 229, 237, 255 Infertility, 203, 229 Infiltration, 6, 13, 32, 134, 135, 223, 230 Inflammatory bowel disease, 132, 137, 139, 141, 147, 148, 178, 230 Influenza, 181, 182, 230 Infusion, 121, 230, 240 Ingestion, 55, 147, 204, 230, 248, 264 Inhalation, 26, 54, 59, 145, 194, 199, 204, 230, 248, 259 Initiation, 39, 58, 139, 141, 230, 251, 265 Initiator, 57, 230 Inlay, 230, 256 Inorganic, 21, 29, 227, 230, 239, 262 Insight, 32, 36, 38, 52, 61, 230 Instillation, 138, 230 Insulator, 230, 239 Insulin, 10, 19, 75, 78, 96, 230 Insulin-dependent diabetes mellitus, 230 Insulin-like, 10, 19, 75, 78, 96, 230 Integrins, 9, 43, 52, 137, 230 Intensive Care, 99, 100, 230 Interferon, 4, 19, 21, 32, 33, 34, 35, 59, 60, 64, 65, 74, 90, 122, 123, 124, 143, 151, 158, 163, 221, 231 Interferon Alfa-2b, 4, 231 Interferon-alpha, 33, 231 Interindividual, 15, 231 Interleukin-1, 5, 129, 130, 152, 231 Interleukin-2, 231 Interleukin-4, 93, 231 Interleukin-6, 81, 231 Interleukin-8, 90, 97, 151, 231 Interleukins, 229, 231 Intermittent, 24, 47, 124, 231, 249 Internal radiation, 231, 232, 253, 270 Interphase, 226, 231 Intervertebral, 226, 232 Intestinal, 117, 195, 205, 217, 232, 236, 244 Intestine, 117, 120, 152, 203, 232, 233 Intoxication, 232, 268, 270 Intracellular, 70, 140, 229, 230, 232, 237, 241, 249, 251, 259 Intracellular Membranes, 232, 237 Intravenous, 5, 124, 135, 153, 180, 230, 232 Intrinsic, 194, 201, 232 Invasive, 17, 228, 232, 235 Involuntary, 201, 218, 232, 240, 255, 260 Ionizing, 195, 217, 232, 254
279
Ions, 201, 215, 216, 227, 232, 252 Irradiation, 36, 232, 270 Ischemia, 18, 200, 232, 239, 255 J Joint, 19, 132, 199, 232, 243, 263 K Kb, 168, 232 Keloid, 142, 146, 208, 232 Keratinocyte growth factor, 37, 232 Keratinocytes, 231, 232 Kidney Disease, 117, 126, 142, 168, 173, 180, 232 Killer Cells, 233 Kinetic, 232, 233 L Labile, 209, 233 Lacrimal, 233, 253 Lacrimal gland, 233, 253 Laminin, 37, 91, 134, 201, 219, 233 Large Intestine, 214, 232, 233, 254, 260 Latency, 9, 31, 133, 134, 233 Latent, 9, 30, 31, 36, 37, 40, 59, 68, 103, 131, 133, 134, 146, 233, 250 Latent period, 36, 233 Lavage, 17, 29, 32, 34, 69, 74, 78, 79, 82, 83, 86, 90, 93, 105, 121, 204, 233 Lectin, 144, 233, 237 Leflunomide, 5, 233 Lens, 198, 205, 233, 269 Lentivirus, 45, 233 Lethal, 23, 30, 131, 133, 135, 233 Leucocyte, 195, 218, 233 Leukemia, 7, 172, 222, 233, 250 Leukocyte Elastase, 135, 233 Leukocytes, 27, 139, 152, 201, 203, 207, 231, 233, 267 Leukotrienes, 6, 199, 234 Library Services, 188, 234 Ligament, 132, 234, 251 Ligands, 44, 55, 137, 147, 151, 206, 230, 234 Ligation, 53, 55, 135, 234 Linkage, 8, 123, 222, 234 Lipid, 6, 8, 28, 29, 44, 56, 91, 140, 199, 207, 230, 234, 239, 244, 266 Lipid Peroxidation, 234, 244 Lipofuscin, 117, 120, 207, 234 Liposomes, 36, 146, 234 Lipoxygenase, 6, 199, 234 Liver Cirrhosis, 142, 234 Liver scan, 234, 257 Lobe, 108, 234 Localization, 20, 42, 96, 228, 234
Localized, 23, 193, 196, 211, 229, 233, 234, 243, 247, 258, 267 Longitudinal Studies, 125, 234 Loop, 43, 235 Lower Esophageal Sphincter, 221, 235 Lucida, 233, 235 Lumen, 44, 152, 217, 235 Lung Transplantation, 12, 18, 62, 69, 71, 82, 87, 91, 100, 101, 106, 122, 153, 235 Lupus, 151, 235 Lymph, 217, 235, 253, 257 Lymph node, 235, 253, 257 Lymphatic, 217, 229, 235, 237, 260, 261 Lymphocyte, 30, 33, 91, 93, 101, 139, 193, 198, 233, 235, 236 Lymphocyte Count, 193, 235 Lymphocytic, 102, 235 Lymphoid, 197, 224, 233, 235 Lymphokine, 5, 235 Lymphoma, 128, 172, 235 Lysine, 214, 227, 235, 250, 266 M Macrophage, 13, 31, 36, 37, 40, 60, 150, 151, 231, 235 Macula, 235 Macula Lutea, 235 Macular Degeneration, 45, 136, 235 Magnetic Resonance Imaging, 235, 257 Major Histocompatibility Complex, 224, 231, 235 Malabsorption, 172, 236 Malignant, 15, 26, 128, 172, 193, 198, 199, 236, 239, 240, 254 Malignant tumor, 236, 239 Malnutrition, 194, 200, 236, 239 Mammary, 236, 263 Mammogram, 204, 236, 238 Manifest, 26, 236 Mannans, 221, 236 Matrilysin, 37, 62, 83, 236 Matrix metalloproteinase, 19, 37, 40, 46, 47, 51, 100, 105, 236 Meat, 214, 236 Meat Products, 214, 236 Mechanical ventilation, 94, 99, 204, 236 Medial, 199, 236 Mediate, 5, 20, 32, 37, 39, 206, 215, 233, 236 Mediator, 12, 19, 20, 30, 46, 55, 59, 231, 236 Medicament, 195, 236 MEDLINE, 169, 171, 173, 236 Megakaryocytes, 96, 203, 236 Melanin, 236, 246, 267
Pulmonary fibrosis
Melanocytes, 236, 237 Melanoma, 172, 237 Membrane Proteins, 52, 234, 237, 252 Memory, 17, 213, 237 Meninges, 206, 216, 237 Meningitis, 137, 147, 148, 237 Mental, iv, 6, 126, 168, 170, 174, 206, 207, 213, 215, 220, 229, 237, 253, 258, 267 Mental Disorders, 126, 237, 253 Mesenchymal, 10, 30, 57, 59, 237 Mesothelial, 144, 237 Metabolic disorder, 224, 237 Metabolite, 202, 214, 237 Metalloporphyrins, 29, 237 Metastasis, 134, 136, 137, 147, 148, 206, 236, 237 Methionine, 214, 237, 262 Methotrexate, 5, 80, 237 Methylprednisolone, 76, 124, 237 MI, 70, 79, 80, 82, 83, 99, 100, 142, 144, 151, 191, 237 Microbe, 237, 265 Microbiology, 41, 85, 112, 201, 237 Microcalcifications, 204, 238 Microcirculation, 234, 238, 247 Microorganism, 209, 238, 245, 269 Microscopy, 13, 23, 201, 238 Migration, 17, 23, 78, 134, 137, 139, 140, 141, 147, 238 Mineralocorticoids, 194, 212, 238 Mitochondria, 28, 238, 240 Mitosis, 198, 238 Mobility, 53, 238 Modification, 138, 196, 222, 238, 253 Monitor, 29, 76, 212, 238, 241 Monoclonal, 5, 227, 232, 238, 254, 270 Monoclonal antibodies, 5, 238 Monocyte, 51, 52, 61, 62, 139, 238 Mononuclear, 60, 141, 152, 224, 238, 267 Morphogenesis, 52, 238 Morphological, 216, 221, 236, 238 Morphology, 37, 46, 199, 205, 238 Motility, 5, 239 Mucolytic, 204, 239 Mucosa, 49, 141, 235, 239, 251, 262 Mucositis, 49, 239, 264 Mucus, 6, 132, 239, 267 Multicenter study, 122, 239 Multiple Myeloma, 137, 147, 239 Multiple sclerosis, 129, 130, 137, 139, 141, 147, 148, 151, 239 Muscle Fibers, 239
280
Muscle Proteins, 211, 239 Muscular Atrophy, 172, 239 Muscular Dystrophies, 216, 239 Myalgia, 230, 239 Mycophenolate mofetil, 65, 101, 112, 153, 239 Myelin, 239 Myelodysplastic syndrome, 96, 239, 260 Myocardial Reperfusion, 239, 255 Myocardial Reperfusion Injury, 239, 255 Myocarditis, 137, 147, 148, 240 Myocardium, 237, 240 Myopia, 240, 255, 256 Myotonic Dystrophy, 172, 240 N Nasal Mucosa, 230, 240 Natural killer cells, 143, 240 NCI, 1, 126, 167, 208, 240 Nebulizer, 138, 240 Need, 3, 5, 156, 162, 163, 184, 194, 208, 236, 240, 265 Needle biopsy, 15, 220, 240 Neonatal, 52, 181, 240 Neonatology, 41, 240 Neoplasia, 144, 172, 240 Neoplasm, 240, 267 Neoplastic, 136, 227, 235, 240 Nephritis, 134, 137, 139, 147, 148, 240 Nephropathy, 130, 134, 139, 145, 233, 240 Nervous System, 172, 206, 236, 240, 241, 262 Networks, 28, 42, 50, 240 Neural, 227, 241, 256 Neuroretinitis, 241, 256 Neurotransmitter, 193, 196, 200, 203, 215, 223, 241, 259, 262 Neutralization, 148, 149, 241 Neutrons, 195, 232, 241, 253 Neutrophil, 52, 85, 91, 96, 97, 130, 132, 135, 145, 151, 241 Neutrophil Activation, 135, 241 Nickel, 103, 241 Nitric Oxide, 19, 37, 42, 48, 53, 86, 100, 241 Nitrogen, 91, 195, 196, 212, 219, 237, 241, 244, 266 Non-small cell lung cancer, 80, 241 Norepinephrine, 194, 215, 241 Nuclear, 10, 27, 44, 53, 119, 181, 201, 209, 218, 221, 222, 241, 242, 254 Nuclear Medicine, 119, 181, 241 Nuclear Proteins, 53, 222, 242 Nuclei, 195, 222, 235, 238, 241, 242, 252
281
Nucleic acid, 22, 37, 222, 227, 229, 241, 242, 253, 257 Nucleic Acid Hybridization, 227, 242 Nucleoproteins, 242 Nucleus, 198, 201, 208, 212, 213, 214, 218, 221, 238, 241, 242, 252, 262, 264 O Occupational Exposure, 113, 242 Ocular, 27, 45, 242 Oligomenorrhea, 242, 248 Omeprazole, 4, 242, 252 Oncogene, 151, 172, 226, 242, 261 Oncogenic, 230, 233, 242 Opacity, 205, 213, 242 Open Reading Frames, 233, 242 Operon, 242, 251, 255 Opportunistic Infections, 153, 193, 242 Opsin, 242, 256, 257 Optic Disk, 214, 235, 242 Optic Nerve, 241, 242, 244, 256 Organ Transplantation, 137, 147, 148, 243 Ossification, 75, 243 Osteoarthritis, 18, 132, 134, 136, 243 Osteomyelitis, 151, 243 Osteopetrosis, 130, 134, 145, 243 Osteoporosis, 16, 134, 243 Ovalbumin, 6, 243 Ovaries, 243, 248 Ovary, 149, 243, 262 Overexpress, 35, 243 Oxidants, 43, 131, 243 Oxidation, 193, 198, 199, 202, 234, 243, 244 Oxidation-Reduction, 202, 243 Oxidative metabolism, 234, 243 Oxidative Stress, 28, 104, 244 Oxygen Consumption, 219, 244, 255 Oxygenase, 107, 244 Oxygenation, 24, 86, 228, 244 P P53 gene, 86, 244 Pachymeningitis, 237, 244 Paediatric, 182, 244 Palliative, 180, 244, 264 Pancreas, 193, 202, 208, 214, 230, 244, 266, 267 Pancreatic, 131, 142, 172, 208, 221, 244 Pancreatic cancer, 172, 244 Pancreatic Insufficiency, 131, 244 Pancreatic Juice, 208, 221, 244 Pancreatitis, 139, 244 Paneth Cells, 195, 244 Paraneoplastic syndrome, 88, 244
Parathyroid, 11, 244, 264 Parathyroid Glands, 244 Parietal, 16, 242, 244, 245, 246, 248 Parietal Lobe, 245 Parotid, 245, 257 Paroxysmal, 172, 245 Patch, 34, 245 Pathogen, 51, 229, 245 Pathologic, 15, 54, 56, 85, 88, 92, 198, 202, 211, 227, 245, 252 Pathologic Processes, 198, 245 Pathologies, 27, 44, 59, 137, 147, 148, 245 Pathophysiology, 5, 19, 24, 245 Patient Education, 177, 186, 188, 191, 245 Pediatrics, 35, 180, 181, 240, 245 Pelvic, 217, 245, 251 Penicillamine, 71, 76, 245 Penicillin, 197, 245, 268 Penis, 245, 250 Pepsin, 3, 245 Peptide T, 45, 134, 245 Perfusion, 228, 245, 265 Perinatal, 52, 245 Peripheral blood, 14, 26, 231, 245, 250 Peripheral stem cells, 224, 246 Peritoneal, 53, 246 Peritoneum, 203, 246 Peritonitis, 135, 246 Phagocyte, 60, 243, 246 Phagocytosis, 55, 246 Pharmacokinetic, 246 Pharmacologic, 5, 15, 28, 68, 101, 197, 246, 265 Pharynx, 221, 230, 246 Phenotype, 9, 14, 28, 31, 39, 42, 43, 46, 50, 58, 59, 210, 222, 246 Phenyl, 148, 246 Phenylalanine, 246, 267 Phospholipases, 246, 259 Phospholipids, 220, 246 Phosphorus, 204, 244, 246 Phosphorylate, 19, 246 Phosphorylated, 50, 246 Phosphorylation, 58, 246 Photosensitivity, 246, 249 Physiologic, 15, 23, 35, 44, 48, 70, 82, 103, 148, 149, 194, 246, 251, 254 Physiology, 14, 22, 23, 24, 25, 65, 67, 72, 73, 74, 77, 78, 81, 83, 84, 86, 87, 91, 93, 95, 97, 98, 101, 102, 104, 108, 109, 247, 255, 268 Pigmentation, 117, 120, 247
Pulmonary fibrosis
Pigments, 205, 209, 247, 256 Pituitary Gland, 212, 220, 247 Plants, 195, 199, 203, 205, 223, 233, 238, 241, 247, 257, 265 Plaque, 197, 247 Plasma cells, 197, 224, 239, 247 Plasmid, 10, 247, 268 Plasmin, 40, 44, 130, 133, 145, 148, 149, 247 Plasminogen, 39, 44, 46, 148, 149, 247 Plasminogen Activators, 247 Platelet Activating Factor, 7, 247 Platelet Activation, 247, 259 Platelet Aggregation, 196, 241, 247 Platelet-Derived Growth Factor, 30, 247 Platelets, 152, 178, 201, 241, 247, 264 Platinum, 235, 248 Plethysmography, 179, 248 Pleura, 16, 248 Pleural, 237, 248 Pneumoconiosis, 248, 259 Pneumonia, 5, 15, 35, 67, 74, 77, 79, 80, 87, 91, 93, 97, 100, 103, 104, 109, 140, 179, 204, 211, 248 Pneumonitis, 5, 32, 39, 91, 113, 204, 248 Pneumothorax, 15, 248 Point Mutation, 86, 248 Poisoning, 201, 204, 218, 232, 248 Polyarthritis, 66, 248 Polycystic, 148, 149, 173, 248 Polycystic Ovary Syndrome, 148, 149, 248 Polymerase, 19, 53, 73, 248, 251, 255 Polymerase Chain Reaction, 53, 73, 248 Polymers, 129, 248, 252 Polymorphic, 104, 207, 248 Polymorphism, 14, 66, 248 Polysaccharide, 198, 206, 223, 249, 252 Porphyria, 4, 249 Porphyria Cutanea Tarda, 4, 249 Porphyria, Hepatic, 249 Porphyrins, 237, 249 Portal Hypertension, 147, 249 Portal Vein, 249 Posterior, 196, 200, 207, 244, 249 Postmenopausal, 243, 249 Postnatal, 249, 261 Postsynaptic, 249, 259 Post-translational, 133, 151, 249 Potassium, 195, 238, 249 Potentiates, 32, 54, 231, 249 Potentiation, 249, 259 Practice Guidelines, 170, 178, 249
282
Precursor, 35, 143, 197, 199, 212, 215, 216, 217, 241, 246, 247, 250, 252, 266, 267, 268 Predisposition, 83, 136, 143, 250 Prednisolone, 237, 250 Prednisone, 21, 48, 71, 123, 124, 250 Preleukemia, 239, 250, 260 Prevalence, 4, 90, 97, 250 Priapism, 182, 250 Primary Biliary Cirrhosis, 147, 250 Primary endpoint, 34, 250 Probe, 12, 250 Procollagen, 10, 74, 87, 250 Progeny, 27, 250 Progesterone, 250, 251, 262 Prognostic factor, 94, 250 Prolactin, 203, 251 Proline, 209, 227, 250, 251 Promoter, 10, 15, 20, 22, 53, 59, 251 Promotor, 251, 256 Prone, 77, 251 Prone Position, 77, 251 Prophylaxis, 142, 251 Proportional, 27, 251 Prospective study, 71, 251 Prostaglandin, 43, 50, 158, 251 Prostaglandins A, 251 Prostate, 172, 202, 251, 267 Protease, 39, 40, 104, 131, 134, 146, 252 Protein C, 15, 52, 69, 117, 120, 133, 141, 194, 196, 201, 239, 252, 267 Protein Conformation, 196, 252 Protein S, 43, 134, 173, 202, 222, 252, 257 Proteinuria, 223, 239, 252 Proteoglycan, 19, 59, 134, 252 Proteolytic, 38, 40, 130, 145, 195, 209, 217, 220, 247, 252 Prothrombin, 252, 264 Protocol, 6, 7, 121, 122, 123, 252 Proton Pump, 4, 242, 252 Proton Pump Inhibitors, 4, 252 Protons, 195, 227, 232, 252, 253 Proximal, 20, 215, 252, 258 Proxy, 27, 252 Psoriasis, 136, 137, 139, 140, 141, 147, 148, 151, 252 Psychiatry, 68, 252, 268 Psychic, 237, 253, 258 Psychoactive, 253, 270 Public Policy, 169, 253 Pulmonary Circulation, 47, 228, 253 Pulmonary Edema, 15, 77, 138, 253
283
Pulmonary hypertension, 13, 14, 15, 37, 47, 211, 253 Pulmonary Sarcoidosis, 75, 78, 253 Pulmonary Ventilation, 253, 255 Pulse, 72, 124, 238, 253 Purines, 253, 259 Purulent, 131, 253 Pyogenic, 243, 253 Pyrimidines, 253, 259 Q Quality of Life, 34, 76, 79, 119, 253 R Race, 238, 253 Radiation, 36, 41, 49, 113, 217, 219, 220, 221, 231, 232, 253, 254, 257, 270 Radiation therapy, 49, 219, 231, 232, 253, 270 Radioactive, 203, 227, 229, 231, 232, 234, 238, 241, 242, 253, 254, 257, 270 Radioactivity, 133, 254 Radiography, 5, 176, 254 Radioimmunotherapy, 113, 254 Radiolabeled, 232, 254, 270 Radiological, 60, 71, 176, 254 Radiology, 23, 57, 66, 77, 86, 92, 103, 176, 241, 254 Radiotherapy, 36, 49, 77, 80, 158, 203, 232, 254, 270 Randomized, 71, 119, 122, 123, 216, 254 Reactive Oxygen Species, 24, 37, 53, 254 Reagent, 130, 134, 145, 254 Recombinant, 6, 8, 9, 15, 23, 43, 122, 130, 134, 145, 146, 231, 254, 268 Recombination, 222, 254 Rectal, 88, 254 Rectum, 198, 203, 209, 214, 220, 221, 230, 233, 251, 254 Red blood cells, 218, 244, 249, 254, 257 Red Nucleus, 200, 254 Reductase, 5, 237, 255 Refer, 1, 204, 209, 221, 226, 234, 235, 241, 254, 255, 259, 265 Reflex, 64, 255 Reflux, 3, 5, 221, 255 Refraction, 240, 255, 260 Refractory, 4, 153, 255 Regeneration, 220, 255 Regimen, 4, 216, 255 Regurgitation, 4, 221, 225, 255 Renin, 144, 197, 255 Reperfusion, 18, 148, 149, 239, 255 Reperfusion Injury, 18, 255
Repressor, 10, 242, 255 Respiration, 80, 97, 104, 106, 109, 198, 205, 238, 243, 255 Respirator, 236, 255, 269 Respiratory distress syndrome, 37, 77, 104, 135, 138, 142, 204, 255 Respiratory failure, 22, 65, 99, 153, 255, 269 Respiratory System, 24, 194, 255 Response Elements, 53, 256 Response rate, 4, 256 Restoration, 22, 56, 239, 255, 256, 270 Retina, 207, 210, 214, 233, 235, 240, 241, 242, 253, 256, 257, 269 Retinal, 136, 142, 214, 215, 242, 256, 257 Retinal Detachment, 142, 214, 256 Retinal Neovascularization, 136, 256 Retinal Vein, 256 Retinitis, 137, 147, 148, 256 Retinoblastoma, 172, 256 Retinoid, 53, 256 Retinol, 256, 257 Retinopathy, 136, 214, 256 Retroviral vector, 222, 256 Reversion, 39, 256 Rheumatic Diseases, 33, 73, 76, 100, 257 Rheumatism, 90, 257 Rhinitis, 137, 147, 181, 257 Rhodopsin, 242, 256, 257 Ribavirin, 4, 33, 257 Ribonuclease, 53, 257 Ribosome, 257, 266 Risk factor, 12, 125, 153, 251, 257 Rod, 201, 217, 257 S Saliva, 257 Salivary, 4, 213, 214, 244, 257 Salivary glands, 213, 214, 257 Saponins, 257, 262 Sarcoidosis, 32, 69, 70, 81, 83, 86, 87, 90, 91, 98, 101, 124, 141, 151, 257 Scans, 119, 257 Schizoid, 258, 270 Schizophrenia, 216, 258, 270 Schizotypal Personality Disorder, 258, 270 Scleroderma, 16, 26, 45, 78, 89, 106, 118, 123, 125, 140, 142, 199, 258 Screening, 45, 47, 130, 134, 145, 208, 258, 267 Scrotum, 258, 268 Secondary tumor, 237, 258
Pulmonary fibrosis
Secretion, 15, 29, 35, 42, 55, 73, 140, 203, 212, 230, 231, 238, 239, 242, 244, 258, 266 Secretory, 7, 195, 242, 258 Sediment, 258, 267 Segmental, 121, 223, 258 Seizures, 245, 258 Selective estrogen receptor modulator, 258, 263 Semen, 251, 258 Seminal vesicles, 258, 268 Semisynthetic, 203, 258 Senile, 243, 258 Sepsis, 145, 258 Septal, 52, 258, 259 Septic, 129, 130, 135, 137, 147, 148, 258 Septum, 23, 258, 259 Septum Pellucidum, 259 Sequence Homology, 245, 259 Sequencing, 248, 259 Serine, 39, 130, 135, 145, 208, 259, 266 Serine Endopeptidases, 259 Serine Proteinase Inhibitors, 135, 259 Serous, 217, 248, 259 Serum, 26, 33, 47, 70, 73, 77, 87, 92, 94, 97, 105, 106, 194, 196, 198, 209, 238, 246, 259, 267 Sex Determination, 173, 259 Shedding, 38, 47, 259 Shock, 129, 130, 135, 217, 259, 266 Shunt, 22, 259 Side effect, 5, 33, 128, 161, 163, 194, 202, 212, 228, 259, 265 Signal Transduction, 8, 12, 19, 21, 37, 50, 53, 60, 259 Silicosis, 32, 59, 259 Skeletal, 196, 239, 259 Skeleton, 193, 232, 251, 259, 260 Skull, 260, 263 Sleep apnea, 24, 47, 260 Small cell lung cancer, 260 Small intestine, 216, 227, 232, 260, 266 Smoking Cessation, 17, 260 Smoldering leukemia, 239, 260 Smooth muscle, 15, 20, 34, 50, 55, 58, 195, 196, 210, 260, 262 Sneezing, 259, 260 Social Environment, 253, 260 Sodium, 113, 131, 195, 224, 238, 260, 263 Soft tissue, 203, 260 Solid tumor, 197, 202, 260 Solvent, 214, 260 Specialist, 183, 214, 260
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Specificity, 7, 16, 52, 194, 199, 204, 233, 250, 260, 265 Spectrum, 3, 105, 212, 260 Spinal cord, 200, 206, 207, 216, 237, 240, 244, 250, 255, 261 Spirometry, 176, 261 Spleen, 196, 213, 235, 257, 261 Splenomegaly, 243, 261 Spondylitis, 82, 261 Sporadic, 97, 249, 256, 261 Sputum, 16, 82, 98, 105, 261 Squamous, 128, 218, 241, 261 Squamous cell carcinoma, 128, 218, 241, 261 Squamous cells, 261 Staging, 82, 125, 136, 143, 257, 261 Steady state, 50, 261 Steel, 261, 268 Stellate, 33, 261 Stem Cell Factor, 38, 208, 261 Stem Cells, 158, 246, 261 Stenosis, 62, 137, 147, 261, 262 Sterile, 121, 244, 261 Sterility, 212, 230, 261 Sterilization, 152, 261 Steroid, 28, 120, 212, 213, 257, 261, 262 Steroid therapy, 120, 262 Stimulant, 21, 262, 268 Stimulus, 60, 211, 215, 216, 231, 233, 255, 262, 264 Stomach, 193, 200, 214, 218, 221, 227, 233, 235, 245, 246, 252, 255, 260, 261, 262 Stool, 209, 233, 262 Strand, 248, 262 Stress, 28, 47, 244, 250, 257, 262 Stricture, 261, 262 Stroke, 126, 137, 147, 148, 168, 205, 262 Stromal, 36, 203, 217, 262 Stromal Cells, 36, 203, 262 Subacute, 13, 229, 262 Subclinical, 229, 258, 262 Subcutaneous, 35, 100, 122, 123, 124, 216, 262 Subspecies, 260, 262 Substance P, 237, 258, 262 Sulfates, 140, 262 Sulfur, 219, 237, 262 Sulfuric acid, 262 Superoxide, 18, 36, 37, 48, 262, 263 Superoxide Dismutase, 18, 36, 37, 48, 263 Support group, 50, 263 Suppression, 5, 112, 137, 147, 212, 263
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Suppressive, 22, 263 Surfactant, 35, 37, 56, 90, 91, 105, 145, 150, 263 Survival Rate, 119, 135, 263 Sweat, 131, 214, 263 Sweat Glands, 214, 263 Symphysis, 207, 251, 263 Symptomatic, 15, 123, 244, 263 Synapse, 194, 263, 266 Synaptic, 241, 259, 263 Synergistic, 68, 150, 251, 263 Synovial, 132, 263 Systolic, 227, 263 T Tacrolimus, 153, 263 Tamoxifen, 77, 158, 258, 263 Telangiectasia, 173, 263 Temporal, 17, 20, 41, 42, 52, 235, 263 Testosterone, 255, 264 Tetany, 244, 264 Thalamic, 200, 264 Thalamic Diseases, 200, 264 Therapeutics, 68, 107, 135, 162, 264 Thermal, 199, 215, 241, 248, 264 Thoracic, 36, 80, 92, 97, 99, 104, 106, 109, 248, 264, 269 Threonine, 245, 259, 264 Threshold, 227, 264 Thrombin, 75, 104, 220, 247, 252, 264 Thrombocytes, 247, 264 Thrombocytopenia, 79, 247, 264 Thrombolytic, 247, 264 Thrombomodulin, 108, 252, 264 Thrombosis, 141, 148, 149, 201, 230, 252, 262, 264 Thrombus, 212, 229, 239, 247, 264, 268 Thymidine, 22, 264 Thymidine Kinase, 22, 264 Thyroid, 178, 244, 264, 267 Thyroid Gland, 244, 264 Tissue Distribution, 204, 265 Tolerance, 34, 49, 193, 223, 265 Tomography, 55, 85, 93, 210, 257, 265 Tone, 15, 47, 218, 265 Tonus, 265 Topical, 91, 214, 227, 265 Toxic, iv, 5, 22, 25, 37, 128, 137, 147, 153, 217, 228, 265 Toxicity, 25, 32, 36, 90, 128, 144, 153, 215, 265 Toxicokinetics, 265 Toxicology, 41, 54, 60, 112, 113, 170, 265
Toxin, 33, 217, 265 Trace element, 203, 208, 209, 241, 265 Trachea, 204, 246, 264, 265 Transcription Factors, 10, 47, 51, 54, 256, 265 Transduction, 21, 50, 53, 146, 259, 265 Transfection, 9, 13, 16, 202, 222, 265 Transferases, 224, 265 Transforming Growth Factor alpha, 30, 266 Transforming Growth Factor beta, 55, 59, 266 Transgenes, 31, 266 Translation, 10, 11, 196, 222, 266 Translational, 43, 50, 266 Translocation, 45, 266 Transmitter, 193, 200, 215, 236, 241, 266 Transplantation, 18, 36, 65, 69, 88, 91, 93, 100, 101, 153, 208, 228, 236, 266 Trauma, 135, 144, 152, 201, 225, 244, 264, 266 Tricuspid Atresia, 211, 266 Triglyceride, 92, 266 Tropoelastin, 37, 266 Trypsin, 131, 135, 146, 208, 217, 266, 270 Tryptophan, 209, 266 Tuberous Sclerosis, 8, 173, 266 Tumor marker, 202, 266 Tumor Necrosis Factor, 5, 30, 70, 100, 113, 152, 267 Tumor suppressor gene, 244, 267 Tumour, 104, 267 Tunica, 217, 239, 267 Tyrosine, 19, 21, 24, 38, 52, 215, 267 U Ulcer, 134, 224, 267 Ulceration, 4, 267 Ulcerative colitis, 137, 147, 148, 150, 151, 230, 267 Unconscious, 213, 228, 267 Univalent, 227, 243, 267 Uraemia, 244, 267 Urea, 137, 263, 267 Urease, 241, 267 Urethra, 152, 245, 251, 267, 268 Uric, 224, 228, 253, 267 Urinalysis, 26, 267 Urinary, 135, 201, 205, 267 Urine, 17, 108, 117, 119, 201, 202, 212, 225, 252, 267, 268 Urokinase, 46, 52, 107, 148, 149, 268
Pulmonary fibrosis
Uroporphyrinogen Decarboxylase, 249, 268 Uterus, 203, 207, 213, 217, 243, 250, 268 Uveal tract, 253, 268 V Vaccine, 182, 252, 268 Vagina, 207, 268 Valine, 245, 268 Vanadium, 23, 268 Vas Deferens, 152, 268 Vascular, 12, 13, 15, 37, 47, 72, 73, 77, 86, 88, 93, 109, 113, 118, 137, 143, 148, 195, 196, 207, 214, 217, 224, 229, 234, 238, 241, 247, 264, 268 Vascular endothelial growth factor, 73, 268 Vascular Resistance, 196, 268 Vasculitis, 4, 244, 268 Vasoactive, 152, 268 Vasoconstriction, 47, 218, 268 Vasodilation, 47, 268 Vasodilators, 241, 268 Vector, 10, 30, 59, 130, 134, 145, 265, 268 Vein, 148, 149, 197, 232, 241, 245, 249, 256, 268 Venous, 179, 201, 252, 266, 268 Venous Thrombosis, 179, 201, 268 Ventilation, 268, 269 Ventilator, 236, 255, 269 Ventricle, 200, 211, 253, 263, 266, 269 Ventricular, 26, 196, 211, 216, 240, 266, 269 Ventricular Dysfunction, 216, 269 Venules, 203, 205, 217, 238, 269 Vertebrae, 232, 261, 269 Veterinary Medicine, 112, 169, 269
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Vinca Alkaloids, 269 Vinorelbine, 80, 269 Viral, 21, 30, 137, 147, 148, 153, 211, 220, 222, 223, 226, 230, 242, 265, 269 Viral Hepatitis, 147, 226, 269 Virulence, 265, 269 Virus, 4, 22, 33, 45, 64, 78, 91, 147, 193, 201, 217, 222, 223, 224, 231, 247, 256, 265, 269 Viscosity, 227, 269 Vital Capacity, 26, 36, 120, 269 Vitreous, 207, 214, 233, 256, 269 Vitreous Hemorrhage, 214, 269 Vitreous Humor, 256, 269 Vitro, 11, 15, 19, 21, 23, 29, 30, 31, 35, 42, 43, 45, 50, 51, 53, 55, 58, 60, 131, 133, 146, 222, 225, 229, 248, 263, 269 Vivo, 9, 17, 19, 21, 23, 24, 31, 33, 38, 39, 40, 43, 44, 45, 50, 51, 52, 53, 54, 55, 58, 132, 133, 222, 225, 229, 243, 263, 269 W White blood cell, 193, 197, 224, 233, 235, 238, 239, 240, 241, 247, 269 Windpipe, 246, 264, 269 Withdrawal, 39, 270 Wound Healing, 38, 55, 58, 134, 136, 143, 206, 208, 220, 230, 236, 270 X Xenograft, 197, 270 X-ray, 119, 176, 210, 220, 221, 232, 236, 241, 253, 254, 257, 270 X-ray therapy, 232, 270 Y Yeasts, 221, 246, 270 Z Zymogen, 208, 252, 270
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Pulmonary fibrosis
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