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

CIRRHOSIS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES J AMES N. ...

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CIRRHOSIS 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 2003 by ICON Group International, Inc. Copyright 2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Cirrhosis: 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: 0-597-83824-0 1. Cirrhosis-Popular works. I. Title.

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

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

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on cirrhosis. 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 CIRRHOSIS ................................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Cirrhosis...................................................................................... 15 E-Journals: PubMed Central ....................................................................................................... 72 The National Library of Medicine: PubMed ................................................................................ 73 CHAPTER 2. NUTRITION AND CIRRHOSIS ..................................................................................... 121 Overview.................................................................................................................................... 121 Finding Nutrition Studies on Cirrhosis .................................................................................... 121 Federal Resources on Nutrition ................................................................................................. 129 Additional Web Resources ......................................................................................................... 129 CHAPTER 3. ALTERNATIVE MEDICINE AND CIRRHOSIS ............................................................... 133 Overview.................................................................................................................................... 133 The Combined Health Information Database............................................................................. 133 National Center for Complementary and Alternative Medicine................................................ 134 Additional Web Resources ......................................................................................................... 145 General References ..................................................................................................................... 149 CHAPTER 4. DISSERTATIONS ON CIRRHOSIS ................................................................................. 151 Overview.................................................................................................................................... 151 Dissertations on Cirrhosis ......................................................................................................... 151 Keeping Current ........................................................................................................................ 152 CHAPTER 5. CLINICAL TRIALS AND CIRRHOSIS ........................................................................... 153 Overview.................................................................................................................................... 153 Recent Trials on Cirrhosis ......................................................................................................... 153 Keeping Current on Clinical Trials ........................................................................................... 161 CHAPTER 6. PATENTS ON CIRRHOSIS ........................................................................................... 163 Overview.................................................................................................................................... 163 Patents on Cirrhosis................................................................................................................... 163 Patent Applications on Cirrhosis............................................................................................... 179 Keeping Current ........................................................................................................................ 195 CHAPTER 7. BOOKS ON CIRRHOSIS ............................................................................................... 197 Overview.................................................................................................................................... 197 Book Summaries: Federal Agencies............................................................................................ 197 Book Summaries: Online Booksellers......................................................................................... 198 The National Library of Medicine Book Index ........................................................................... 200 Chapters on Cirrhosis ................................................................................................................ 201 Directories.................................................................................................................................. 204 CHAPTER 8. MULTIMEDIA ON CIRRHOSIS .................................................................................... 205 Overview.................................................................................................................................... 205 Video Recordings ....................................................................................................................... 205 Audio Recordings....................................................................................................................... 211 Bibliography: Multimedia on Cirrhosis ..................................................................................... 212 CHAPTER 9. PERIODICALS AND NEWS ON CIRRHOSIS ................................................................. 215 Overview.................................................................................................................................... 215 News Services and Press Releases.............................................................................................. 215 Newsletter Articles .................................................................................................................... 217 Academic Periodicals covering Cirrhosis ................................................................................... 219 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 221 Overview.................................................................................................................................... 221 U.S. Pharmacopeia..................................................................................................................... 221

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Commercial Databases ............................................................................................................... 222 Researching Orphan Drugs ....................................................................................................... 223 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 227 Overview.................................................................................................................................... 227 NIH Guidelines.......................................................................................................................... 227 NIH Databases........................................................................................................................... 229 Other Commercial Databases..................................................................................................... 233 The Genome Project and Cirrhosis............................................................................................. 234 APPENDIX B. PATIENT RESOURCES ............................................................................................... 239 Overview.................................................................................................................................... 239 Patient Guideline Sources.......................................................................................................... 239 Associations and Cirrhosis......................................................................................................... 245 Finding Associations.................................................................................................................. 245 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 247 Overview.................................................................................................................................... 247 Preparation................................................................................................................................. 247 Finding a Local Medical Library................................................................................................ 247 Medical Libraries in the U.S. and Canada ................................................................................. 247 ONLINE GLOSSARIES................................................................................................................ 253 Online Dictionary Directories ................................................................................................... 258 CIRRHOSIS DICTIONARY ........................................................................................................ 259 INDEX .............................................................................................................................................. 361

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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 cirrhosis 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 cirrhosis, 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 cirrhosis, 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 cirrhosis. 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 cirrhosis, 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 cirrhosis. 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 CIRRHOSIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on cirrhosis.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and cirrhosis, 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 “cirrhosis” (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: •

Relationship of Acute Transfusion-Associated Hepatitis to the Development of Cirrhosis in the Presence of Alcohol Abuse Source: Annals of Internal Medicine. 134(2): 120-124. January 16, 2001. Contact: Available from American College of Physicians. American Society of Internal Medicine. 190 North Independence Mall West, Philadelphia, PA 19106-1572. Website: www.acponline.org. Summary: Although concomitant (occurring at the same time) alcoholism is widely believed to enhance liver disease progression in persons with hepatitis C virus (HCV) infection, this relationship has not been well quantified. This article reports on a study undertaken to quantify the relationship of transfusion associated HCV infection and history of heavy alcohol abuse to the development of cirrhosis (liver scarring). The

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retrospective cohort study featured extensive followup of 1,030 patients in prospective investigations of transfusion associated viral hepatitis conducted in the United States between 1968 and 1980. Development of cirrhosis and history of heavy alcohol abuse were determined from review of interviews with patients or their proxies, medical records, death certificates, and autopsy and biopsy reports. The absolute risk for cirrhosis was 17 percent among patients with transfusion associated HCV; 3.2 percent among patients with transfusion associated nonA, nonB, nonC hepatitis; and 2.8 percent among controls. A history of heavy alcohol abuse was associated with a fourfold increased risk for cirrhosis. Hepatitis C virus infection plus a history of heavy alcohol abuse led to a substantial increase in risk for cirrhosis, compared with controls without such a history. The authors stress that this finding emphasizes the need to counsel such patients about their drinking habits. 2 tables. 19 references. •

Risk Factors for Primary Biliary Cirrhosis in a Cohort of Patients from the United States Source: Hepatology. 33(1): 16-21. January 2001. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Although the etiology (cause) of primary biliary cirrhosis (PBC) remains unknown, environmental factors may act to trigger the disease in genetically susceptible hosts. This article reports on a study undertaken to assess specific risk factors. In the study, the authors conducted a survey using standardized NHANES questions to 241 PBC patients in the United States, 261 of their siblings, and 141 friends without PBC. The overall response rate was 199 of 241 (83 percent) among PBC cases, 171 of 261 (67 percent) among siblings, and 141 of 225 (62.7 percent) among friend controls. The female to male ratio among cases in this sample was approximately 10 to 1, the mean age was 53 years, and 97 percent were Caucasian. Other autoimmune diseases reported most frequently by PBC cases included Sjogren's syndrome (17.4 percent) and Raynaud's syndrome (12.5 percent). Approximately 6 percent of cases reported at least one family member with PBC. Adjusted odds ratios (OR) were elevated for cases compared with friends for other autoimmune diseases, smoking, tonsillectomy, and vaginal or urinary tract infection (UTI) in females only. Similarly elevated ORs were observed for these risk factors when cases were compared with their siblings. The higher rate of UTI among cases is particularly interesting in light of previous data, and raises the possibility of an infectious etiology for PBC and of molecular mimicry as an etiologic mechanism. The significance of smoking supports the findings of previous studies and raises the issue of the influence of smoking on the immune system. 5 tables. 34 references.

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Hepatitis C, Cryoglobulinemia, and Cirrhosis: A Meta-Analysis Source: Hepatology. 36(4 Part 1): 978-985. October 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Approximately 40 percent of patients with chronic hepatitis C virus (HCV) infection develop detectable serum cryoglobulins or cryoprecipitates (CP), although most do not show clinical or physical signs of syndromic cryoglobulinemia. Although association of HCV with the extrahepatic (outside the liver) complications of cryoglobulinemia is widely recognized, the relationship of cryoglobulinemia with liver disease is unclear. This article reports on a study of the relationship between CP and cirrhosis that also determined whether the development of CP is a true covariate for

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progressive liver disease or a confounding variable that impacts cirrhosis because of patient age, duration of disease, or differences in gender. The authors performed a metaanalysis of 19 studies published between 1994 and 2001. The incidence of cirrhosis (liver scarring) was compared in patients with and without CP after adjustments for accepted risk factors for progressive liver disease, including age, gender, and estimated duration of disease (EDD). A total of 2,323 patients with chronic HCV were identified, with 1,022 (44 percent) having detectable CP. Cirrhosis was present in 40 percent of patients with CP but only 17 percent of patients with CP. After adjusted for age, gender, and EDD, the combined odds ratio for incidence of cirrhosis in patients CP positive versus CP negative was 4.87, indicating a highly significant association between cirrhosis and cryoglobulinemia. The authors conclude that cryoglobulins may be a useful prognostic indicator for increased risk of cirrhosis with chronic hepatitis C. 1 figure. 4 tables. 44 references. •

Minimizing Ascites: Complication of Cirrhosis Signals Clinical Deterioration Source: Postgraduate Medicine. 109(2): 91-96, 101-103. February 2001. Contact: Available from McGraw-Hill, Inc. 1221 Avenue of the Americas, New York, NY 10020. (612) 832-7869. Summary: Ascites, the pathologic accumulation of fluid in the peritoneal cavity, is a common and serious complication of cirrhosis (scarring) of the liver. The development of ascites is associated with a grave prognosis: 50 percent of patients die within 2 years of diagnosis. This article describes strategies to minimize ascites and its sequelae. Proper management with a combination of dietary, medical, and surgical approaches is essential to prolong life and improve its quality. Patients with ascites are at risk for ascitic fluid infections and neurohormonal dysregulation that can lead to hepatorenal syndrome. Early recognition of these complications allows therapeutic interventions that minimize further clinical deterioration in already chronically ill patients. Treatment goals include symptoms relief, correction of underlying pathophysiologic abnormalities (i.e., renal sodium retention, sinusoidal portal hypertension), prevention and treatment of complications of ascites, and improvement of outcome. Treatment options range from bed rest to orthotopic liver transplantation, and can include dietary sodium restriction, diuretic therapy, large volume paracentesis (removal of 5 liters or more of ascitic fluid during a single session), peritoneovenous shunt (to return ascitic fluid directly from the peritoneal cavity to the systemic circulation), transjugular intrahepatic portasystemic shunt (TIPS), and liver transplantation. Potential complications of ascites include refractory ascites, hepatorenal syndrome, and spontaneous bacterial peritonitis. 3 tables. 17 references.

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Evaluation of Helicobacter Pylori Diagnostic Methods in Patients With Liver Cirrhosis Source: Alimentary Pharmacology and Therapeutics. 16(7):1283-1289. July 2002. Contact: Available from Alimentary Pharmacology and Therapeutics. Blackwell Science Ltd., Osney Mead, Oxford OX2 OEL, UK. +44(0)1865 206206. Fax +44(0)1865 721205. Email: [email protected]. Website: www.blackwell-science.com. Summary: Helicobacter pylori associated peptic ulcer is a frequent complication in patients with cirrhosis (scarring of the liver) and its morbidity rate (associated illness or disease complications) is high. In spite of this, diagnostic methods for H. pylori infection have not been fully evaluated in these patients. This article reports on a study undertaken to evaluate H. pylori diagnostic methods in patients with liver cirrhosis (n =

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101). Results showed that 62 patients were positive for H. pylori and 35 were negative for H. pylori infection; four were indeterminate. The sensitivity and specificity were 90.4 percent and 100 percent, respectively, for antral histology; 100 percent and 100 percent for gastric body histology; 90.4 percent and 100 percent for antral immunohistochemistry; 96.2 percent and 96.7 percent for body immunochemistry; 85.7 percent and 97 percent for rapid urease test; 83.6 percent and 55.9 percent for serology; 96.4 percent and 97.1 percent for 13C urea breath test; and 75.4 percent and 94.1 percent for fecal antigen. The authors conclude that the most reliable tests for H. pylori infection in cirrhosis patients were the 13C urea breath test and gastric body histology. 1 figure. 4 tables. 28 references. •

Hepatorenal Syndrome in Cirrhosis: Pathogenesis and Treatment Source: Gastroenterology. 122(6): 1658-1676. 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Website: www.gastrojournal.org. Summary: Hepatorenal syndrome (HRS) is a major complication in cirrhosis (liver scarring), with an annual incidence in patients with ascites (fluid accumulation) of approximately 8 percent. HRS develops at the latest phase of the disease and, although initially considered not to have an impact on the patient's prognosis (patients would die with and not by the kidney failure), there is now evidence that HRS is an important determinant in survival. This article reviews the publications on HRS, highlighting those aspects of HRS that are important to understand the pathogenesis (development of the disease) and the rational basis of the modern therapy of this syndrome. The most characteristic feature of HRS is a functional renal (kidney) failure caused by an intense renal vasoconstriction, the syndrome is also a more generalized process affecting the heart, brain, and the splanchnic organs (the internal organs). Long term administration of IV albumin and vasoconstrictors or the correction of portal hypertension with a TIPS (transjugular intrahepatic portacaval shunt) are effective treatments of HRS, improve the survival rate, and may serve as a bridge to liver transplantation, which is the treatment of choice in these patients. 11 figures. 2 tables. 187 references.

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Optimal Timing of Liver Transplantation for Primary Bilary Cirrhosis Source: Hepatology. 28(1): 33-38. July 1998. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: In 1989, the authors of this article reported on the efficacy of liver transplantation in primary biliary sclerosis (PBC) by demonstrating that patient survival following transplantation was significantly better than without transplantation as predicted by a mathematical survival model. In this article, the same authors report on a study undertaken to determine an optimal time to perform liver transplantation. A total of 143 patients with PBC undergoing liver transplantation were followed prospectively. Disease severity was measured immediately before transplantation by a summary score (risk score) that is used in the Mayo natural history model and includes age, bilirubin, albumin, prothrombin time, and presence or absence of edema. The influence of disease severity immediately pretransplantation on resource utilization for liver transplantation was assessed. Compared with the 1989 report, liver transplantation in this group was performed at an earlier stage (e.g., median risk score of 7.5 versus 8.3 in the earlier study). Following transplantation, patient survival probabilities at 1, 2, and 5 years were 93 percent, 90 percent, and 88 percent, respectively. The risk of death following

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transplantation remained low until reaching a risk score of 7.8. By contrast, risk scores in excess of 7.8 were associated with a progressively higher mortality rate. Resource utilization measured by the number of days in the intensive care unit and hospital and the requirement for intraoperative blood transfusions was significantly greater in recipients who had higher risk scores before transplantation. The authors conclude that the optimal timing for liver transplantation in patients with PBC, as determined by survival and resource utilization, appears to be at a risk score of about 7.8. 4 figures. 3 tables. 17 references. (AA-M). •

Long-Term Management of Cirrhosis: Appropriate Supportive Care Is both Critical and Difficult Source: Postgraduate Medicine. 109(3): 101-118. March 2001. Contact: Available from McGraw-Hill, Inc. 1221 Avenue of the Americas, New York, NY 10020. (612) 832-7869. Summary: In the United States, about 26,000 of the 3 million people who have chronic liver disease die each year because of hepatic cirrhosis (liver scarring). Liver transplantation offers the best hope of survival for many of these patients, but the number of patients awaiting transplant far exceeds the number of organs available. This article (the last in a four part series on cirrhosis) offers a guide for primary care physicians who are caring for patients with chronic liver disease. The focus is on strategies to slow the course of liver disease and improve both the quality and length of life for these patients. The authors stress that early consultation with a liver transplant center can be helpful. The transplant hepatologist (liver specialist) and surgeon can help with triage decisions, guide workup, provide advice about patient care, optimize the timing of transplantation, offer specialized diagnostic and therapeutic options, and help the treating physician stay up to date on the continuous changes in this complex field. The authors offer a ten-point program for the comprehensive management of the patient with cirrhosis. The authors conclude that it is often the skill and diligence of the primary care physician in diagnosing liver disease, identifying and treating correctable causes, optimizing the patient's health and nutrition, and anticipating and preventing catastrophic complications that determine whether the patient lives or dies. Appended to the article is a lengthy list of resources on cirrhosis, including organizations, web sites, and publications, separated by those designed for physicians and those specifically for patients. 1 figure. 3 tables. 27 references.

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Management of Primary Biliary Cirrhosis Source: Hepatology. 31(4): 1005-1013. April 2000. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Primary biliary cirrhosis (PBC) is a presumed autoimmune disease of the liver, which predominantly affects women once over the age of 20 years. Most cases are diagnosed when asymptomatic (60 percent). This article offers guidelines to assist physicians in the recognition, diagnosis, and management of patients with PBC. The antimitochondrial antibody is present in serum (blood) in most, but not all, patients with PBC. The disease generally progresses slowly, but survival is less than an age and gender matched general population. The symptomatic patients may have fatigue, generalized pruritis (itching), portal hypertension (high blood pressure), osteoporosis, skin xanthomata (yellowish nodules), fat soluble vitamin deficiencies, and or recurrent asymptomatic urinary tract infections (UTI). Many non liver autoimmune diseases are

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found in association with PBC and may prompt initial presentation. To date, immunosuppressive therapy has not been shown to prolong survival in PBC. The use of urodeoxycholic acid (UDCA) can delay the time to liver transplantation or death (typically given in a dose of 13 to 15 mg per kg daily). This therapy also causes a significant improvement of all the biochemical markers of cholestasis but has no beneficial effects on any of the symptoms or associated disorders. Treatment with UDCA does not obviate the need for liver transplantation. Therapies to prevent complications arising from malabsorption, portal hypertension, and or osteoporosis are required as well. Good control of pruritus can be achieved in most patients. PBC is diagnosed with increasing frequency, but the agent(s) responsible for this slowly progressive destruction of the bile ducts remains elusive and hence a specific therapy remains unavailable. 3 figures. 1 table. 105 references. •

Epidemiology and Natural History of Primary Biliary Cirrhosis in a U.S. Community Source: Gastroenterology. 119(6): 1631-1636. December 2000. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Primary biliary cirrhosis is a chronic, cholestatic disorder characterized by progressive inflammation and destruction of the small bile ducts. The epidemiology of primary biliary cirrhosis (PBC) has not been studied systematically in the United States. In this article, the authors report the incidence (new cases) and prevalence (existing cases) of this condition in the general population. The authors also examine the validity of the Mayo natural history model for PBC among these unselected patients from the community. The cases were identified from the Rochester Epidemiology Project, which entails a computerized index of diagnoses from the health care encounters of residents of Olmsted County, Minnesota. The authors estimated the incidence and prevalence of PBC in this population and compared the actual survival of patients with PBC in the community with the survival predicted for PBC patients by the Mayo natural history model. The age adjusted (to 1990 U.S. whites) incidence of PBC per 100,000 person years was 4.5 for women, 0.7 for men, and 2.7 overall. The age and sex adjusted prevalence per 100,000 persons was 65.4 for women, 12.1 for men, and 40.2 overall. The authors conclude that the Mayo natural history model accurately predicted the actual survival of these patients. These results indicate that the incidence and prevalence in this country are among the highest reported. Outcomes among these unselected patients from a community population further validated the Mayo natural history model of PBC. 2 figures. 2 tables. 38 references.

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High Prevalence of Sleep Disturbance in Cirrhosis Source: Hepatology. 27(2): 339-345. February 1998. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Sleep disturbance is a classic sign of hepatic encephalopathy, but there are limited data regarding its prevalence in patients who have liver cirrhosis without overt hepatic encephalopathy. This article reports on a study that assessed the characteristics of sleep in cirrhosis using a sleep questionnaire (n = 44) and actigraphy (n = 20). The results were compared with those of subjects with chronic renal failure and those of healthy controls. Presence of subclinical hepatic encephalopathy, chronotypology profile, and each individual's affective state were also analyzed. The questionnaire indicated that an elevated number of patients with cirrhosis (47.7 percent) and patients

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with chronic renal failure (38.6 percent) complained of unsatisfactory sleep compared with healthy controls (4.5 percent). Actigraphy corroborated the deterioration of sleep parameters in cirrhotic patients with unsatisfactory sleep. The actigraph is a sensor that translates physical motion to a numeric representation. The sleep disturbance in cirrhosis was not associated with clinical parameters nor with cognitive impairment. Cirrhotic subjects and patients with chronic renal failure with unsatisfactory sleep showed higher scores for depression and anxiety, raising the possibility that the effects of chronic disease may underlie the pathogenesis of sleep disturbance. However, in contrast to chronic renal failure, unsatisfactory sleep in cirrhosis was associated with delayed bedtime, delayed wake-up time, and evening chronotypology. The authors conclude that sleep disturbance is frequent in patients with cirrhosis without hepatic encephalopathy and may be related to abnormalities of the circadian timekeeping system. 3 figures. 4 tables. 40 references. (AA-M). •

Hepatic Encephalopathy: Metabolic Consequence of Cirrhosis Often is Reversible Source: Postgraduate Medicine. 109(2): 52-54, 57-60, 63-65, 69-70. February 2001. Contact: Available from McGraw-Hill, Inc. 1221 Avenue of the Americas, New York, NY 10020. (612) 832-7869. Summary: This article discusses hepatic encephalopathy, a condition characterized by neuropsychiatric manifestations ranging from a slightly altered mental status to coma, and neuromuscular symptoms may be present. This complication of chronic or acute liver disease is a result of the failure of the liver to detoxify toxins originating in the intestine. The pathogenesis (how it occurs) probably is multifactorial, although the predominant causative agent appears to be ammonia. About 30 percent of patients with cirrhosis (scarring of the liver) die in hepatic coma. The molecular basis of neurotoxicity of ammonia or other agents implicated in the condition is poorly understood. Therapy includes timely recognition and correction of precipitating factors. Once the condition is manifested, standard therapy is acute administration of lactulose, a disaccharide that is undigested in the small intestine. The beneficial action of lactulose is not fully understood. The use of oral antibiotics and BCAAs (branched chain amino acids) is of some benefit in patients who do not respond to lactulose. Limitation of protein in the diet may be useful for short periods but is not recommended for long term use because of potential worsening of already poor nutrition. The ultimate therapy for hepatic encephalopathy is orthotopic liver transplantation. Future research will likely focus on the correction of alterations in neurotransmission. 2 figures. 4 tables. 20 references.

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High Prevalence of Celiac Sprue Among Patients with Primary Biliary Cirrhosis Source: Journal of Clinical Gastroenterology. 25(1): 328-329. July 1997. Contact: Available from Lippincott-Raven Publishers. P.O. Box 1550, Hagerstown, MD 21741. (800) 638-3030 or (301) 714-2300. Summary: This article explores the high prevalence of celiac sprue among patients with primary biliary cirrhosis (PBC). The authors note that, although coexisting PBC and celiac sprue have been described, celiac is sufficiently common in western Europe for chance to explain isolated cases. The authors screened their patients with PBC for celiac sprue by serum testing, with confirmation by duodenal biopsy. Of 57 patients, 6 (11 percent) tested positive. Four of these agreed to have a biopsy taken, and all had villous atrophy, yielding a minimum prevalence of 1 in 14 (7 percent). Apart from anemia in one patient, none of the four had symptoms or routine laboratory abnormalities suggestive of celiac sprue. None had improvement in liver biochemical tests after 12 to

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24 months on gluten-free diets, despite the disappearance of the immune marker. The authors conclude that celiac sprue is common among patients with PBC and they should be routinely screened for this condition. Symptoms wrongly attributed to PBC may respond to gluten exclusion, and both conditions are potent risk factors for osteoporosis. 20 references. (AA-M). •

Update on Primary Biliary Cirrhosis Source: Canadian Journal of Gastroenterology. 14(1): 43-48. January 2000. Contact: Available from Pulsus Group, Inc. 2902 South Sheridan Way, Oakville, Ontario, Canada L6J 7L6. Fax (905) 829-4799. E-mail: [email protected]. Summary: This article offers an update on primary biliary cirrhosis (PBC), a chronic inflammatory condition of the liver characterized by generalized pruritis (itching), enlargement and hardening of the liver, fatigue, weight loss, and diarrhea with pale, bulky stools. The diagnosis of PBC is most often made in the asymptomatic phase, sometimes before the development of abnormal liver biochemistry. The antimitochondrial antibody remains the predominant hallmark. The etiology (cause) of PBC remains elusive; studies suggest that the interlobular bile duct destruction is immune based, and associated autoimmune diseases are common. There are no markers that predict outcome in asymptomatic patients, whose chance of survival is less than that of age and sex matched populations, but much better than the median survival of eight years in patients with symptomatic PBC. Symptoms common in this disease include fatigue, pruritis, and xanthelasma (soft yellow spots or plaque occurring on the eyelids), as well as complications of portal hypertension (high blood pressure) and osteoporosis. Treatment includes symptomatic and preventive measures, as well as specific therapeutic measures. Immunosuppressive therapy has yielded disappointing results in the long term management of PBC, and the only therapy shown to improve survival in the hydrophobic dihydroxy bile acid, urosdeoxycholic acid. Treatment at a dose of 13 to 15 milligrams per kilogram of body weight per day is optimal, given in separate doses or as a single dose at least 4 hours from giving the oral anion exchange resin cholestyramine, which may be used to control pruritis. However, liver transplantation remains the only cure for this disease. Recurrence after transplantation takes place but is rarely symptomatic and does not deter from the benefits of transplantation. 55 references.

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Treatment of Patients with Hepatitis C and Cirrhosis Source: Hepatology. 36(5 Supplemental 1): S185-S194. November 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: This article offers guidelines for the treatment of patients with hepatitis C and cirrhosis (scarring of the liver). The author notes that determining recommendations for this patient population is difficult. Few prospective studies have focused on the treatment of patients with advanced disease, and response rates appear to be lower and serious side effects more frequent in patients with cirrhosis. In patients with compensated cirrhosis, combination therapy with interferon alfa and ribavirin results in a sustained virological response (SVR) in 33 to 41 percent of patients. Responses to combination therapy are not significantly higher using peginterferon alfa 1a or 2b, compared with standard interferon. In using peginterferon in combination therapy, the benefits of once weekly dosing need to be weighed against the higher risks of cytopenias and greater costs with the pegylated formulations. Combination therapy results in some

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degree of histological improvement even in patients who are virological nonresponders. These findings provide the scientific basis for ongoing studies of maintenance therapy with peginterferon to prevent complications of cirrhosis in nonresponders patients with hepatitis C. Recommendations for the management of decompensated cirrhosis and of recurrent hepatitis C after liver transplantation are difficult because of limitations of data, most of which are derived from uncontrolled case series. Combination therapy is poorly tolerated in both groups and rates of response are low. Thus, while the medical need is great, treatment of patients with decompensated cirrhosis or with recurrent hepatitis C after transplantation should be undertaken cautiously and only within the confines of prospective clinical trials. 2 figures. 1 table. 16 references. •

Caring for the Patient with Primary Biliary Cirrhosis Source: IM. Internal Medicine. 17(5): 64-66, 68, 73-76. May 1996. Contact: Available from Medical Economics. 5 Paragon Drive, Montvale, NJ 07645. (800) 432-4570. Summary: This article provides an overview to the diagnosis and management of primary biliary cirrhosis (PBC). Topics include the pathogenesis of PBC; how to recognize and diagnose PBC; symptoms and signs; disease progression and prognosis; treatment options, including symptomatic, preventive, and specific therapies; patient issues, including pregnancy, hypercholesterolemia, recurrent urinary tract infections, and alcohol consumption; and followup ambulatory care. 2 figures. 4 tables. 29 references.

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Primary Biliary Cirrhosis: Don't Be Deceived by a 'Tanned' Glow Source: AJN. American Journal of Nursing. 99(12): 38-39. December 1999. Contact: Available from Lippincott Williams and Wilkins. AJN, P.O. Box 50480, Boulder, CO 80322-0480. (800) 627-0484 or (303) 604-1464. Summary: This article provides nurses with an overview of primary biliary cirrhosis (PBC), a slowly progressive chronic liver disease that causes inflammatory destruction of the bile ducts, bile acid buildup, cirrhosis, and ultimately liver failure. The etiology of PBC is unknown, but it is suspected to be an autoimmune disorder. Many patients with PBC are asymptomatic; intense pruritis (itching) is commonly the presenting symptom. Patients may also report painful joints or bones, indigestion or nausea, persistent abdominal ache in the upper right quadrant, and fluid retention. Dark urine, pale stools, easy bruising or bleeding, esophageal varices, increased skin pigmentation, and jaundice mark late stage disease. Diagnosis is confirmed by liver biopsy. Treatment with ursodeoxycholic acid may slow progression of the disease; other interventions focus on increasing quality of life and delaying the need for liver transplant. The author concludes by reviewing patient education strategies for patients with PBC. 1 figure.

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Chronic Hepatitis C Virus Infection Causes a Significant Reduction in Quality of Life in the Absence of Cirrhosis Source: Hepatology. 27(1): 209-212. January 1998. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000.

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Summary: This article reports on a study that assessed the effects of chronic hepatitis C virus (HCV) infection, in the absence of cirrhosis (liver scarring), on patients quality of life (QOL). Assessment was done by using the short form 36 (SF36) symptomatology questionnaire. Patients with chronic hepatitis C were polysymptomatic (had many symptoms) and had significant reductions in their SF36 scores for all of the modalities tested. By contrast, patients with chronic hepatitis B virus (HBV) infection showed a reduction in the SF36 scores that assessed mental function, but no decrease in the scores that measured physical symptoms, indicating that the symptoms associated with chronic HCV infection are qualitatively different from those associated with chronic HBV. Patients with chronic HCV infection who had used intravenous drugs in the past had the greatest impairment in QOL scores, but the reduction was found even in patients who had never used drugs. The reduction in QOL could not be attributed to the degree of liver inflammation or to the way the infection was acquired. The authors conclude that chronic infection with HCV per se gives rise to physical symptoms that reduce the QOL of those who have it. 2 figures. 1 table. 13 references. (AA-M). •

Clinical Significance of Hepatitis C Virus Infection to Alcoholics with Cirrhosis in Korea Source: Journal of Gastroenterology and Hepatology. 15(11): 1282-1286. November 2000. Contact: Available from Blackwell Science. 54 University Street, Carlton South 3053, Victoria, Australia. +61393470300. Fax +61393475001. E-mail: [email protected]. Website: www.blackwell-science.com. Summary: This article reports on a study undertaken to investigate the prevalence and clinical significance of hepatitis C virus (HCV) infection and its relationship with the development of hepatocellular carcinoma (HCC, liver cancer). In the study, 162 consecutive alcoholic Korean patients with cirrhosis were studied. Alcohol intake and parenteral risk factors were investigated by interview using a questionnaire. All patients had consumed at least 80 grams of alcohol per day for at least the past 5 years. Patients were categorized into 3 groups: anti HCV or HBsAg (group A); cases with HBsAg only (group B), and cases with anti HCV only (group C). Anti-HCV was present in 17 cases (10.5 percent) and HBsAg was present in 47 cases (29 percent). No patient had both antiHCV and HBsAg. Group C subjects were the oldest, but the duration of drinking in this group was similar to that of group A. There was no significant difference in the daily alcohol intake among the three groups of patients. Previous surgical operations and tattooing were more frequent in group C. Only one patient in group C was an intravenous drug user. The combined rate of HCC was significantly higher in groups B and C than in group A (34 percent, 23.5 percent, and 6.1 percent, respectively). Laboratory data showed a higher platelet count, higher albumin level, lower bilirubin lever. and lower aspartate amino transferase or alanine aminotransferase ratio in group C patients than in the other two groups. The authors conclude that hepatitis C virus infection is frequent in alcoholic patients with cirrhosis in Korea. Hepatitis C virus, as well as hepatitis B virus, infection may have a synergistic effect on the development of HCC in alcoholic patients. 1 figure. 3 tables. 28 references.

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Hepatorenal Syndrome in Patients with Cirrhosis Source: Journal of Gastroenterology and Hepatology. 17(7): 739-747. July 2002. Contact: Available from Blackwell Science. 54 University Street, Carlton South 3053, Victoria, Australia. +61393470300. Fax +61393475001. E-mail: [email protected]. Website: www.blackwell-science.com.

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Summary: This article reviews type 1 hepatorenal syndrome (HRS), a severe complication of end-stage cirrhosis (liver scarring). Type 1 HRS is an acute functional renal failure (i.e. glomerular hypofiltration) with no other explanation than the presence of the circulatory and neurohumoral alterations associated with severe chronic liver disease. Plasma volume expansion does not improve renal (kidney) function. In contrast, administration of the vasopressin analog terlipressin, a splanchnic and systemic vasoconstrictor, may improve renal function and be used while awaiting liver transplantation. 3 figures. 3 tables. 63 references. •

Higher Dose and Longer Duration of Interferon Alpha-2a Reduced the Incidence of Cirrhosis in Chronic Hepatitis C (commentary) Source: ACP Journal Club. 130(2): 37. March-April 1999. Contact: Available from American College of Physicians-American Society of Internal Medicine (ACP-ASIM). 190 North Independence Mall West, Philadelphia, PA 191061572. Summary: This brief article offers a summary of a recent research study, with an accompanying commentary. The study was undertaken to measure whether an increased dose and longer duration of interferon alfa 1a (INF) therapy is more effective in patients with chronic hepatitis C than standard doses for preventing the development of cirrhosis. The study comprised 244 patients (mean age 37 years, 64 percent men) with confirmed hepatitis C. Of these, 124 patients were allocated to the reinforced regimen, and 120 to the standard regimen. Patients in the reinforced group had a higher rate of maintaining normal levels of alanine transaminase (ALT), undetectable HCV levels, and a lower incidence of cirrhosis than patients in the standard group. Patients in the reinforced group also had higher rates of flulike syndrome (68 percent versus 54 percent), nausea or vomiting (60 percent versus 38 percent), and weight loss (96 percent versus 81 percent), but not thyroiditis, suicide attempts, or irritability. In the commentary, the author notes that the lower frequency of cirrhosis in the reinforced therapy group is curious and that lack of the standard 12 month duration of treatment for the control group makes interpretation of the results difficult. As expected, most patients in the reinforced group experienced more side effects than controls, but only a few withdrew from the study, generally confirming the high motivation of these patients to pursue treatment for this recalcitrant disease. 1 table. 2 references.

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Treatment of Primary Biliary Cirrhosis: Review Source: Journal of Gastroenterology and Hepatology. 11(7): 605-609. July 1996. Summary: This review article covers the treatment of primary biliary cirrhosis (PBC), a slowly progressive chronic cholestatic disease of the liver thought to be caused by immune destruction of the interlobular bile ducts. Therapeutic regimens should aim to control symptoms, prevent complications, and control disease progression. Preventative therapy includes regular screening for thyroid dysfunction and replacement therapy when necessary, and administration of the fat soluble vitamins A, D, and K for hyperbilirubinemia. Esophageal varices may develop early in the course of PBC; nonselective beta blocker therapy should be used as prophylaxis against variceal hemorrhage. The only specific therapy shown to benefit patients with PBC is ursodeoxycholic acid (UDCA). Treatment with UDCA delays disease progression, but does not result in a cure. Currently, liver transplantation is the only definitive treatment available for end stage disease. 29 references. (AA-M).

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Ursodeoxycholic Acid in Primary Biliary Cirrhosis: A Review Source: Practical Gastroenterology. 19(2): 23, 24, 26. February 1995. Summary: This review article explores the use of ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis (PBC). The author reviews the experimental evidence that points to several possible mechanisms for the beneficial action of this agent, including displacement of more toxic endogenous bile acids, immunomodulation, and induction of choleresis producing increased excretion of toxic compounds. The author notes that several biochemical markers have been evaluated for their potential usefulness in assessing prognosis and response to therapy, but none has yet been shown to be clearly reliable. Trial results suggest that UDCA is not effective in late-stage disease and may even induce hepatic decompensation; therefore, early diagnosis and intervention are crucial. 13 references. (AA-M).

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Treatment of Chronic Hepatitis B Virus Infection in Special Groups of Patients: Decompensated Cirrhosis, Immunosuppressed and Paediatric Patients Source: Journal of Gastroenterology and Hepatology. 15(Supplement): E71-E78. May 2000. Contact: Available from Blackwell Science. 54 University Street, Carlton South 3053, Victoria, Australia. +61393470300. Fax +61393475001. E-mail: [email protected]. Website: www.blackwell-science.com. Summary: Treatment of special groups of patients (i.e., patients with decompensated cirrhosis, immunocompromised patients, and children) is challenging and requires different treatment strategies. This article explores the management of chronic hepatitis B in these special populations. Patients with decompensated liver disease have a poor prognosis and are difficult to treat. Chances of survival for this group are limited without liver transplantation. Interferon alpha (IFN alpha) is presently the recommended treatment for patients with clinically stable chronic hepatitis B. The aim of treatment is to permanently suppress or eliminate HBV infection and thereby induce remission of liver disease. The author notes that there is increasing interest in the use of nucleoside analogues in the treatment of decompensated liver disease and those going for liver transplantation. The author discusses the use of thymosin alpha 1 and lamivudine as treatment options. Chronic hepatitis B is common in immunosuppressed patients, including antiHIV positive patients, patients with chronic renal failure, and patients undergoing organ transplantation. Unfortunately, their response to IFN therapy is poor, mostly because of high level viraemia (levels of virus in the blood) and depressed cell mediated immunity. The prevalence of hepatitis B in Asian children is probably similar to that in adults. Infection acquired early in life may not progress to liver disease until later in childhood or early adulthood. However, both cirrhosis and liver cancer (hepatocellular carcinoma, or HCC) have been documented in children. It is therefore important to consider effective therapy for children with chronic HBV infection and to monitor these children closely for HCC. 64 references.

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Cost-Effectiveness of Ursodeoxycholic Acid Therapy in Primary Biliary Cirrhosis Source: Hepatology. 29(1): 21-26. January 1999. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Ursodeoxycholic acid (UDCA) is a safe, effective treatment for patients with primary biliary cirrhosis (PBC), but the cost of the drug has raised cost effectiveness

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concerns. This article reports on a study undertaken to determine the cost effectiveness of UDCA in PBC. The authors compared the costs and outcomes of managing PBC in patients with and without UDCA. From two previously published trials, the effectiveness of UDCA was determined by comparing the annual reduction in the development of ascites, varices, variceal bleeding, encephalopathy, liver transplantation, and death between the treatment groups. Average annual costs for each of these events were estimated from the literature and from institutional data. Approximately twice as many major events occurred in the placebo group as in the UDCA group. The relative risk of liver transplantation and of development of esophageal varices was significantly higher in the placebo group than in the UDCA group. There were no significant increases in the of ascites, variceal bleeding, encephalopathy, or death between the two groups. On the basis of the estimated annual cost of managing these events and the annual cost of UDCA ($2,500), there was an annual cost savings per patient of $1,372. Compared with the placebo group, patients receiving UDCA had a lower incidence of major complications and lower medical care costs. 6 figures. 5 tables. 21 references. (AAM).

Federally Funded Research on Cirrhosis The U.S. Government supports a variety of research studies relating to cirrhosis. 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 cirrhosis. 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 cirrhosis. The following is typical of the type of information found when searching the CRISP database for cirrhosis: •

Project Title: ACUTE HEPATITIS C INFECTION FOLLOWING CD8 DEPLETION Principal Investigator & Institution: Cawthon, Andrew G.; Children's Research Institute 700 Children's Dr Columbus, Oh 43205 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: (provided by the applicant): The hepatitis C virus (HCV) infects approximately 2% of the global population. The majority (70%) of individuals exposed to the virus develop a persistent, life-long infection that over a period of years can result in cirrhosis of the liver or even hepatocellular carcinoma. It is thought that T cell mediated immune responses are important for spontaneous resolution of infection but the relative contribution of CD4+ and CD8+ subsets are not known. In order to directly address the role of CD8+ T cells during acute HCV infection, chimpanzees will be

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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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temporarily depleted of CD8+ T cells prior to challenge with HCV. This experimental approach will address the following aims: 1) To assess how HCV replication and liver pathology is altered by depletion of CD8+ T cells prior to infection, 2) To study the evolution of the CD4+ T cell response to acute HCV infection during the absence and recovery of the CD8+ T cell compartment, and 3) To determine if eliminating the selective pressure mediated by CDS+ T cells alters the evolution of class I and class II MHC restricted HCV epitopes. Results from the experiments proposed in this research plan should contribute to our understanding of HCV pathogenesis by providing a detailed temporal analysis of the kinetics of viral replication and liver pathology during the absence and recovery of the CDS+ T cell compartment following HCV infection. These studies will also provide important new information as to the relative importance of CD8+ and CD4+ T cell responses in the control of HCV infection while determining if a correlation exists between the emergence of antigen specific T cells, the evolution of escape mutations, and the kinetics of virus replication in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADENOSINERGIC THERAPY FOR TREATMENT OF HEPATIC FIBROSIS Principal Investigator & Institution: Ito, Bruce R.; Metabasis Therapeutics, Inc. 9390 Towne Centre Dr, Ste 200 San Diego, Ca 921213026 Timing: Fiscal Year 2001; Project Start 28-SEP-2001; Project End 31-MAR-2002 Summary: Hepatic fibrosis, and its irreversible form, cirrhosis, afflicts millions of individuals in the US and is a major cause of death for those with chronic liver disease. The long-term objective for the proposed research is the discovery of effective and safe anti-fibrotic agents for treating liver fibrosis and thereby decreasing the risk of cirrhosis in individuals with liver disease. Activation and trans-differentiation of the hepatic stellate cell (HSC) into the collagen-forming myofibroblast are key events involved in liver fibrosis. We, and others, have shown that stimulation of adenosine receptors on other matrix forming cells leads to inhibition of activation, proliferation, and synthesis of connective tissue proteins. We propose that inhibition/ reversal of HSC activation in fibrosis can be achieved through stimulation of adenosine receptors on HSCs. The research plan includes the use of various subtype specific adenosine receptor agonists, antagonists, and agents that modulate adenosine metabolism and biosynthesis. Using these biological tools and other molecular probes, all available at Metabasis Therapeutics, rat HSCs will be studied in order to confirm the presence of adenosine receptors and probe their function. After identification of the subtype, the concept will be tested using an in-vivo model of fibrosis. PROPOSED COMMERCIAL APPLICATIONS: Given the worldwide increase in liver disease resulting in hepatic fibrosis/ cirrhosis, and the current lack of proven therapies, the medical need and potential market for a therapeutic to treat hepatic fibrosis are large. The research in this proposal will provide the scientific and commercial foundation to support the development of a novel small- molecule therapeutic for the treatment of hepatic fibrosis/cirrhosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ADULT TO ADULT LIVING DONOR LIVER TRANSPLANTATION Principal Investigator & Institution: Fisher, Robert A.; Surgery; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 17-SEP-2002; Project End 31-AUG-2009

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Summary: (provided by applicant):Over the past decade a growing shortage of donated organs has greatly increased the number of patients who have developed complications of end-stage cirrhosis including hepatocellular carcinoma (HCC) and the mortality for patients awaiting liver transplantation (LT). Living donor liver transplantation (LDLT) was conceived as a way to increase the availability of donated organs and was initiated in infants and children more than a decade ago. Controlled trials demonstrated the safety and efficacy of this procedure. Recently, LDLT has been adapted for the adult. Since then patients, their families and the transplant community have embraced this procedure despite reports of donor morbidity, mortality and early reports that recipients may have increased post-operative complications and reduced survival compared to CADLT. The specific aims of the LDLT cohort study is to define the short and long term risks of morbidity and mortality for the adult donor and to determine the efficacy of this procedure for the adult recipient compared to patients undergoing LT with a cadaveric liver (CADLT). Individuals interested in becoming living donors will be asked to participate in this study. Those who are selected and undergo the surgical procedure will be followed at periodic intervals to define the long term morbidity and mortality of the procedure. Individuals not selected as living donors will be matched to the actual donors 2:1 by age, race and gender and also followed prospectively as a donor control group. Individuals being evaluated for LT will be asked if they would be interested in undergoing LDLT. Those patients who identify an acceptable donor and undergo LDLT will be followed prospectively at periodic intervals to define the short and long term morbidity and mortality associated with this procedure. Those patients who are unable to identify a living donor will be matched to an actual LDLT recipient 2:1 by age, race, gender, disease etiology and severity of liver disease (MELD score). These patients will act as the recipient control group and will and be followed prospectively before and after they undergo CADLT. Ancillary studies accompanying the main trial will specifically evaluate the ability of LDLT to improve the long term outcome of patients with HCC and to evaluate the effects of donation and LDLT on hepatic histology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALCOHOL AND HIV PROTEASE INHIBITORS INTERACTIONS Principal Investigator & Institution: Feierman, Dennis E.; Anesthesiology; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): There is great interest and possible concern in the use of ethanol by HIV infected patients. Ethanol has been shown to induce cytochrome P450 (CYP) 3A, an isoform responsible for the metabolism of HIV PIs (HIV-PIs). The goal of this proposal is to evaluate the effects of ethanol consumption on the pharmacokinetics, specifically AUC and Cmax, of orally administered HIV-protease inhibitors. Two specific objectives are derived from this goal and are addressed in this application that will utilize two rodent models of ethanol consumption and its interaction on drug disposition.S.A.I: To characterize the pharmacokinetics of orally administered HIV protease inhibitors in rats fed the Leiber-DeCarli ethanol-containing diet, and pair fed and ad-lib controls. This model was chosen since it has been shown that ethanol can induce CYP3A without significant liver pathology and may be analogous to early alcohol disease. S.A.II: To characterize the pharmacokinetics of orally administered HIV protease inhibitors in rats fed ethanol and liquid diet via the intragastric tube feeding method. This model of ethanol consumption was chosen since it has been shown to be a better inducer of CYP3A and also cause substantial liver pathology.1) Characterize and compare the pharmacokinetics of select HIV protease

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inhibitors (HIV-PI) such as saquinavir and indinavir after their oral administration in these models (and controls) chronically fed ethanol. We will also ascertain the effects of pretreatment with triacetyloleandomycin (TAO), a specific inhibitor of CYP3A, on the pharmacokinetics of rally administered saquinavir and indinavir.2) Characterize and compare the pharmacokinetics of saquinavir and indinavir after oral co-administration with ethanol in these models.3) Validate the induction of CYP3A activity, content and specific inhibition of CYP3A by TAO in liver and small bowel in these rats. Since paraglycoprotein (pgp) can affect the bioavailability of HIV protease inhibitors we will also characterize the effects of chronic ethanol on pgp content.The success of antiretroviral medication therapies for the treatment of HIV-disease is now well documented. These benefits are only tenable when therapeutic levels of the antiviral treatments are maintained. Understanding drug interactions and induction of HIV-PI metabolism remains a critical goal for those individuals receiving treatment. Many individuals taking these medications also consume ethanol, acutely and chronically. Because of the importance of CYP3A4 with respect to HIV-PI drug metabolism, and its induction by ethanol, the interactions of HIV-PI and ethanol are of clinical importance and are the major focus of this proposal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALCOHOL AS A MODULATOR OF PREFIBROTIC LIVER INJURY Principal Investigator & Institution: Clemens, Mark G.; Professor and Chair; Biology; University of North Carolina Charlotte Office of Research Services Charlotte, Nc 282230001 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2003 Summary: Alcohol is implicated as the etiologic agent in greater than 50% of deaths due to liver cirrhosis, a growing national health concern. It is widely accepted that ethanolinduced oxidative injury can result in inflammation, steatohepatitis, hepatocellular carcinoma and fibrosis. However, it is unknown why only a subpopulation of alcoholic liver disease patients present with end stage liver cirrhosis. Likewise, factors contributing to increased obesity-related susceptibility to the deleterious effects of ethanol are poorly understood. This NIAAA R03 has as its primary focus to achieve a basic understanding of whether differences in the severity of alcoholic liver disease can be explained, in part, by alcoholinduced acceleration of preexisting liver injury. This proposal builds on our recent observation that combined hyperlipidemic mice that overexpress apolipoprotein C-I maintained on a chow diet develop prefibrotic liver injury. The hypothesis that will be tested is that alcohol can exacerbate preexisting liver injury initiated by chronic hyperlipidemia. In this study, normolipidemic and hyperlipidemic mice fed alcohol or a control diet will be evaluated for changes in plasma lipids and lipoproteins. Intravital microscopy will be used to monitor liver microcirculation, tissue damage and collagen deposition. Tissue evaluation will indicate the metabolic health and extent of liver injury. This study is of immediate interest because while hyperlipidemia is pandemic in the US, the observation that chronic hyperlipidemia can result in liver injury was previously unappreciated. With our recent observation that chronic hyperlipidemia can result in liver injury we will determine whether alcohol can accelerate the development of liver disease in a spontaneous liver injury model where the damage is initiated by preexisting hyperlipidemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ALCOHOL IN MEXICAN-ORIGIN GROUPS: US AND MEXICAN SURVEYS Principal Investigator & Institution: Greenfield, Thomas K.; Center Director and Senior Scientist; Public Health Institute 555 12Th St, 10Th Fl Oakland, Ca 94607 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): Based on the 2000 census, over 32.8 million Hispanics in the US represent 12% of the county's total population. People of Mexican origin constitute the largest, fastest growing subgroup. They are now two-thirds of all US Hispanics, and this subgroup has grown 53% since 1990. Numerous indicators show that such alcohol-related problems as alcohol dependence and such adverse social and health consequences as cirrhosis disproportionately affect Mexican Americans- health disparities that NIAAA is committed to addressing. This research will conduct a secondary analysis of three datasets, two drawn from existing Alcohol Research Group US National Alcohol Surveys (NASs), each including large Hispanic oversamples, and the 1998 Mexican National Survey of Addictions (ENA) conducted by our collaborators at the National Institute of Psychiatry, Mexico City. Questionnaires for the ENA (n = approximately 5,712) used NAS alcohol items and scales, so assuring considerable comparability. The US surveys were conducted in 1995 (N9) as face-to-face interviews (n = 4,925; 1,589 Hispanics; 964 of Mexican descent), and in 2000 (N10+Supplement) as telephone surveys (n = 8,980; 1,132 Hispanics; est. 679 of Mexican descent) of adults 18 or older. Following preliminary analyses, we plan to pool the Mexican-descent NAS samples, limiting age range to 18-65 (pooled n = 1,542) for comparison with the ENA. Specific Aims include (1) comparing and contrasting the prevalence, predictors and correlates of heavy drinking, alcohol use disorders (AUD), and other alcohol-related problems among men and women of Mexican descent living in the two countries (US and Mexico); (2) analyzing and comparing the comorbidity of AUD and drug abuse, and AUD and depression, among these groups; (3) investigating the risk curves between key parameters of drinking pattern (volume and frequency of heavy drinking) and AUD and a range of alcohol-related health and social harms in the two Mexican- origin populations, considering the role of demographic mediators such as gender, age and (for the US) acculturation; and (4) exploring the association of alcohol treatment in relation to AUD and other alcohol-related problems, health harms, drug abuse, and depression among Mexican Americans in the US. This research accords with the NIAAA strategic action plan for addressing health disparities: using a rigorous study design, it aims to provide critically needed knowledge in detail about drinking patterns and alcohol-related consequences of a key ethnic minority population-Mexican descent Hispanic individuals-known to be at risk for alcohol dependence and other health harms from drinking. Results will inform provision of culturally appropriate health services and prevention program planning. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ALCOHOL REDUCTION IN MEDICAL ILLNESSES:HCV AS PROTOTYPE Principal Investigator & Institution: Dawson, Neal V.; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Alcohol use is discouraged or contraindicated for patients with a variety of medical illnesses. For many diseases directly caused by alcohol, the use of alcohol may be associated with recurrent symptoms shortly after its

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consumption, e.g., pancreatitis or gastritis, and the prohibition against alcohol is straightforward. However, for many chronic diseases, the use of alcohol is not associated with any short-term symptoms or sequelae. The course of these chronic diseases (or their treatments) among non-abusing/nondependent patients can be adversely affected by even moderate alcohol use, e.g., chronic hepatitis, (nonalcoholic) cirrhosis, severe diabetes, or the use of the 'blood thinner', warfarin. Chronic Hepatitis C virus (HCV) infection is a prototypical example of a disease in which alcohol use tends to cause no symptoms. Even moderate chronic alcohol use can be associated with an increased likelihood of cirrhosis and liver cancer. HCV infection rates and prognosis are related to alcohol use in multiple ways. Alcohol use during HCV treatment is associated with a decreased likelihood of viral clearance. Long-term alcohol use may increase the proliferation of HCV and the associated liver damage even with moderate alcohol consumption. Greatly reducing or eliminating alcohol use may importantly enhance the prognoses of patients, even if they are not candidates for specific HCV treatments. Despite having diagnoses that warrant abstinence from alcohol, many patients continue to drink alcohol. Little is known about why patients continue to consume alcohol in the face of diagnoses that warrant a reduction in use or abstinence. The current study is designed to determine factors that lead to continuing alcohol intake among alcohol nonabusing/nondependent patients who are advised to stop drinking by health care providers. In Phase 1, focus groups (patients and providers) will be used to discover issues that may be associated with continued drinking. In Phase 2, questionnaire items will be developed based on the data gleaned from Phase 1. The potential pool of items will be administered to 10 patients per item and factor analyzed. In Phase 3, the items retained from the pool of potential items will be used to create a questionnaire that will be tested for its ability to predict alcohol reduction or cessation. Since alcohol use is common in the U.S. and since most patients who currently have HCV are not candidates for treatment, abstinence from alcohol use represents a major opportunity to prevent a decline in the health and quality of life of patients with HCV and similar diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALCOHOL/CELLULAR IMMUNITY IN HCV AND HIV INFECTION Principal Investigator & Institution: Chang, Kyong-Mi M.; Assistant Professor; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 28-SEP-2000; Project End 31-JUL-2005 Summary: Up to 3% of the world population is infected with hepatitis C virus (HCV), a hepatotropic RNA virus that causes acute and chronic hepatitis as well as cirrhosis and hepatocellular carcinoma. HCV infection results in chronicity in most cases (85%) despite detectable antiviral immune response, and recent studies suggest that virusspecific T cells play an important role in the outcome of HCV infection. Interestingly, HCV infection is up to 7 fold more prevalent in alcoholic individuals than in the general population, and chronic alcohol use in HCV-infected patients is associated with accelerated liver disease progression and development of liver cancer. While alcohol is known to suppress cellular immune response, little is known about the effect of alcohol on HCV-specific T cell response in HCV-infected patients. Therefore, the primary aim of this application is to determine if chronic alcohol use results in a pathogenetic HCVspecific T cell response that promotes further liver damage than virus control. In addition, we will determine the extent to which this may be reversed upon alcohol cessation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ALCOHOLISM & LUNG INJURY--CIRRHOSIS & GLUTATHIONE DEF Principal Investigator & Institution: Moss, Marc Marc.; Assistant Professor; Internal Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2003 Summary: The acute respiratory distress syndrome (ARDS) is a severe form of acute edematous lung injury that afflicts approximately 150,000 individuals per year in the United States. Despite three decades of research concerning ARDS, there are presently no effective therapies and the mortality from this syndrome remains unacceptably high at 40-60 percent. The ability of the lung to neutralize the harmful effects of oxygen radicals has been postulated to be a critical step in preventing the development and decreasing the severity of ARDS. Initially, we hypothesized that the presence of preexisting co-morbid conditions, which independently reduce the anti-oxidant capacity of the lung, will result in an increased incidence and severity of ARDS in critically ill patients. We have previously reported that chronic alcohol abuse, without hepatic dysfunction, decreases pulmonary glutathione concentrations and alters surfactant function in both animals and humans, and increases the incidence and severity of ARDS in critically ill patients. Based on the profound effects of chronic hepatic dysfunction on systemic glutathione homeostasis, we hypothesize that cirrhosis secondary to chronic alcohol abuse will lead to a dramatic reduction in pulmonary glutathione reserve with subsequent impairment of surfactant function, thereby markedly increasing the risk of critically ill cirrhotic patients to develop ARDS. In this first part of this proposal, we will determine lung lavage glutathione concentrations and surfactant properties in control subjects and patients with clinically stable cirrhosis. In the second part of the proposal, we will examine how cirrhosis alters the pulmonary response to sepsis. Finally, we will further explore the epidemiological association between cirrhosis and ARDS using a large national database. The results of these studies will create a strong foundation of evidence supporting the potential use of glutathione replacement therapy to decrease lung injury in patients with cirrhosis secondary to alcohol abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ALCOHOLISM:ALTERED ALVEOLAR MATRIX AND ACUTE LUNG INJURY Principal Investigator & Institution: Brown, Lou Ann S.; Professor; Pediatrics; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: (Adapted from Applicant's Abstract): Acute Respiratory Distress Syndrome (ARDS) is a common and severe form of acute lung injury that is associated with mortality of approximately 50 percent. A prospective study of 351 critically ill patients recently identified a history of chronic alcohol abuse with an increased incidence and severity of ARDS, regardless of the at-risk diagnosis. This observation identifies chronic alcohol abuse as the first reported comorbid variable that significantly increases the patient's risk of developing ARDS. Glutathione (GSH) is an essential component of the pulmonary antioxidant system and decreased GSH in the epithelial lining fluid has been associated with ARDS. Studies in the investigator's laboratory demonstrated that alcoholic adults without cirrhosis have and 80 percent decrease in GSH in the epithelial lining fluid, possibly due to decreased GSH availability from plasma. In a rat model of chronic ethanol ingestion, decreased GSH in the epithelial lining fluid and alveolar type II cells was associated with increased susceptibility to sepis-mediated acute lung injury.

22

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The mechanisms by which ethanol-induced GSH depletion increases susceptibility to acute lung injury is the focus of this application. One hallmark of ARDS is altered alveolar matrix homeostasis as characterized by excessive alveolar matrix deposition and matrix turnover. Studies in the investigator's laboratory have demonstrated that in the rat model, ethanol-induced GSH depletion was associated with alveolar type II cells that produce an altered, unstable extracellular matrix that was unable to support type II cell functions. When sepsis was superimposed on ethanol ingestion, the lavage fluid had greater gelatinase activity. Prevention of many of these altered parameters with GSH precursors indicates the central role of GSH depletion in the process. This lead to the following hypothesis: chronic ethanol ingestion predisposes to acute lung injury by decreasing alveolar GSH which subsequently alters the homeostasis of the alveolar epithelial extracellular matrix. In the first three aims, the investigators will use the rat model of chronic ethanol ingestion to determine if ethanol predisposes to acute lung injury via altered matrix homeostasis (Aim1), if sepsis potentiates the ethanol-induced effects on matrix homeostasis (Aim 2) and if GSH availability mediates these effects on matrix homeostasis (Aim3). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIVIRAL & ANTIFIBROTIC LIVER THERAPY OF HCV+ DRINKERS Principal Investigator & Institution: Lieber, Charles S.; Professor of Medicine & Pathology; None; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-MAY-2005 Summary: We plan to evaluate a combined antiviral, antifibrotic and antioxidant treatment in the progression of liver disease of heretofore excluded patients with hepatitis C namely alcohol drinkers. Abstainers or alcohol consumers will be given state- of-the-art antiviral treatment (pegylated interferon + ribavirin) for 24-48 weeks. Another innovative aspect of this proposal is the supplemention with an anti-fibrotic agent, namely polyenylphosphatidylcholine (PPC) extracted from soybeans, or placebo, administered for 3 years (concomitantly with the antiviral treatment and thereafter). Current therapy neglects the fact that what causes the major medical symptoms and eventually the demise of the patient is liver fibrosis, resulting cirrhosis and associated complications, including hepatocellular carcinoma. If the fibrotic process could be stopped or even prevented, the hepatitis C virus would lose much of its impact on health. Available anti-fibrotic agents are too toxic to be used in patients, except for one, namely PPC, which has been shown in various experimental models to have striking anti-fibrotic actions, and which was found recently to be beneficial in HCV+ patients in terms of their circulating levels of transaminases. Fibrosis was not assessed, but documentation of the effects of PPC on fibrosis in HCV+ patients is being proposed here. It is noteworthy that PPC was discovered to have also significant anti- oxidant effects. This may be important in HCV+ patients since various studies have now indicated that HCV is associated with an oxidative stress. Another innovative aspect is the inclusion of drinkers who thus far were excluded from standard antiviral treatment, mainly because of concerns about exacerbation of mental disorders, reliability and compliance. However, the latter objection has now been overcome by the availability of pegylated interferon which can be administered once a week by the therapist in a controlled fashion. For both PPC and ribavirin, compliance will be monitored by incorporation of markers, such as riboflavin, that can be measured in the urine. Spot checks of blood levels of dilinoleoylphosphatidylcholine (DLPC, the main

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phosphatidylcholine species of PPC) will also be performed. Accordingly, support is requested for a a double-blind, randomized placebo controlled study to assess the efficacy of this novel approach for the treatment of liver disease in HCV+ alcohol consumers or abstainers. Funds are requested for special laboratory tests, study nurses, travel to meetings, patient monitoring expenses and a core office. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AQUAPORIN-2 EXCRETION IN DISORDERS OF WATER BALANCE Principal Investigator & Institution: Cadnapaphornchai, Melissa A.; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-JUL-2005 Summary: (adapted from the application) Normal water metabolism is essential to body fluid homeostasis. The major determinants of normal water balance include arginine vasopressin (AVP), renal function, and thirst. Recent investigations have described the cloning and characterization of the water channel aquaporin-2 (AQP-2), which is located in the principal cell of the kidney collecting duct. Under the influence of AVP, AQP-2 inserts into the apical membrane, allowing reabsorption of water to occur. Studies in animals and humans suggest that alterations in the regulation and expression of AQP-2 in certain physiologic and pathologic states may contribute to such complications as hyponatremia, hypoosmolality, and edema. During exocytic shuttling of AQP-2 to the apical collecting duct membrane, a small percentage of AQP-2 is lost in the urine. Measurement of this urinary AQP-2 protein can be reliably performed by radioimmunoassay; this test represents a novel tool for evaluation of AVP action in the collecting duct of the human kidney in health and disease. In these studies, we will examine urinary AQP-2 excretion in patients during pregnancy and the menstrual cycle, and in patients with congestive heart failure, cirrhosis, nephrotic syndrome, and acquired nephrogenic diabetes insipidus due to lithium therapy or autosomal dominant polycystic kidney disease. An interpretation of the relationship between urinary AQP-2, serum and urine osmolality, and plasma AVP will provide insight into the control of body fluid homeostasis. The role of the vasopressin V2 receptor antagonist, CIPC-41061, in the treatment of volume overload, edema, and hyponatremia will be explored. A comprehensive understanding of AQP-2 regulation in humans will lead to unique and more direct interventions in the therapy of disordered water metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AUTOANTIGEN ARRAYS TO SELECT VACCINES FOR MODEL OF PBC Principal Investigator & Institution: Utz, Paul J.; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 23-SEP-2002; Project End 31-MAY-2004 Summary: (provided by applicant): The broad, long-term objective of this proposal is to use autoantibody profiling to guide the selection of DNA tolerizing vaccines for the treatment of an animal model of primary biliary cirrhosis (PBC) called experimental autoimmune cholangitis (EAC). We will test the hypothesis that large-scale, parallel detection of autoantibody profiles can be used to explore epitope spreading, the role played by a subset of inflammatory cytokines in the initiation and propagation of autoimmunity, and ultimately in selection of antigen-specific tolerizing therapies. We will use biochemical, immunological, and molecular biological techniques to validate

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Cirrhosis

and extend our ongoing protein array platform in exploring three specific aims in this proposal: (i.) to construct a PBC autoantigen microarray suitable for the identification of human and murine autoantibodies. This array will be used to identify dominant B cell epitopes in the EAC model, and to determine the precise ordering of epitope spreading in EAC. (ii.) to determine whether interleukin-4 (IL-4) and interferon-gamma (IFNy) are required for the development of EAC. An imbalance between Thl and Th2 lymphocytes is thought to play an important role in some autoimmune diseases, and IL-4 and IFN3' represent critical cytokines in the pathogenesis of autoimmunity. (iii.) to employ DNA vaccination to prevent and treat EAC using cDNAs encoding autoantigens identified using protein microarrays developed in the first aim. The results of this proposal will determine the long-term usefulness of the newly described EAC animal model of PBC. Successful treatment of EAC using plasmids encoding prominent autoantigens may herald an era of customized, antigen- or tissue- specific tolerizing therapy in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AUTOIMMUNITY CENTERS OF EXCELLENCE Principal Investigator & Institution: Chess, Leonard; Professor; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 28-SEP-1999; Project End 31-MAR-2008 Summary: (provided by applicant): The overall goals of this ACE renewal application will be to further develop our interdisciplinary basic and clinical research program at Columbia primarily focused on the evaluation of novel therapeutic approaches to human autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid and psoriatic arthritis (RA), multiple sclerosis (MS), type I diabetes mellitus (TIDM), biliary cirrhosis and scleroderma. In each of these diseases, there are ongoing basic and clinical research programs involving pathophysiologic and/or clinical immunotherapeutic studies. We hypothesize that there are four principal events involved in the immunopathogenesis of these diseases: (1) predisposing genes establish a T-cell repertoire capable of recognizing self peptides intrinsic to the autoimmune process; (2) previously tolerant autoreactive T-cell clones are activated, expand to change the T cell repertoire to reflect autoreactive effector T cells and migrate to sites of inflammation; (3) regulatory mechanisms, including cytokines and CD4+ and CD8+ regulatory T cells fail and (4) pathogenic autoantibodies and T cells effect tissue injury. We predict that reducing the clonal expansion and migration of relevant autoreactive T cells by blockade of TCR signaling with agents like anti-CD3 or interruption of the signaling and migration of autoreactive memory T cells with agents like anti-VLA-1 could down-modulate disease activity. We propose to test these hypotheses during the natural history of disease and during specific immune intervention. In this ACE renewal, we plan to continue ongoing studies of anti-CD3 therapy of TIDM, initiate trials of biliary cirrhosis employing Mycophenolate Mofetil and continue pre-clinical assessment of the VLA-1 pathway as a prelude to clinical trials with anti-VLA-1 moAbs anticipated to begin in 2004. During these studies, we will: (1) identify by PCR based CDR3 length techniques and TCR sequencing, autoantigen-driven expansions in the CD4 and CD8 cz_ TCR repertoire; (2) Identify changes in the T cell functional response to autoantigens and (3) directly study the regulatory interactions of TH1, TH2 as well as CD4+ and CD8+ T cells in controlling the TCR repertoire. In select patients, we will directly study cells at the site of inflammation (CNS, skin, kidney, joints) using HVS immortalization techniques as well as by laser capture technology for repertoire and microarray analysis of activated genes. In addition, we plan new basic studies of the

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control of the autoreactive T cell repertoire in autoimmune disease by analysis of EAE in the mouse and studies of human regulatory cells in TIDM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BACULOVIRUS MEDIATED GENE DELIVERY OF HEPATITIS C VIRUS Principal Investigator & Institution: Isom, Harriet C.; Distinguished Professor; Microbiology and Immunology; Pennsylvania State Univ Hershey Med Ctr 500 University Dr Hershey, Pa 17033 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2003 Summary: (Applicant abstract): Chronic hepatitis C virus (HCV) infection is associated with the development of cirrhosis, an elevated risk of hepatocellular carcinoma and is currently responsible for almost 30 percent of end-stage liver disease in need of transplantation in the United States. At present, no means of prevention of HCV infection exists and treatments are unsatisfactory. HCV is highly species-specific. Only humans and a few high primates are susceptible. The only animal model for HCV vaccine or antiviral research is the endangered chimpanzee. One of the major reasons that vaccine development and antiviral therapy are lacking for HCV stems from the fact that there are no satisfactory small animal or in vitro model systems for studying HCV replication. The applicant has recently reported a novel in vitro system for delivering a replication competent HBV to cells of hepatic origin by using an HBV recombinant baculovirus. In HBV baculovirus infected HepG2 cells, HBV transcripts, intracellular and secreted HBV antigens are produced and replication occurs as evidenced by the presence of high levels of intracellular replicative intermediates and protected HBV DNA in the medium. Covalently closed circular DNA is present indicating that, in this system, HBV core particles are capable of delivering newly synthesized HBV genomes back into the nucleus of infected cells. She has also demonstrated that the HBV recombinant baculovirus system can be used to monitor the effects of an antiviral on multiple aspects of the HBV life cycle include formation of newly synthesized CCC DNA as well as the effects on preexisting CCC DNA. Based on the success with generation and usage of the HBV recombinant baculovirus system, she will test in this proposal the following hypothesis: An HCV recombinant baculovirus can be generated which is replication competent in human hepatic cells in culture and can be used to study molecular aspects of HCV replication and effects of specific anitivirals on HCV replication. The Specific Aims are: 1. To generate recombinant baculoviruses that contain all or part of the HCV cDNA under the control of mammalian promoters. 2. To test the ability of HCV-recombinant baculoviruses to express HCV gene products and replicate HCV in human cells of hepatic origin. 3. To use recombinant HCV baculovirus to evaluate the direct effect of interferon treatment on evolution of quasispecies during HCV replication in cells of hepatic origin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BASES OF CIRRHOSIS IN ALCOHOLIC LIVER DISEASE Principal Investigator & Institution: Zern, Mark A.; Director, Div. Gastroenterology; Internal Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2001; Project Start 01-SEP-1988; Project End 31-MAR-2006 Summary: This proposal is a continuation of our studies which attempt to elucidate the molecular bases of cirrhosis in alcoholic liver disease. Hepatic fibrogenes caused by

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alcohol abuse or other etiologies is a complex process that involves a balance between liver cell proliferation and cell death, as well as the increased deposition and modeling of extracellular matrix (ECM) proteins. Our recent studies provide evidence for the significance of one factor, tissue transglutaminase (tTG), in many of these interactions. This ubiquitous enzyme has characteristics that may induce either apoptosis or cell proliferation, and it appears to contribute to the fibrotic process in a number of ways. This proposal is an attempt to elucidate the mechanisms by which tTG affects the process of hepatic mitogenesis or apoptosis, especially as it pertains to ethanol administration. Specific Aims: 1) To determine the pathways and functional significance of alpha-1 adrenergic signaling in hepatocytes; 2) To investigate the downstream effects of alpha-1 adrenergic signaling on hepatocyte mitogenesis; and 3) To delineate the mechanisms by which tTGase cross-linking activity inhibits proliferation and enhances apoptosis in hepatocytes. These studies will entail determining whether phenylephrineinduced hepatocyte mitogenesis acts through alpha-1B adrenergic receptor binding coupled to the tTGase G-protein subunit, Galphah, whether this activates the MAPK pathway, and by what mechanism this activation may be occurring. In addition, the mechanism by which tTGase cross-linking activity may affect upstream events in the apoptosis cascade will also be explored. Health Relatedness: It is hoped that by better understanding the molecular mechanisms by which ethanol affects fibrogenesis, hepatic mitogenesis, and apoptosis, more effective and rational therapeutic intervention may be developed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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

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micropuncture, and patch clamping techniques. Signal transduction systems involved in their action will be studied by monitoring changes in the concentrations of secondary messengers. Understanding transport systems and their underlying mechanisms of biliary secretion in normal and CF mice will help to formulate therapeutic approaches to overcome the CFTR defect. This project, in turn, will provide the candidate with an excellent opportunity to broaden and develop research and cognitive skills to become independent researcher, as well as help to successfully compete for future research grants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTEINS

BIOGENESIS

AND

FUNCTION

OF

CONNECTIVE

TISSUE

Principal Investigator & Institution: Bornstein, Paul; Professor; Biochemistry; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; 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: CARDIOPROTECTIVE THALASSEMIA

EFFECT--NEW

CHELATORS

FOR

Principal Investigator & Institution: Hershko, Chaim; Hebrew University of Jerusalem Jerusalem 91904, Israel Jerusalem, Timing: Fiscal Year 2001; Project Start 01-JUN-1999; Project End 31-MAY-2002 Summary: Research on the pathogenesis of myocardial iron toxicity, the most critical life-limiting complication of thalassemic iron overload, has been seriously hindered by

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failure to develop an animal model simulating transfusional siderosis. Consequently, we have developed a system of cultured rat cardiomyocytes in which iron-loading with non-transferrin iron results in structural and functional abnormalities analogous with hemosiderotic myocardiopathy. In the present proposal we wish to test the hypothesis that (a) depletion of the chelatable cellular labile iron pool may permit recovery of heart cell function, documented by reversal of the iron-induced abnormalities in contractility and rhythmicity, increased lipid peroxidation, loss of sarcolemmal thiolic proteins, increased lysosomal fragility and abnormal mitochondrial respiratory function (b) that hexadentate chelators offer a predictable protective effect whereas tridentate and bidentate chelators (such as L1) may cause internal iron redistribution and a paradoxical enhancement of the harmful Fenton reaction and; (c) that lipophilic chelators are more efficient in penetrating heart cells allowing reversal of existing damage whereas hydrophilic chelators may have superior ability to prevent iron-induced damage. Hypertransfused rats with selective radioiron probes of hepatocellular and reticuloendothelial iron stores will be used to define the pools of iron available for in vivo mobilization. The ability of ascorbate to enhance chelating efficiency and of alphatocopherol to prevent peroxidative damage will be explored in both experimental systems. The proposed studies represent an essential link between the pharmacologic chemistry and potential clinical application of new iron chelators by allowing insight into their mechanism of action and cardioprotective effect, providing vital informal for the development of new strategies for the management of iron overload in thalassemic patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CD36 AND HEPATIC STELLATE CELL ACTIVATION Principal Investigator & Institution: Devilliers, Willem Js.; Medicine; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2001; Project Start 01-AUG-2000; Project End 31-JUL-2003 Summary: The central hypothesis to be examined in this R21 proposal is that the class B scavenger receptor, CD36, plays an important role in hepatic stellate cell activation and hepatic fibrogenesis through the alcohol-induced generation of lipid peroxidation products and activation of the nuclear transcription factor, peroxisome proliferatoractivated receptor gamma (PPAR-G). The major difficulty in devising specific therapies for alcoholic liver disease has been our limited understanding concerning the mechanisms underlying the progressive nature of the liver injury and fibrosis in this disease process. The class B scavenger receptor CD36 binds oxidized LDL (OxLDL) and is critical in macrophage foam cell formation and lipid flux. Oxidized cholesterol esters and lipid peroxidation products have been shown to act as ligands for PPAR-G in cells. The expression of CD36, which takes up oxidized cholesterol esters from OxLDL, is positively regulated by PPAR-G, thereby establishing a positive feedback control loop through which oxidized LDL induces greater CD36 expression which in turn leads to increased OxLDL accumulation in cells. The CD36-thrombospondin complex is required on the cell surface for the formation of activated transforming growth factor-beta (TGFb). We present preliminary data that PPAR-G agonists similarly increases CD36 expression and function in hepatic stellate cells, linking alcohol-induced generation of lipid peroxidation products and hepatic fibrosis. It is well documented in experimental models of alcoholic liver disease that addition of polyunsaturated fatty acids to the diet enhances liver injury and fibrosis. It is our working hypothesis that the CD36 scavenger receptor is upregulated in alcoholic liver disease and is critical for stellate cell activation and fibrogenesis. We therefore propose basic studies in vitro and in animal models of

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liver fibrosis that address the specific role of CD36 class B scavenger receptors in hepatic stellate cell activation. We believe the proposed research is likely to generate data that will lead to a regular research project grant. The specific aims of this R21 Experimental/Developmental Proposal are: Aim 1: To determine the extent to which PPARG activation and CD36 expression regulate stellate cell activation. Stellate cell activation will be measured by Collagen expression and secretion of activated TGF-B. Aim 2: To document that stellate cells from spontaneously hypertensive rats deficient in CD36 are resistant to activation and fibrogenesis. Moreover, we will determine whether the over expression of CD36 in these CD36-deficient stellate using an adenoviral vector will reconstitute their ability to become activated in response to lipid peroxidation products. Aim 3: To determine the influence of hepatic stellate cell CD36 expression on the development of hepatic fibrosis in rodent models. We will determine whether spontaneously hypertensive rats and CD36-deficient mice are resistant to the development of hepatic fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHRONIC HEPATITIS C: MOLECULAR & CELLULAR MARKERS Principal Investigator & Institution: Farrell, Geoffrey C.; University of Sydney Main Quadrangle, Bld A14 Sydney, 2006 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Only a minority of HCV-infected individuals have progressive forms of chronic hepatitis that will result in cirrhosis in 20 to 30 years. This project is concerned with the biological basis of disease progression in chronic hepatitis C. We have noted that, to date, viral factors and the systemic immune response to HCV are poorly correlated with disease progression. The key pathobiological process that determines progression of liver disease in chronic hepatitis C is fibrogenesis, with hepatocyte cell death and proliferation playing lesser roles. In the present proposal, these processes are conceptualized as responses to hepatic inflammation and oxidative stress causing activation of hepatic stellate cells and liver cell injury. Thus our overall objective is to characterize how interactions between HCV, the hepatic inflammatory response and liver cells promote fibrogenesis and disease progression in chronic hepatitis C. In particular, we will test the hypothesis that, in the early stages of chronic HCV infection, an intrahepatic "molecular map" can be created to identify subsets of individuals who will develop progression of liver disease. We will then seek to identify patterns of hepatic gene expression that correlate with the pathogenesis of fibrosis, hepatocyte death and proliferation. A particular focus will be on the identification of genes not previously known to be associated with individual susceptibility to HCV. A unique feature of these studies is that they will be performed on serial liver biopsy samples obtained at 3 to 5 year intervals from 200 patients with mild to moderate chronic hepatitis C who will be followed prospectively and monitored by quantitative liver functional assessments. The Specific Aims are: 1) To establish the relationship between cytokine mediators of the hepatic inflammatory response, macrophage activation and the presence of oxidative stress in the liver, and to compare these with characteristics of the HCV infection in hepatocytes and other cell types; 2) To determine whether expression of these cytokines and/or oxidative stress correlate with the activity of hepatic fibrogenesis, using both cross-sectional and prospective longitudinal approaches. 3) To identify hepatic genes previously not known to be associated with a progressive course for hepatitis C. The findings may allow those individuals most at risk of progressive liver disease from HCV to be identified at a time when they are most likely to respond to antiviral therapy. It will also allow the design of adjunctive

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treatments more appropriately targeted towards the key pathogenic processes that determine disease progression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CIRRHOSIS AND ITS COMPLICATIONS Principal Investigator & Institution: Garcia-Tsao, Guadalupe; Professor; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 31-AUG-2004 Summary: The candidate, Dr. Guadalupe Garcia-Tsao, is Associate Professor in the Department of Internal Medicine at the Yale University School of Medicine. She has devoted her career to patient-oriented research (POR) in the area of cirrhosis and in complications. She has been involved in a wide range of POR, from descriptive studies to multicenter randomized clinical trials. Her studies in the area of varices, variceal hemorrhage, ascites and spontaneous bacterial peritonitis have made significant contributions to the management of patients with cirrhosis, the sixth leading cause of death in the United States in individuals between the ages of 25 and 65, the productive years of life. She is recognized as a clinical research in the area of portal hypertension as attested by invitations to chair abstract selection committees and to serve as session moderator at important scientific meetings, as well as invitations to write editorials, review articles and to become panel member at international consensus panels. Ascites is one of the main complications of cirrhosis and portal hypertension and Dr. GarciaTsao's short tem goals are to focus on this complication. One of these goals is to implement a randomized trial comparing the transjugular intrahepatic porto-systemic shunt with serial large-volume paracenteses in the treatment of patients with refractory ascites. This multicenter trial, partially funded by a VA Merit Review, will analyze not only differences in efficacy but also differences in quality of life and cost, and the results can potentially change current standards of care for patients with cirrhosis. R. GarciaTsao's long-term career goals are to continue to perform POR focused on prophylactic therapy and identification of prognostic factors in chronic liver disease as well as furthering her training in health services research. Dr. Garcia-Tsao has devoted a great deal of effort toward mentoring beginning clinical investigators in POR, especially in her capacity as co-Director of the Liver Center's Clinical Core. Yale University is one of the major teaching and research institutions of the United States and as such has wellestablished research and educational resources that will continue to be utilized by the candidate. The proposed award will allow her to carry out her research and mentoring objectives successful so that she can continue to make significant contributions in the field of cirrhosis and its complications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COGNITIVE MECHANISMS OF ALCOHOL ABUSE Principal Investigator & Institution: Fillmore, Mark T.; Assistant Professor; Psychology; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-MAY-2004 Summary: (provided by applicant): Excessive alcohol use during a drinking episode (i.e., a binge) contributes to many adverse health and social consequences. Binge drinkers are more likely to drive while intoxicated and to suffer blackouts and hangover. A continued pattern of binge drinking poses immediate health risks (e.g., alcohol poisoning, acute alcoholic hepatitis), and long-term consequences, such as alcohol dependence and liver cirrhosis. Given that even mild doses of alcohol impair

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cognitive processes that control behavior, it is important to understand how such disturbances also can reduce control over alcohol intake once a drinking episode has begun. The proposed project aims to determine how the inability to curtail alcohol consumption during a drinking episode is linked to alcohol-induced impairment of cognitive processes involved in the self-control and regulation of behavior. The research will examine acute alcohol impairment of cognitive functions in young non-dependent drinkers. The project combines measures of alcohol effects on cognitive inhibitory processes with traditional abuse liability indices based on subjective rewarding effects of the drug and its ability to reinforce self-administration. Studies will determine the degree to which alcohol abuse potential is influenced by two mechanisms of drug action: 1) reward-enhancing effects (i.e., elevation of an approach "go" mechanism); and 2) impairment of cognitive inhibitory processes (i.e., suppression of an avoidance "stop" mechanism). Multiple strategies will test the role of acute cognitive impairment in the abuse liability of alcohol. A drug-reinforcement model will test the degree to which preload alcohol doses "prime" subsequent drug self-administration by impairing inhibitory control processes that regulate behavior. The research also will test an indirect alcohol antagonist drug. caffeine, and an approved medication for alcohol abuse, naltrexone, for their ability to reduce alcohol self-administration by blocking its impairing effects on inhibitory control. The research has several long-term objectives. The findings will provide an understanding of how drinkers' susceptibility to alcohol's acute cognitive-impairing effects can pose an early-onset risk factor for later alcohol dependence by promoting a continued pattern of abusive binge drinking. The research strategies also will provide methods for testing the role of cognitive mechanisms in the treatment efficacy of existing pharmacotherapies. such as naltrexone, as well as some investigational medications that might operate via cognitive mechanisms (e.g., acamprosate). Finally, the proposed experiments will provide initial methods and protocols for studying alcohol use in combination with other drugs of abuse that also disrupt cognitive functions, such as cocaine, for which binge use is also a common pattern of drug-taking. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONNECTIVE TISSUE GROWTH FACTOR IN HEPATIC FIBROSIS Principal Investigator & Institution: Brigstock, David R.; Children's Research Institute 700 Children's Dr Columbus, Oh 43205 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-MAY-2006 Summary: The broad long-term objectives are to establish the role of connective tissue growth factor (CTGF) in causing fibrotic disease. CTGF is a highly pro-fibrogenic molecule which is over- expressed in all fibrotic lesions examined to date. It is transcriptionally activated by transforming growth factor-beta (TGF-beta) and mediates many of the matrix-inducing properties that have previously been attributed to TGFbeta. The studies described in this proposal focus on the role of CTGF in liver fibrosis, including that related to alcohol abuse. Preliminary data show that CTGF is overexpressed in fibrotic livers and is produced by hepatic stellate cells (HSCs), the principal fibrogenic cell type, both in response to TGF-beta and as a function of activation. HSCs show enhanced adhesion and levels of alpha smooth muscle actin in response to CTGF. In addition, ethanol and its fibrogenic metabolite, acetaldehyde, stimulate CTGF transcription in fibroblasts. Our hypothesis is that local up-regulation of CTGF in the liver drives the fibrogenic response, including that initiated by alcohol. Our Specific Aims are (1) To determine mechanisms of CTGF regulation in HSCs, including the role played by TGF-beta and acetaldehyde (which stimulate HSCs and CTGF production) as

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well as retinoic acid and TNF-alpha (which inhibit HSC function and CTGF production); (2) To determine the effects of CTGF on HSC function by examining HSC DNA synthesis, division, matrix metabolism, vitamin A content, and adhesion in HSCs treated with or over-expressing various mass forms (1OkDa, 16-20kDa, 38kDa) of CTGF which occur naturally in vivo and which are a product of HSCs maintained in vitro, and to determine the role of CTGF-stimulated kinases in these processes; and (3) To produce recombinant adeno-associated viruses for the delivery of the CTGF gene into the liver in vivo to directly establish the ability of 10 kDa and 38kDa CTGF to stimulate liver fibrosis. These studies will define the fibrogenic properties of CTGF in terms of its regulation, biological properties, signaling mechanisms and protein structure. In addition, these studies will help establish whether CTGF is a therapeutic target for treating fibrosis, which is a contributing factor in 45 percent of deaths in the USA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONTROL OF CAMP-MEDIATED GLUCAGON RESPONSE BY BILE ACIDS Principal Investigator & Institution: Bouscarel, Bernard E.; Associate Research Professor; Medicine; George Washington University 2121 I St Nw Washington, Dc 20052 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-JUL-2006 Summary: Cholestatic liver disease with cirrhosis in particular, is the 9th leading cause of death in the USA. Prognosis is poor, with a generally irreversible condition marked by progressive destruction of liver cells. Around 50 percent of patients with liver disease and 80 percent of cirrhotic patients display glucose intolerance associated with decreased gluconeogenic response to glucagon. Regulation of helpatocellular metabolism by glucagon is in part through increased cAMP synthesis. The central hypothesis is that certain bile acids alter the glucagon receptor-stimulatory G protein (Gs) coupling through a phosphorylation/dephosphorylation mechanism and that these alterations are responsible for attenuation and delayed recovery of glucagon responsiveness in cholestasis. We have shown that bile acids inhibit hepatic glucagoninduced cAMP synthesis at physiologic concentrations. The effect was at the level of receptor-Gs coupling, most likely through phosphorylation, and was mediated by a calcium-dependent PKC. We have reported that hepatic glucagon-mediated cAMP production was attenuated in cholestasis in hamster induced by ligation of the common bile duct (BDL). Bile acids were either without or with reduced effects after BDL suggesting that the site of cAMP synthesis cascade altered in cholestasis is the same as that altered by bile acids. Specific aims will test the hypotheses: 1)that short-term incubation of hepatocytes with bile acids leads to decreased glucagon receptor-Gs coupling through a phosphorylation/dephosphorylation mechanism involving PKC; 2)that alteration of both glucagon receptor-Gs coupling and receptor dephosphorylation are responsible for the respective attenuation and delayed recovery of glucagon responsiveness in cholestasis. In HEK293 clones expressing glucagon receptor, and in hepatocytes from BDL hamsters we will study the respective effect of physiologic/pathophysiologic bile acid concentrations and cholestasis on receptor/Gs coupling and phosphorylation using a multifaceted approach designed to determine the protein phosphorylation target. We will study the role of protein phosphatases on the time course of glucagon response recovery in cholestasis. Knowledge gained from these studies will have bearing on both diagnosis and treatment of cholestatic hepatobiliary disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DETERMINANTS OF HEPATITIS C & E MORBIDITY IN EGYPT Principal Investigator & Institution: Strickland, George T.; Epidemiology and Prev Medicine; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2003; Project Start 15-SEP-2000; Project End 31-AUG-2005 Summary: By using new molecular virological techniques, Non-A Non-B hepatitis patients have now been categorized into those infected with hepatitis C virus (HCV), a parenterally transmitted flavivirus, and hepatitis E virus (HEV), a fecal-oral transmitted "hepatitis E-like virus." WHO estimates that 170 million are infected with HCV, the most common cause of chronic viral hepatitis (CVH), post-necrotic cirrhosis of the liver and hepatocellular carcinoma (HCC). HEV is primarily transmitted in developing countries where it is the most common cause of acute viral hepatitis (AVH) and fulminating hepatitis, particularly in pregnant women. We and others have documented that the highest prevalence of HCV, and also possibly HEV, in the world occurs in Egypt. We have established a Network of Egyptians and Americans who are studying viral hepatitis and its cost to the country. In this ICIDR proposal, we will extend the work of this Network to include investigations of: (1) the effect that the host genome has on chronicity and cirrhosis following HCV infection (Project 1); (2) the host, viral, and environmental determinants of HCC and (because HCV is lymphotrophic as well as hepatotrophic) non-Hodgkins lymphoma (NHL, Project 2); and the epidemiology and complications of HEV (Project 3). Projects 1 & 2 will have case-control studies. The former will compare: (a) chronic carriers of HCV RNA vs. subjects who clear infection and (b) those with HCV who develop cirrhosis vs. those that show no signs of disease; while the latter compares HCC or NHL cases vs. age- and gender-matched controls. Projects 1-3 will have prospective cohort studies of 10,000 inhabitants of two villages with prevalence of anti-HCV of 9% and 24% and anti-HCV of 51 and 70%, respectively. Their goals will be to determine incidence of, and risk determinants for cirrhosis (Project 1), HCC and NHL (Project 2), and HEV infection and disease (Project 3). A cohort of pregnant women and children will be studied to assess HEV morbidity in pregnancy and exposures and disease in infancy. Domestic animals and peri-domestic rodents will be studied to determine whether HEV has a zoonotic component in Egypt. Viral genotypes, host class I and II alleles and candidate genes, e.g., chemokine receptors and HDL, a possible HCV receptor, and environmental exposures and their impact on host genes (p53 genetic fingerprinting) will be assayed. Because the scientific, administrative, logistic and laboratory network is in place and both HCV and HEV have such a high prevalence in Egypt, these investigations have a high probability of early success. Explanations for these very important questions can be obtained at a fraction of the cost and time as they could be found elsewhere, and the results should lead to the development of better interventions to prevent the two most important causes of liver disease in the world. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIABETES MECHANISMS

IN

HEMOCHROMATOSIS:

PREVALENCE

AND

Principal Investigator & Institution: Mcclain, Donald A.; Professor and Director; Internal Medicine; University of Utah 200 S University St Salt Lake City, Ut 84112 Timing: Fiscal Year 2002; Project Start 01-MAR-2002; Project End 31-OCT-2006 Summary: Although the hemochromatosis gene (HFE) has been identified there is little information about the diabetes that often accompanies the disease. We hypothesize nondiabetic homozygotes for mutations in HFE will exhibit a defect in insulin secretion

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as iron overload develops. This notion is supported by preliminary data obtained in HFE mutant mice. The insulin deficiency will progress to type 2 diabetes only if insulin resistance also occurs, either from cirrhosis or inheritance of type 2 diabetes genes. Insulin resistance from cirrhosis is hypothesized to result from excess carbohydrate delivery to peripheral tissues, resulting in excess hexosamine generation, an established cause of insulin resistance. Our specific aims are to: 1. Determine the prevalence of impaired glucose intolerance (IGT) and diabetes in clinically unselected individuals with hemochromatosis by oral glucose tolerance criteria. 2. Determine if a defect in insulin secretion exists in nondiabetic homozygotes with or without iron overload. This will be accomplished using the frequently sampled intravenous glucose tolerance test (FSIVGTT) with insulin levels. Reversibility of the defect will be examined after subjects have undergone phlebotomy. The hypothesis will be verified in studies of isolated islets from mice carrying disrupted or mutant HFE genes. 3. Using animal models, determine if diabetes in hemochromatosis results only when insulin resistance is superimposed on an iron- mediated defect in insulin secretion. 4. Determine the sequence and relative contributions of insulin resistance and hepatic glucose production (HGP) in the evolution of diabetes in human hemochromatosis. Insulin resistance and HGP will be quantified by the hyperinsulinemic euglycemic clamp and stable isotope techniques in subjects with hemochromatosis who have normal or IGT, with or without hepatic involvement. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT OF CIRRHOSIS AND SHUNTS ON DRUG DISPOSITION Principal Investigator & Institution: Gorski, J. Christopher.; Associate Professor of Medicine; Medicine; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): It is well established that hepatic cirrhosis results in reduced clearance of drugs that are highly metabolized and an enhanced sensitivity to the pharmacological and adverse actions of drugs. Chronic alcohol consumption and hepatitis C are the two most common causes of cirrhosis in the United States with an incidence of 3.1 per 1000 people. The development of portal hypertension is the primary mechanism behind several major complications of cirrhosis such as bleeding from gastroesophageal varices, hepatic encephalopathy, and ascites. Transjugular intrahepatic portosystemic shunts (TIPS) and other surgical shunts are performed to manage these complications of portal hypertension. We have demonstrated that in addition to a reduction in hepatic clearance, cirrhotic patients with TIPS experience an increase in intestinal availability of midazolam, a selective cytochrome P450 3A (CYP3A) substrate. This increased bioavailability primarily reflects a functional lack of intestinal wall firstpass metabolism relative to cirrhotics without TIPS and healthy volunteers. The mechanism for this lack of intestinal wall metabolism is unknown. We propose to characterize the mechanism and consequences of this loss of intestinal wall CYP3A activity in cirrhotics with TIPS by directly examining the CYP3A protein and mRNA levels, intestinal permeability, and in vivo hepatic and intestinal CYP3A activity before, immediately after, and I month after TIPS placement. Cirrhotic patients with TIPS, and potentially other types of portosystemic shunts, are expected to be at risk for excessive pharmacological effects or suffer from an increased incidence of adverse reactions following CYP3A substrate administration. We will examine the susceptibility of these individuals to adverse drug reactions and drug-drug interaction by examining the ability of erythromycin to prolong the QT interval and clarithromycin to inhibit

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metabolism of buspirone, a CYP3A substrate. Finally, the expression of other enzymes such as UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs) and pglycoprotein may also be altered in cirrhosis. We will characterize the changes in these enzymes using the partial clearance of acetaminophen to glucuronide (UGT) and sulfate (SULT) conjugates and the disposition of fexofenadine in cirrhotics with and without TIPS and healthy volunteers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT OF HEPATOTOXINS & ADOMET ON LIVER GENE EXPRESSION Principal Investigator & Institution: Kruger, Warren D.; Member; Fox Chase Cancer Center Philadelphia, Pa 19111 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Chronic liver disease such as cirrhosis, hepatitis, fibrosis, and fatty liver, is associated with reduced levels of S-Adenosylmethionine (AdoMet) in the liver. AdoMct affects a variety of metabolic pathways including methylation, anti-oxidant defense and polyamine production. Evidence from a variety of model systems suggest that dietary supplementation with AdoMet can attenuate liver damage and improve liver function. Despite these intriguing observations, little is known about the effect of AdoMet supplementation at the molecular level. In this R21 exploratory proposal we will examine the effects of AdoMet supplementation at the level of gene expression on a global scale using a rodent model. We will test the hypothesis that hepatotoxins, such as alcohol, have discreet effects on gene expression and that AdoMet supplementation can reverse at least some of these effects. Our experimental approach will use Wistar rats that are assigned to one of six groups: untreated AdoMet treated, alcohol treated, alcohol+AdoMet treated, CCI_ treated, and CC14+AdoMet treated. Using DNA microarrays we will compare global gene expression patterns in each of these groups and determine what! genes and biological pathways are affected by various hepatotoxins and AdoMet supplementation. In addition, we will measure various AdoMet metabolites in the liver to determine the effect of these treatments on AdoMet metabolism. From these studies we will determine how liver hepatotoxins and AdoMet affect gene expression profiles. This information should be informative as to what types of biological pathways are perturbed by these treatments. This knowledge will be useful in understanding the molecular changes that characterized liver disease and the molecular basis for clinical improvement with AdoMet in liver disease. This work may also be useful in the identification of biological pathways affected in chronic liver disease that are not affected by AdoMet supplementation, which may represent other correctable targets in chronic liver disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECTS OF RETINOIC ACID AND ACETALDEHYDE ON COLLAGEN Principal Investigator & Institution: Wang, Lan; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Acetaldehyde (AC), an alcohol metabolite, induces type I Collagen production in hepatic stellate cells (HSC), constituting a critical part of the pathogenesis of alcoholic cirrhosis. However, little is known about the mechanism of the AC effects. One feature of the activated Collagen producing HSC is the loss of

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retinoid storage. Our study, based on the hypothesis that the loss of retinoic acid (RA) plays a role in alcoholic cirrhosis, has indicated that a) RA inhibits the basal activity of a2(I) Collagen promoter and represses the AC induced activation of the promoter in transdifferentiated HSC; b) RA induces the expression of RA receptor b (RARb) while AC decreases RARb land retinoid X receptor alpa (RXR a) in HSC; c) the RA effect on a2(I) Collagen promoter does not occurs at the RA response element (RARE) site we studied. RAR and RXR are known to function as heterodimers. RXR can also act independently of RAR. We hypothesize that RXR a is an equally essential part of the regulation of a 2(I) collagen promoter by RA, and that the cis-acting element(s) in the promoter may preferentially interact with RXR in the RA-RAR/RXR regulatory mechanism. Our Specific Aims are to: 1) examine the regulatory role of RXR in CC2(l) Collagen expression in HSC and the influence of RA and AC on RXR expression in HSC; 2) determine whether RAR and/or RXR bind to the rat a2(I) Collagen promoter and characterize the nature of the binding; and 3) identify other possible trans-acting factor(s), such as the cofactors of nuclear retinoid receptors), SP-1 and AP-2, in the R-A regulatory pathway on a2(I) Collagen expression specifically in HSC. We hope that this project will extend our understanding of the mechanism(s) for the activation of type I Collagen expression in liver fibrogenesis and ultimately lead to potential treatment and prevention of cirrhosis. This project is the continuation of ongoing studies the candidate has performed under the mentorship of Dr. Esteban Mezey who has made ma or contributions in the field of alcoholic liver pathogenesis. It is an essential part of the structured career development plan, to extend Dr. Wang's knowledge and to further develop her skills, leading to an independent academic career. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENDOTHELIN AND LIVER CIRRHOSIS Principal Investigator & Institution: Gandhi, Chandrashekhar R.; Research Assistant Professor of Surgery; Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 25-SEP-1998; Project End 31-AUG-2003 Summary: The current pharmacologic and surgical therapies for portal hypertension a notoriously frustrating, often fatal, clinical complication of liver cirrhosis, have limited success due to the lack of clear understanding of its pathophysiology. Our work strongly indicates a major role of endothelin-1 (ET-1), a powerful vasoconstrictor, mitogen and fibrogen, in these pathologies. We observed progressive increases in hepatic ET-1 and its receptors during carbon tetrachloride (CC14)-induced cirrhosis in rats, and in cirrhotic humans. We demonstrated that a ET-1 receptor antagonist TAK-044 ameliorates portal hypertension and hepatic injury in CC14-treated rats. Further, we have shown that ET-1 stimulates the synthesis of a potent fibrogenic agent transforming growth factor-beta1, and exerts contractile and fibrogenic effects in perisinusoidal stellate cells. Stellate cells, the physiologic regulators of hepatic architecture and vascular tone, proliferate and transform into highly contractile and excessively fibrogenic myofibroblasts during liver cirrhosis. ET-1 also stimulates synthesis of a potent hepatic vasoconstrictor and systemic vasodilator platelet-activating factor (PAF) in Kupffer cells. PAF has been suggested to play a major role in hemodynamic abnormalities associated with cirrhosis. These observations indicate that interactions between ET-1, stellate cells and Kupffer cells are the major mechanism in the pathogenesis and complications of liver cirrhosis. Therefore, we propose to distinguish precise sites of changes in ET-1 and its receptors during the development of CC14induced cirrhosis using the techniques of immunohistochemistry, in situ hybridization

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and cell fractionation. We will also delineate the mechanisms of (1) the elevated ET-1 levels during the development of cirrhosis; (2) the actions of ET-1 in causing structural and functional changes in stellate cells; and (3) the interactions between ET-1 and Kupffer cells with specific focus on PAF synthesis. Finally, we propose to evaluate the therapeutic potential of ET-1 receptor antagonists by administering them to rats (a) during the entire period of CC14 treatment; (b) from the time of transition between fibrosis and cirrhosis; and (c) after the development of cirrhosis to ascertain amelioration or reversal of the pathologic process. Thus, in addition to the determination of the molecular mechanisms of the role of ET-1 in liver cirrhosis, this investigation will provide valuable information for the development of appropriate therapeutic strategies for liver cirrhosis and its complications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENZYMATIC DIFFERENCES AMONG HEPATITIS C VIRUS GENOTYPES Principal Investigator & Institution: Frick, David N.; Biochem and Molecular Biology; New York Medical College Valhalla, Ny 10595 Timing: Fiscal Year 2003; Project Start 15-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Almost one in every fifty-five Americans have been exposed to the Hepatitis C Virus (HCV), but most are unaware of their infection because the virus causes few acute symptoms. If left untreated, the majority of HCV infections lead to chronic active hepatitis that eventually progresses to cirrhosis, cancer, or liver failure. Current therapies involving the drugs interferon and ribavirin are costly and produce debilitating side effects, frequently worse than the symptoms produced by HCV itself. Newer treatments are, however, quite effective against certain viral genotypes. This proposal will examine the HCV proteins most directly involved in viral replication, the NS3 Helicase and NS5B polymerase, as putative targets for the drug ribavirin and as targets for new antiviral agents. In addition to its established role as a modulator of the immune system, ribavirin has been proposed to eliminate viruses as a mutagen or through direct effects on viral replicative proteins. One popular hypothesis states that ribavirin's enhancement of the already high HCV mutation rate leads to a catastrophe of errors and subsequent virus elimination. Here, ribavirin effects will be examined in vitro, in enzyme assays, and in vivo, using a novel HCV replicon that should allow the assessment of replication fidelity. To attempt to relate ribavirin effects to genotype-specific drug response, all experiments will be repeated with the three most common American HCV genotypes, two that normally do not respond to therapy (la and lb) and one that frequently responds to therapy (2a). The polymerase and helicase proteins from each genotype will also be characterized to define conserved and divergent properties. A rigorous biochemical approach will be used to define enzyme differences because sequence data alone does not accurately predict protein structure or function. Preliminary data show that different genotypes encode enzymes with markedly different properties, hampering current rational drug design efforts. Structure-based site-directed mutagenesis will be used to determine the genetic basis for HCV enzyme variability. The biological consequences (i.e. replication rate, fidelity, protein expression) of HCV genetic variation will then be analyzed in a replicon system. The delineation of genetic variations responsible for certain phenotypes might allow the prediction of patient response to current or future HCV therapies, and the clear identification of conserved HCV enzyme properties will aid future HCV drug development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EPIDEMIOLOGY OF PRIMARY BILIARY CIRRHOSIS Principal Investigator & Institution: Gershwin, M. Eric.; Professor of Medicine; Internal Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: Primary biliary cirrhosis (PBC) is an enigmatic autoimmune disease characterized by female predominance, high titer anti- mitochondrial antibodies (AMA), small bile duct destruction, and liver failure. Our group was the first to clone and identify the mitochondrial antigens, a family of phylogenetically conserved 2- oxo acid dehydrogenase proteins recognized by T and B cells in PBC. In addition, recent data has provided us with the basis for the following working hypotheses. We submit that PBC is most likely the result of an inappropriate or malcontrolled response to an environmental (either chemical or biological) insult. The initiating insult in PBC could be either a urinary tract infection (UTI) or an exposure to halogen containing chemicals. In the case of UTI's, there are high degrees of homology between the mitochondrial proteins present in micro-organisms that characteristically cause UTI's and their eukaryotic (i.e. human) analogs. Alternatively, the liver-based metabolism of halogenated hydrocarbons as xenobiotics generates activated halogen containing intermediates that react to form halogen modified proteins. In both, UTIs and halogenated chemical exposures, the introduction of these foreign proteins may initiate an immunological response that results in the immune system inappropriately targeting self proteins. These insults, which appear to be necessary but are not sufficient to elicit an autoimune response, given their widespread occurrence, needs to occur in conjunction with other disease associated contributory factors (i.e. genetic background) to produce PBC. We propose to take advantage of our strengths, including a nationwide network of PBC researchers, to accomplish this goal. We will collect and analyze data on demographics (race/ethnicity, socio-economic status, place of birth), medical history, reproductive history (parity, birth outcomes/complications, fertility problems, oral contraceptive use), menstrual history (age at menarche, age at menopause, average cycle length, cycle regularity) and lifestyle factors (smoking, physical activity, occupation and occupational exposures) using a questionnaire that we have tested in a preliminary study of 201 patients and 171 unaffected siblings. The project data will be collected from a sample of 2000 cases from 17 medical centers around the country and an equal number of matched (on age, gender and residence) random-digit dialed controls. The proposed study would be the first comprehensive epidemiologic study of PBC to be conducted in the United States, and directed at testing our thesis in the hope of improving our understanding of this serious disease and potentially identifying preventive measures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ESOPHAGEAL VARICES BY B-ADRENERGIC BLOCKERS Principal Investigator & Institution: Groszmann, Roberto J.; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 20-APR-1993; Project End 31-MAR-2003 Summary: Cirrhosis is the fifth leading cause of death in the United States in individuals under the age of 65, the productive years of life. It affects men and women equally, and impacts on all races and socio- economical levels. Portal hypertension is the main complication of cirrhosis, regardless of etiology. Gastroesophageal varices and variceal hemorrhage are a direct consequence of portal hypertension and account in large part for the high mortality of cirrhosis. Non-selective beta- adrenergic blockers decrease

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portal pressure and have been shown to prevent the first variceal hemorrhage in patients with cirrhosis and varices. Early portal hypotensive therapy, before the patients develop varices, would be beneficial not only because it may prevent or delay the formation of varices (and variceal hemorrhage) but because it may prevent or delay the development of other complications of portal hypertension, such a ascites. This ongoing multi-center, prospective, randomized, placebo-controlled, double-blind trial was designed with the primary aim of investigating if early therapy with timolol, a nonselective beta-adrenergic blocker, can prevent or delay the development of varices in patients with cirrhosis and portal hypertension. Secondary aims will examine whether timolol prevents or delays other complications of portal hypertension such as ascites and porto-systemic encephalopathy, as well as liver transplantation or death. Patients with cirrhosis, without varices on endoscopy and with portal hypertension (portal pressure greater than 6 mmHg) are included in the study. This grant application was funded in April of 1993 and patient randomization began in August of 1993. Patient accrual took longer than originally estimated, however it is now certain that the number of 190 patients required for the study will have been randomized by the end of the current funding period (March 1998), since at the writing of this proposal 158 patients had already been randomized. In calculating sample size, we assumed a rate of development of varices of 50 percent at 4 years in the control arm, to be reduced to 30 percent in the timolol arm. So far our observed rates for development of varices are consistent with our planned estimates. However, we have now estimated that a minimum follow-up of 4 years (after last patient is recruited) is necessary to ensure high statistical power (80 percent at the 2-sided 0.05 level). The trial is highly significant for the promise it holds for the treatment of cirrhosis of all etiologies and for an understanding of the natural history of the disease. The four centers involved are widely renown for their studies in this area and have collaborated productively in the past, including the only published double-blind trial of propranolol in the prevention of first variceal hemorrhage in patients with cirrhosis and varices. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ETHANOL METABOLISM

CONSUMPTION

AND

LIVER

AND

BRAIN

Principal Investigator & Institution: Cunningham, Carol C.; Professor; Biochemistry; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: The basis for ethanol-related alterations in the organism is intimately linked to the metabolism of ethanol and the changes ethanol elicits in normal metabolic pathways. While this principle is applicable in all organs affected by ethanol, the response in different tissues can vary widely. Thus, a study of the metabolism associated with ethanol can be focused on different responses in different organs. The studies encompassed in this application for a Senior Scientist award are directed toward the effects of ethanol on metabolic systems in liver and brain. With regard to the liver studies, the major goal is to relate alterations in metabolism to development of alcoholic liver disease. Included are studies of the effects of ethanol on 1) the integrity of the mitochondrial oxidative phosphorylation system and 2) the synthesis of ATP via the glycolytic pathway. Experiments are included to examine how ethanol-elicited alterations in the above mechanisms affect the structural and functional integrity of the hepatocyte. The interplay between oxidative stress and cellular energy state in the ethanol- related loss of hepatocyte viability will also be evaluated. The metabolic studies in the brain, which are a new area for me, are focused on establishing alterations in

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glucose and neurotransmitter metabolism that accompany the behavioral changes occurring when an individual self-administers ethanol. The synthetic pathways for the amino acid and biogenic amine neurotransmitters will be investigated in a rodent selfadministration model. The purpose for the Senior Scientist application is to obtain enough research time to allow me to add the neurotransmitter metabolism study while I maintain current effort on my liver-ethanol program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTION AND REGULATION OF CGMP GATED RENAL K+ CHANNELS Principal Investigator & Institution: Desir, Gary V.; Professor of Medicine; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 01-APR-1994; Project End 31-MAR-2002 Summary: (Adapted from the Applicant's Abstract): The kidney is the main organ involved in the long term regulation of total body potassium. Disorders of potassium balance occur frequently in patients who have hypertension, congestive heart failure, cirrhosis of the liver and renal dysfunction. Hypokalemia causes significant cardiovascular morbidity and mortality in patients treated with diuretics. Furthermore, abnormal regulation of K channels may play a role in the pathogenesis of hypertension. This laboratory is focused on the study of renal potassium channels. This work has let to the discovery of several novel K channel genes. One of these genes encode a cGMPactivated, K-selective channel (KCNA 10a) which is expressed in kidney, heart, muscle and blood vessels. KCNA10a has kinetic properties similar to those of the nitric oxide sensitive K channels detected in pulmonary artery smooth muscle cells. The work now proposed is an extension of the original proposal. The investigative team has recently succeeded in optimizing KCNA10a current expression in Xenopus oocytes and are now able to study its kinetic properties of the single channel level in detail. They will then determine if it is a hetero-multimeric protein and if its expression levels and/or kinetic properties are modulated by any of the live previously cloned a subunits. They will investigate the regulation of KCNA10a by cGMP and ask whether cGMP activates by binding to the cGMP-binding domain and/or via protein phosphorylation. Finally, a panel of high affinity polyclonal antibodies specific for the KCNA10a protein will be developed in order to examine its tissue distribution and membrane localization. The intent is that studies already carried out and those that are proposed in the current application will provide insight into the mechanisms by which K balance is maintained and should, therefore, have direct clinical applications. It is also hoped that the discovery of new molecular structures will expand the existing physiological framework of potassium homeostasis and will lead to the development of new therapeutic agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FUNCTIONAL INTERACTIONS

ANALYSIS

OF

HCV-B

LYMPHOCYTE

Principal Investigator & Institution: Chambers, Thomas J.; Associate Professor; Molecular Microbiol and Immun; St. Louis University St. Louis, Mo 63110 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: The hepatitis C viruses (HCV) are small RNA viruses within the family Flaviviridae, distinguished from other members by their capacity to cause persistent infection in humans with serious consequences such as chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. The mechanisms by which HCV established

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that the HCV major envelope glycoprotein E2 interacts with the cell surface molecule CD81, which may serve as a virus receptor. CD81 is expressed on many different human cell types, including B lymphocytes, where it is known to associate with other molecules including CD19, MHC Class II antigen, lymphocytes, where it is known to associate with other molecules including CD19, MHC Class II antigen, and the C3 receptor. CD81 participates in several functional activities of B cells, including aggregation, adhesion, and antigen- receptor-mediated activation. B cell abnormalities have been associated with chronic HCV infection, including polyclonal activation with or without cryoglobulinemia, several other dyscrasias, and some rare lymphomas. In addition, the propensity for delayed seroconversion during acute HCV infection and the emergence of antibody-escape mutants during the chronic phase of disease raises the question of whether fundamental disturbances in normal B cell function occur as a consequence of either their infection with virus or chronic exposed to E2 glycoproteins on circulating virus. Although it has not been established that antibody responses to HCV are important correlates of protein against persistent infection, defective B cell function and impaired humoral immunity could contribute to inefficient clearance of virus in some cases, particular if other factors such as cytotoxic T cell responses are weak. We propose to investigate the hypothesis that interaction of E2 with CD81 on the plasma membrane of B lymphocytes and/or within intracellular compartments, leads to alterations in the properties of this multi-functional ell surface protein that in turn compartments, leads to alterations in the properties of this multi-functional cell surface protein that in turn affect the capacity of B ell s to respond normally to viral antigens. Such alterations could include higher thresholds for activation, reduced antigen presenting capacity and/or defective complement regulation. Using model systems, and clinical specimens of HCVinfected individuals, we specifically will: 1) Investigate whether chronic infection with HCV is associated with disturbances in B cell function, such as reduced level of CD81 expression, impaired responsiveness to antigen, and other in vitro measures of activation; 2) Determiner whether exogenous E2 interacts with CD81 on B cell lines and whether such interaction leads to alterations in CD81-associated events; 3) Determine whether E2 interacts with CD81 during intracellular synthesis and processing in B cells, and whether there are functional consequences for cell surface CD81 expression and function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE EXPRESSION IN THE HUMAN ALCOHOLIC BRAIN Principal Investigator & Institution: Harris, Robert A.; Professor of Pharmacology; Neurobiology; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2001; Project Start 01-AUG-2000; Project End 31-MAY-2005 Summary: (Adapted from the Investigator's Abstract) The overall goal of this project is to identify genes which are differentially expressed in alcoholics as compared to nonalcoholics. This will be accomplished by collecting autopsy material from individuals extensively characterized for drinking history, other pathologies, drug and tobacco use, brain histology, and genotype. In addition to the existing Australian Brain Bank, one of the most extensive for alcoholic cases available in the world, emphasis will be placed on collecting additional cases with specific attributes, such as abstinent alcoholics. Gene expression will be measured in frontal and motor cortex by microarrays that simultaneously measure levels of up 7000 expressed genes from a single sample of brain RNA. Our preliminary results demonstrate the feasibility of these approaches and suggest changes in gene expression consistent with published studies as well as changes in novel genes. About 30 genes of particular merit and interest will be selected for

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detailed analysis with a particular emphasis on correlating changes in mRNA expression to protein expression. Gene expression in the alcoholic brain may be changed due to predisposing factors (susceptibility genes), as a consequence of chronic ethanol exposure (alcohol responsive genes) or as a consequence of alcoholic neuropathology, other pathology (e.g., cirrhosis) or co-morbidity (e.g., tobacco use). We propose that careful case selection for analysis of gene expression will allow us to distinguish among (at least some of) these possibilities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GROWTH HEPATOCYTES

CONTROL

OF

NORMAL

AND

CIRRHOTIC

Principal Investigator & Institution: Behrns, Kevin E.; Associate Professor of Surgery; Surgery; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Hepatocytes are unique parenchymal cells that divide and regenerate the liver in response to major injury. This regenerative capacity, however, leads to disordered hepatocyte growth in the chronically injured, cirrhotic liver. Hepatocytes in the cirrhotic liver respond differently to growth control signals. Most hepatocellular carcinomas arise in a cirrhotic liver, providing evidence that cirrhotic hepatocytes have altered growth control behavior. Cirrhosis is a major worldwide health problem that is expected to increase in prevalence because of increasing alcohol abuse and dissemination of the hepatitis B and C viruses, all major causes of cirrhosis. In an earlier proposal (K08), we hypothesized that cirrhotic hepatocytes would be less sensitive to apoptosis. Indeed, studies confirmed that cirrhotic hepatocytes are less responsive to multiple apoptotic agents including tumor necrosis factor a (TNFalpha), transforming growth factor beta (TGFbeta), and ultraviolet-C irradiation (UV-C). The resistance to TGFbeta-induced apoptosis is of special interest because this cytokine is a known inhibitor of hepatocyte growth, and it is present in high concentrations in the cirrhotic liver. The mechanisms by which TGFR induces hepatocyte apoptosis are not well known, but our studies in primary normal mouse hepatocytes suggest that this occurs through a caspase-8 dependent mechanism that requires the generation of reactive oxygen species, depolarization of the mitochondria with cytochrome c release, and caspase-3 activation. This is the first demonstration of caspase-8 dependence. The mechanisms that inhibit this pathway in cirrhotic hepatocytes are unknown, but may involve other TGFR-activated pathways such as the Smad signaling pathway. We hypothesize that the Smad signaling pathway is necessary for hepatocyte apoptosis, and that defects in this pathway are present in cirrhotic hepatocytes. Alterations in the Smad signaling pathway may alter pro- or antiapoptotic factors that govern the cellular balance between survival and death. In this proposal, we aim to determine if the Smad signal transduction pathway is necessary for TGFbeta-induced hepatocyte apoptosis. In addition, because cirrhotic hepatocytes exhibit resistance to apoptosis that may be due to changes in expression of pro-and antiapoptotic factors, we hypothesize that normal and cirrhotic hepatocytes differ in their gene expression profiles. We propose to identify and characterize differences in gene expression profiles between normal and cirrhotic hepatocytes in response to apoptotic stimuli. Examination of these hypotheses will allow our laboratory to growth both in depth and in breadth, because we will use new microarray technology provided within the UNC Genomics Core and Microarray Facility. We will continue to seek counsel from our K08 mentors (Drs. David Brenner and Lola Reid) and use liberally the UNC Center

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for Gastrointestinal Biology and Disease for core facilities such as the Molecular Imaging Core. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HCV & ALCOHOL-- EPIDEMIOLOGY & HOST-VIRUS CORRELATES Principal Investigator & Institution: Peters, Marion G.; Professor; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-JUL-2005 Summary: Alcohol and hepatitis C virus (HCV) infection are recognized as independent causes of chronic liver disease and cirrhosis. Further, significant alcohol ingestion, defined variably as >30 gnvday (women) or >50-60 grnlday (men) has been associated with more severe histological disease, including cirrhosis and hepatocellular carcinoma and an accelerated rate of disease progression in patients with chronic HCV infection. The effect of more limited alcohol intake or non-daily drinking patterns on the progression of HCV disease are not known. In this study, we will establish a prospective cohort of at least 550 HCV-infected patients who drink varying amounts of alcohol at study entry. Total lifetime alcohol intake, patterns of alcohol ingestion, and periods of abstinence will be ascertained using validated questionnaires (Skinner, 1979; Russell, 1991) at study entry and annually for four years. Additional data collected at study entry include demographic, epidemiological and dietary history (including duration of HCV infection, mode of acquisition, use of iron supplements). A comprehensive evaluation of HCV RNA including viral titer in serum, liver and peripheral blood mononuclear cells (PBMCs), and baseline quasispecies complexity, will be obtained. Subjects with an alcohol intake of >30 gm/day (females) or >60 gm/day (males) will be counseled to completely abstain. A subset of 150 subjects drinking <15 gm/day (females) or <30 gm/day (males) of alcohol will be randomized to abstinence or no change in alcohol intake (control group). Annually we will readminister an alcohol questionnaire (12-month quantity/frequency questionnaire, National Alcohol Survey) and perform tests for ferritin, transfenin saturation, and serum aminotransferase activity. HCV viral quasispecies variability (assessed by heteroduplex mobility assay) HCV RNA quantitation and cytokine profiles will be compared in different tissue sources (serum, PBMCs and liver). Liver biopsies will be obtained at baseline and at the end of 4 years follow-up to assess severity and progression of liver disease. This study will determine 1) the quantity and pattern of alcohol intake associated with progression of HCV liver disease; 2) whether abstinence from alcohol among "moderate" or "light" drinkers reduces the rate of HCV disease progression; and 3) the host (including proinflammatory or profibrotic host genes which may be activated in the presence of alcohol) and viral factors (including quasispecies heterogeneity which may be altered by alcohol ingestion) which underlie the enhanced rate of disease progression in HCVinfected patients using alcohol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HCV QUASISPECIES DYNAMICS AND LIVER TRANSPLANT Principal Investigator & Institution: Vargas, Hugo E.; Associate Professor; Mayo Clinic Arizona Sc Johnson Research Medical Building Scottsdale, Az 85259 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2005 Summary: (provided by applicant): HCV related cirrhosis is the leading cause of liver transplantation in this country and in Europe. A significant proportion of patients have a rapid recurrence of hepatitis that leads to graft loss and mortality. The dynamic nature

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of HCV populations could underlie its biology, including immune evasion and persistence. We propose to study the transmission and evolution of HCV quasispecies 65 liver transplantation recipients. Aim 1: Is there a selection of viral variants within quasispecies at the time of transmission? We hypothesize that not all viral variants present in infectious blood are able to establish infection in a susceptible host. Therefore, we will compare the composition of viral quasispecies in all 65 transplant recipients using single-strand conformation polymorphism (SSCP), cloning and sequencing to evaluate changes that correlate with the clinical course. This analysis will be conducted in the highly variable E2 and conserved 5' untranslated (5'UTR) regions. Aim 2: How does the HCV quasispecies distribution evolve over time in the natural course of infection and does it have a prognostic value with respect to outcome? We hypothesize that in OLT recipients infected with HCV, the quasispecies composition evolves in the E2 and 5'UTR regions and these changes correlate with the clinical outcome. Therefore, we will analyze quasispecies complexity, divergence and genetic drift longitudinally using SSCP and heteroduplex mobility assays in all 65 infected recipients. We will correlate quasispecies behavior with clinical outcome of the infection. Aim 3: What is the biological basis of selective transmission and evolution of quasispecies in the E2 and 5'UTR regions? We hypothesize that the selection and evolution of variants within the 5'UTR quasispecies is related to differences in viral fitness associated to its competence to direct translation. We will clone representative 5'UTR fragments into bicistronic dual luciferase reporter plasmid and we will measure and compare their translation efficiency in vitro. We hypothesize that E2 region quasispecies variants bound by antibodies are less efficient in establishing infection in the graft. Furthermore, we postulate that new viral variants appearing during the infection represent mutants which escape immune detection. We will separate viral variants bound in immunocomplexes from "free" virus and compare the variants using SSCP, cloning and sequencing. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HCV-ALCOHOL EPIDEMIOLOGY

INTERACTIONS--

PATHOGENESIS

AND

Principal Investigator & Institution: Stapleton, Jack T.; Professor; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 31-AUG-2003 Summary: Hepatitis C is the commonest cause of chronic hepatitis in the US and can lead to progressive liver injury with the development of cirrhosis, liver failure and liver cancer. Liver injury may be caused by an interaction of the virus with the host immune response leading to inflammation and fibrosis in the liver. We plan to examine the mechanism of HCV induced liver injury in three distinct groups of patients: 1) those with chronic HCV infection and evidence of moderate to severe necroinflammatory disease, who are at average risk of progression to cirrhosis; 2) those with persisting viremia but normal or minimally elevated transaminases and normal or mildly inflamed liver biopsies, who are at low risk of progression to cirrhosis; and 3) patients with chronic HCV liver disease and active daily alcohol use (greater than 50 gm/day), who are at the highest risk of progression of liver disease. Specifically, we propose to evaluate the role of intrahepatic viral load on immune response and liver injury by measuring liver derived CTL response and cytokine production and correlating the immune response to the degree of liver injury. The response in the liver will be compared with that seen in the periphery to determine whether there is compartmentalization of immune responses and whether peripheral immune response

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can correlate with the injury and immune response seen in the liver. The role of antiviral therapy and alcohol on these responses will also be studied. These studies may lead to insights on the mechanism of liver injury and help define those patients who are most likely to have progressive liver injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEMOCHROMATOSIS--EPIDEMIOLOGY MECHANISMS

AND

MOLECULAR

Principal Investigator & Institution: Beutler, Ernest N.; Chairman; Scripps Research Institute 10550 N Torrey Pines Rd La Jolla, Ca 920371000 Timing: Fiscal Year 2001; Project Start 28-APR-1998; Project End 31-MAR-2003 Summary: Hereditary hemochromatosis, a disease characterized by excess iron absorption leading to diabetes, cardiomyopathy, cirrhosis, and arthropathies, is arguably the most common clinically important genetic disorder of Europeans. Recently an HLA Class 1 gene, HLA-H was implicated in the etiology of this disease. Over 80 percent of hemochromatosis patients are homozygous for a C282Y mutation. Compound heterozygotes for C282Y and H62D appear to have an increased incidence of the disease. Sixty-thousand adults undergoing health care screening in the KaiserPermanente system will be screened, determining serum iron, iron binding capacity, ferritin, and mutations in HLA-H. Patients classified as having hemochromatosis will be phlebotomized to remove excess iron and to measure iron stores. This will establish the relationship between genotype, age, sex and clinical state, and size of iron stores, and provide data that can be used to guide programs screening for hemochromatosis. The hypotheses that heterozygotes are more susceptible to cardiovascular disease and other disorders and that they are benefited by being less susceptible to iron deficiency anemia will be tested using the extensive Kaiser-Permanente database. Hemochromatosis mutations, other than those known, will be sought. The HLA-H gene product may function like other HLA class 1 genes, binding peptides and associating with proteins such as beta2 microglobulin, calreticulin, transporter associated with antigen processing (TAP) and tapascin. Alternatively, it may function as a signaling molecule, like the Fc receptor. Determining how the HLA-H gene product functions should provide insight into its role in maintaining iron homeostasis. This will be done by using immunoprecipitating HLA-H containing complexes, determining HLA-H Fc receptor signaling properties and measuring the binding of peptides and other small molecules by HLA-H. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEPATIC NEUROCHEMISTRY

ENCEPHALOPATHY--NEUROPSYCHOLOGY

&

Principal Investigator & Institution: Thomas, Michael A.; Associate Professor; Radiological Sciences; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 05-AUG-1999; Project End 31-JUL-2004 Summary: (Verbatim from the Applicant's Abstract) Hepatic Encephalopathy (HE) is a well-recognized complication of cirrhosis. These patients display a variety of neuropsychological deficits as well as clinical and serum ammonia abnormalities. Subclinical hepatic Encephalopathy (SHE) is a subtler accompaniment of cirrhosis that is associated with neuropsychological abnormalities without significant neurologic findings such as asterixis. Although neuropsychological tests are the current standard

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Cirrhosis

for diagnosing SHE, the results are non-specific and reveal little about the underlying neurochemical processes. Cerebral Magnetic Resonance Spectroscopic (MRS) metabolic alterations and MRI signal abnormalities in the basal ganglia reveal a relationship between neuropsychological functioning and biochemical abnormalities found in patients with SHE. This study will involve collaboration among hematologists, radiologists, psychiatrists, MR physicists and neuropsychologists. We will identify a total of 60 liver failure patietns who have SHE and compare them to 60 healthy control subjects. These patients and healthy controls will undergo clinical assessment by hepatologists and neuropsychiatric evaluation by psychiatrists. Subsequently, they will undergo a comprehensive series of neuropsychological tests to characterize the nature of their neurocognitive deficits. Following these tests, all subjects will undergo MR Imaging and Spectroscopic (MRI/MRS) examinations. We aim to use 1H MRS to meare and compare absolute cerebral metabolite levels of myo-inositol, choline, and glutamine/glutamate in the frontal lobe, parietal lobe and basal ganglia of a matched group of SHE patients and healthy controls. The resulting MRS and MRI data will be quantitatively analyzed and correlated with the results of neuropsychological testing and clinical examination. Multivariate methods and correlational analysis will be used to test hypotheses regarding differences between SHE patients and controls. We hypothesize that myo-inositol will be decreased, glutamine/glutamate will be increased and choline will be decreased in patietns with SHE. We propose that these underlying biochemical abnormalities will be correlated with clinical, neuropsychiatric and neuropsychological aspects of SHE. If these relationships are found, they will provide an improved biochemical understanding of the underlined aspects of SHE as characterized y clinical and neuropsychological testing. This enhanced understanding of pathophysiology will improve our ability to diagnose and treat this condition, resulting in improved patient outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEPATIC STELLATE CELL ACTIVATION INDUCED BY HCV Principal Investigator & Institution: Brenner, David A.; Professor; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Hepatitis C virus (HCV) infection is the main cause of chronic liver diseases in the US. Current antiviral treatments only cure the infection in half of the patients. The remaining patients often develop progressive hepatic fibrosis, leading to cirrhosis and hepatocellular carcinoma. These patients are sensitive to the hepatotoxic effects of alcohol, since moderate alcohol consumption accelerates fibrosis progression. Unfortunately, there are no effective antifibrotic treatments for patients with chronic liver diseases. The overall goal of this project is to define the mechanisms by which HCV leads to liver fibrosis and to identify potential targets of therapy. We will also investigate the mechanisms by which alcohol consumption aggravates the effects of HCV. We will use recently developed tools to express the HCV in the mouse liver and in liver cells and a well-characterized model of alcohol-induced liver injury. This proposal is based on several underlying hypotheses: 1) HCV directly interacts with hepatic stellate cells (HSCs), the main fibrogenic cell type, to induce liver fibrosis; 2) Fibrogenic products from hepatocytes expressing the HCV replicon induce fibrogenic actions in HSCs; 3) Alcohol administration induces the development of liver fibrosis in transgenic mice expressing the whole HCV genome; and 4) HSCs isolated from patients with HCV induced liver cirrhosis show phenotypical and functional features of activated HSCs and non-parenchymal liver cells are infected by HCV in patients. The specific aims to be

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addressed in this project are: 1) To determine whether HCV proteins induce fibrogenic actions in primary cultured HSCs; 2) To determine whether hepatocytes and lymphocytes expressing the HCV induce fibrogenic actions in HSCs; 3) To investigate the mechanisms by which alcohol consumption aggravates HCV-induced liver fibrosis; and 4) To investigate the phenotypical and functional features of HSCs isolated from patients with HCV-induced liver cirrhosis and whether non-parenchymal liver cells are infected by HCV in patients. The experimental design will use primary cultures of HSCs, cultured cells expressing the HCV genomic replicon, and transgenic mice expressing the whole HCV genome in the liver. By combining in vivo and in vitro studies, our goal is to discover new insights into the molecular pathogenesis of HCVinduced liver fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEPATITIS C PATHOGENESIS & THE HUMAN GENOME Principal Investigator & Institution: Thomas, David D.; Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Neither viral nor environmental factors explain the heterogeneous outcome of hepatitis C virus (HCV) infection. This and research on other chronic viral illnesses suggest host genomic polymorphisms are important. In the past, host-viral interaction has been difficult to investigate because of the complexity of both HCV pathogenesis and the human genome. However, the biology of HCV is unfolding and major technologic advances now make large-scale genotyping feasible. In this investigation, these new molecular tools are used to test the hypothesis that HCV pathogenesis, and in particular viral clearance and cirrhosis is influenced by the host genome. To accomplish this research, a DNA library will be constructed from subjects in four large HCVinfected cohorts, including 565 who have cleared viremia, 256 with cirrhosis, and more than one thousand with persistent viremia but no detectable cirrhosis. Polymorphisms in human leukocyte antigen alleles and putative pathogenic genes will be characterized and distortions in their frequency evaluated according to outcome. The molecular basis for observed associations will be further assessed coupling information on genetic linkage and HCV biology. Possible confounding factors (such as alcohol ingestion, HIV infection, or HCV genotype with cirrhosis) also will be examined using existing, detailed clinical databases. Success is anticipated at modest expense since experienced researchers will be using existing molecular tools to investigate large established cohorts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HEPATITIS C VIRAL QUASISPECIES WITHIN THE LIVER Principal Investigator & Institution: Di Bisceglie, Adrian M.; Professor of Internal Medicine; Internal Medicine; St. Louis University St. Louis, Mo 63110 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: This application proposes to examine the biological significance of liverspecific hepatitis C viral (HCV) quasispecies variants. HCV is a positive single-stranded blood-borne RNA virus which infects humans and may cause chronic liver injury including hepatitis, cirrhosis and hepatocellular carcinoma through chronic infection. The liver is the major site of replication of HCV although HCV RNA is also found in the blood of infected individuals. The genome of HCV varies considerably in nucleotide sequence from isolate to isolate, allowing HCV to be divided into genotypes and

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subtypes. However, multiple isolates from a single infected individual may also have considerable variability in nucleotide and amino acid sequence, particularly within the hypervariable region (HVR1) of the envelope gene. HRV1 is a sequence of approximately 27 amino acids at the likely N terminus of the HCV E2 glycoprotein. Variations in HRV1 provide markers for identification and tracing of HCV quasispecies variants. Quasispecies arise because of the high error frequency associated with viral RNA replication and immune pressure appears to be a factor in their selection. Preliminary experiments conducted by the applicants have shown that a greater number of HCV quasispecies variants are found within the liver compared to serum, even allowing for differences in viral load and that some liver-specific variants appear to be present. The applicants hypothesize that an excess of HCV quasispecies variants are continually being produced by errors in replication of HCV RNA within hepatocytes, some of which are cleared from serum by neutralizing antibodies, leaving behind in the circulation those variants which have escaped immune clearance. The significance of these differences will be examined through cloning and sequencing quasispecies variants present in both serum and liver. Changes in HCV quasispecies over time will be sought by comparing nucleotide sequence in HRV1 region before and after liver transplantation. The presence of possible neutralizing antibodies in serum directed against liver-specific quasispecies variants will be sought by enzyme-linked immunoassays based on peptides synthesized according to nucleotide sequences of the various cloned quasispecies. In addition, immunoreactivity to the whole of the E1 and E2 proteins cloned and expressed in mammalian cells will be determined. Differences in presence, titer and reactivity of antibodies against quasispecies will be compared to determine whether neutralizing antibodies account for clearance of some quasispecies from serum but not liver. These studies have great potential significance for understanding of viral clearance, development of persistent infection and for the development of a vaccine against HCV. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEPATITIS VIRUS, ALCOHOL EXPOSURE AND OXIDATIVE STRESS Principal Investigator & Institution: Hassan, Manal M.; Gastrointestinal Med Oncology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2003 Summary: (provided by applicant) Hepatitis C virus (HCV) infection and alcohol abuse are the 2 major risk factors for hepatocellular carcinoma (HCC) in this country. The higher prevalence of HCV infection in the general population has resulted in a significant increase of the incidence of HCC in the United States. Although both HCV and alcohol can independently induce liver disease, exposure to both agents may accelerate the course of liver pathology and/or lead to more severe injury. The mechanism underlying the synergistic effect of HCV and alcohol intake is not well understood. One hypothesis is that both HCV and alcohol intake may contribute to chronic hepatitis, cirrhosis and subsequent liver cancer through enhanced oxidative stress. It is known that alcohol could induce oxidative stress and lipid peroxidation. Interestingly, a recent study has reported that HCV encodes a selenium (Se)-dependent antioxidant enzyme, glutathione peroxidase, GPx, and GPx may have a regulatory role in HCV replication. The virus-induced overexpression of GPx may lead to a decreased level of Se in the host due to the competition of HCV for Se. In fact, patients with HCV have been shown to have a significant decline in their serum Se. On the other hand, the hepatotoxicity of ethanol and its associated malnutrition will further reduce the cellular

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Se level. This additive decline in the Se level will make the cell more susceptible to reactive oxygen species (ROS). Previous studies have shown an association between oxidative DNA damage and either alcohol exposure or chronic viral infection. It seems that chronic HCV infection may lead to an increased ROS, overexpression of GPx and reduced serum level of Se. When the Se-GPx level is low, the virus will be more provoked for replication, leading to a higher viral load in the infected cell. Eighty newlydiagnosed HCC patients will be recruited from University of Texas MD Anderson Cancer Center (UTMDACC). The current project will explore the effect of dietary selenium intake and its interaction with HCV and alcohol intake in HCC in a casecontrol study. Eighty healthy individuals (first control group), matched with cases by age, sex and ethnicity, will be recruited from the patients non-blood relatives and friends from UTMDACC. To have a control group with comparable prevalence of HCV infection, 80 patients with liver cirrhosis, who have no evidence of HCC (second control group), will be recruited from Baylor College of Medicine. Information on alcohol intake, dietary Se intake and other risk factors will be collected by a questionnaire. The frequency and profile of hepatitis B virus (HBV) and HCV infection will be determined by measuring serum HBsAg, anti-HBC, anti-HCV, and HCV-RNA. Oxidative stress will be evaluated by measuring the levels of serum Se, GPx activity, lipid peroxides, and 8hydroxy-deoxyguanosine (8-OH-dG), a marker of oxidative DNA damage. The expression of GPx and the level of 8-OH-dG will also be measured in tissue samples from cirrhotic and HCC patients. Serum Se, GPx activity, lipid peroxides and oxidative DNA damage will be measured in relation to HCV and alcohol intake history. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HGF AND HEPATOCYTES IN NEOPLASIA AND LIVER FAILURE Principal Investigator & Institution: Michalopoulos, George K.; Professor and Chairman; Pathology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 15-AUG-1981; Project End 31-MAY-2002 Summary: In this renewal application we designed experiments aimed to capitalize on two major advances which occurred during the last funding period; 1. HGF biology: Hepatocyte Growth Factor (HGF) is now fully cloned and sequenced, in part from work funded by this grant in its earlier periods. Its receptor (encoded by the proto-oncogene c-met) is now well characterized. Activation of HGF by urokinase is now well documented. 2. In its new location in the university of Pittsburgh the lab has now access to hepatic tissue from the largest liver transplantation program in the world. Approximately 450 cases of liver at end stages of disease is available annually. The lab has now access to an existing collection of frozen tissue and paraffin blocks from hundreds of well defined stages of human hepatic disease. It also has access to all the new livers resected from transplantation cases. The project is now focusing on utilizing the new knowledge on HGF biology and the access of human liver tissues to focus on two lethal forms of human liver disease where growth disregulation leads to death: A. Hepatocellular Carcinoma (HCC). This is the most frequent cancer in the world. HGF is mitogenic and motogenic in normal human hepatocytes but is only motogenic and sometimes mitoinhibitory in human hepatocellular carcinomas. We will examine the role of HGF as a mitogen, motogen and mitoinhibitor in the evolution of human hepatocellular carcinoma from its earliest stages (atypical adenomatous hyperplasia, (AAH) seen as solitary nodules in cirrhosis), to its most advanced widely invasive forms. The role of HGF activation by urokinase in the evolution of this disease will be also examined. The potential mitoinhibitory effects of HGF on HCC, if properly

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documented understood, may have a therapeutic potential in this disease. B. Fulminant liver Failure (FHF): In this condition, hepatocyte regeneration ceases, stem cell compartment (ductular hepatocytes) becomes activated, solitary clonal growths of hepatocytes (pseudoadenomas) grow to a hugh size. HGF levels in the plasma are extremely high. We will investigate; a. the role of HGF as a mitogen, motogen and morphogen in the evolution of new cell populations in this disease; b. the role of high doses of HGF in the inhibition of hepatocyte regeneration (leading to death of the patient); c. the effect of high doses of HGF in the activation of the stem cell compartment in the human liver. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IDENTIFICATION OF HEPATITIS C VIRUS BINDING PROTEINS Principal Investigator & Institution: Gale, Michael J.; Assistant Professor; Microbiology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Hepatitis C virus (HCV) is a hepatotropic RNA virus that infects more than 200 million people worldwide. HCV is transmitted via percutaneous exposure to contaminated blood or blood products. Acute exposure to HCV most often leads to chronic infection characterized by persistent virus replication, hepatitis and the development of fibrosis and cirrhosis. The molecular basis for the hepatotropism of HCV has not been defined, in part, because of the lack of a suitable culture system by which to propagate native HCV infection. HCV binding and entry into the host cell is thought to occur through specific interactions of the HCV surface glycoproteins, E1 and E2, with surface proteins expressed on the target cell. We have adapted and developed new strategies by which to identify candidate HCV receptor proteins, and by which to assess the role of each candidate receptor in mediating the processes of virus binding and entry that direct HCV infection. We will utilize these novel strategies to investigate the hypothesis that HCV tropism is mediated by E1 and/or E2 glycoprotein interactions with liver-specific cell surface receptor proteins. In Aim 1 of this proposal we will utilize a cell-based expression/binding assay system to screen a liver-specific cDNA library for candidate cellular receptors that bind to one or both HCV glycoproteins. Aim 2 will employ a novel HCV-pseudotyped virus system to assess the role of each candidate receptor protein in supporting HCV binding and entry into the host cell. This pilot project will identify cellular HCV-binding proteins that direct viral tropism and that participate in the processes of HCV binding and entry. The proposed studies will provide novel insights into the HCV infectious cycle, and will establish a foundation for future work aimed at understanding the virus-cell interactions that confer HCV tropism and infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IDENTIFYING DETERMINANTS OF HCV TROPISM Principal Investigator & Institution: Dragic, Tatjana; Assistant Professor; Microbiology and Immunology; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-MAR-2008 Summary: (provided by applicant): It is estimated that 170 million people worldwide are infected with the Hepatitis C virus (HCV) and are at risk of developing chronic hepatitis or cirrhosis, the latter often leading to hepatocellular carcinoma. There is currently no vaccine and licensed therapies are associated with modest efficacies and significant toxicities. Despite the urgency of this worldwide public health problem, our

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basic understanding of HCV replication and pathogenesis remains poor due to a lack of key experimental models. For example, difficulties in culturing the virus in vitro and expressing native, fusogenic envelope glycoproteins have greatly limited studies of HCV tropism and entry. These are critical aspects of viral biology because the host range and pathogenesis of enveloped virus infection is largely determined by the selective interaction of viral envelope glycoproteins with cell-surface receptors. A major goal in HCV research is to understand how HCV targets the liver and by what mechanism it enters host cells. Recently, a major breakthrough in the field has been the development of retroviruses pseudotyped with HCV envelope glycoproteins that specifically mediate infection of primary hepatocytes, as well as certain other human cells. We will use this new experimental system to study HCV entry into target cells. Alterations in naturally occurring HCV envelope glycoproteins may predicate differences in receptor usage and target cell tropism in vivo. To investigate the range of HCV cellular tropism, pseudotypes incorporating envelope glycoproteins from clinical HCV isolates will be tested for their ability to enter relevant primary cells and cell lines. A functional cDNA cloning approach will be used to identify cell-surface receptors that specifically mediate HCV entry into different target cells. However, these receptors may be ubiquitously expressed and HCV targeting to different cell types may be determined by another mechanism. We recently demonstrated that L-SIGN and DC-SIGN are specific HCVcapture receptors and we will explore whether they mediate infection of target cells in trans, thereby determining HCV tropism. The major objective of our work is to identify the basic protein interactions that mediate HCV tropism, which will serve as a foundation for detailed structure/function analyses of HCV receptors and envelope glycoproteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNE RESPONSES AND ACHOHOLIC LIVER DISEASE Principal Investigator & Institution: Jerrells, Thomas R.; Professor; Pathology and Microbiology; University of Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 31-MAR-2003 Summary: (Adapted from the Investigator's Abstract) Alcoholic liver disease (ALD) is a serious consequence of alcohol abuse and results in a great deal of morbidity and mortality in the United States. The mechanisms that lead to ALD are poorly understood, and it is not known what factors are involved in the susceptibility for the development of ALD. The prevailing opinion is that some factor initiates an inflammatory response in the liver that is uncontrolled and ultimately results in the characteristic fibrosis associated with this process. Data from this laboratory have shown that a condition that resembles the sequence of events in ALD can be initiated in ethanol (ETOH)-fed C57Bl/6 mice after activation of T-lymphocytes by specific antigen or concanavalin A. These activation stimuli induce steatosis and hepatitis only in ETOH-fed mice, which ultimately result in liver damage evidenced by elevated serum levels of ALT and AST. These data support our suggestion that at least one factor involved in initiation and development of ALD is a specific immune response in the liver. To test this hypothesis we propose to use these murine models of ALD and a model of viral hepatitis to define the mechanisms responsible for this immune - mediated liver damage. It is our specific hypothesis that initiation of the inflammatory process is the result of specific T cellmediated killing, either through direct cellular cytotoxicity or through the production of cytotoxic cytokines of the infected hepatocyte. Further, we hypothesize that corticosteroid production associated with ETOH consumption has a twofold effect in this system. First, the immune response is suppressed by corticosteroids to inhibit the

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ability to control the replication of the infectious agents, results in more inflammation. Second, corticosteroids sensitizes hepatocytes to enhance destruction of these cells by either direct T-cell-mediated lysis or lysis mediated by inflammatory cytokines such as tumor necrosis factor. The proposed research will also define the specific cells that initiate or mediate liver damage as well as the role of the inflammatory response and inflammatory cytokines in these models of experimental ALD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOGENICITY OF HEPATITIS C VIRUS (HCV) LIKE PARTICLES Principal Investigator & Institution: Barber, Glen N.; Associate Professor; Microbiology and Immunology; University of Miami Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Hepatitis C virus [HCV], a member of the Flaviviridae, is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Acute infection with HCV is associated with persistent viral replication in approximately 80-90% of cases, with an estimated 200 million people infected worldwide. Presently, the only effective therapy against HCV infection is type I interferon [IFN] currently in combination with the nucleoside analogue ribavirin. However, response rates vary from 5% to 50%, depending on race and gender, thus leaving many infected individuals untreatable. Presently, there is no vaccine for HCV and therefore a collective need to develop preventive strategies as well as new therapies. The search for effective vaccines is hampered, however, by the inability to grow candidate HCV vaccine preparations in vitro and by the prevalence of numerous HCV quasispecies that have evolved due to the virus lacking a proof reading mechanism while replicating. Since HCV cannot be efficiently manufactured for vaccine assessment, we have synthesized, in mammalian cells, highly immunogenic, non-infectious HCVlike particles comprised of the core, E1 and E2 products of HCV. This was achieved by cloning the core/El/E2 genomic region of HCV into the relatively simple, nonpathogenic negative-stranded virus, vesicular stomatitis virus (VSV). Following infection of tissue cultured mammalian cells with VSV/HCV recombinant viruses, high levels of authentic core/El/E2 HCV proteins were generated that autoassembled into HCV-virus-like particles (VLPs). Importantly, our preliminary data further indicates that VSV/HCV induced cell-mediated and humoral activity to all the structural proteins in immunized mice. Thus, our HCV expression system may have the capacity to generate effective, multivalent immune respones to a variety of HCV encoded proteins. Given this data, we aim to analyze the potency of the rVSVs system that expresses HCV gene products or purified HCV-like particles themselves, in vaccine studies designed to further evaluate whether robust cell-mediated and humoral responses can be safely and effectively obtained to multiple HCV epitopes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMPACT OF HIV ON HEPATITIS C INFECTION IN HEMOPHILIA Principal Investigator & Institution: Ragni, Margaret V.; Professor; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 11-APR-2001; Project End 31-MAR-2005 Summary: (provided by applicant) The purpose of this study is to determine the impact of HIV infection on hepatitis C virus (HCV) liver disease outcome, and the prevalence, risk factors, and viral and immunologic characteristics of liver disease in HCV-infected

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hemophiliacs, both HIV(+) and HIV(-). Approximately 826 HCV-infected hemophiliacs from 10 U.S. hemophilia treatment centers will be available for study. This group is unique in that patients are well characterized, closely followed, the time of HCV infection is known, HCV infection duration is greater than 20 years, and the incidence of liver disease progression is increasing. The specific objectives of this study include: (1) a cross-sectional cohort study in which hemophiliacs with HCV infection, both HIV(+) and HIV(-), are enrolled and undergo transjugular liver biopsy to determine the prevalence of cirrhosis and fibrosis progression rate. (2) a cross-sectional study comparing HCV-infected patients, both HIV- and HIV+, to determine clinical, life-style, and laboratory, e.g. biochemical, serologic, molecular biologic, and immunologic characteristics associated with development of cirrhosis and stage of fibrosis progression. (3) a cytokine study, comparing cytokine mRNA levels, interleukin-6 (IL-6), interleukin-10 (IL-10), and transforming growth factor-beta (TGF-beta 1 and TGF-beta 2) in liver tissue, cytokine immunoassay levels in plasma, and cytokine expression genotypes with liver histopathologic score and with fibrosis progression rate in prospectively-biopsied hemophiliacs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACTIVATION

INTEGRIN

SIGNALING

IN

HEPATIC

STELLATE

CELL

Principal Investigator & Institution: Luxon, Bruce A.; Associate Professor; Internal Medicine; St. Louis University St. Louis, Mo 63110 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAR-2007 Summary: (provided by applicant): This proposal has the long term goal to elucidate the role that integrins have in hepatic stellate cell activation and hepatic fibrosis. Hepatic stellate cells are responsible for producing most of the extracellular matrix components ("scar" tissue) found in a wide variety of hepatic diseases. Stellate cells in normal liver are "quiescent" (non-scar forming) but undergo a process called "activation" in which they begin to proliferate and synthesize fibrous tissue leading to cirrhosis. Integrins are receptors located on the cell surface of stellate cells that allow the stellate cells to interact with the hepatic extracellular matrix. Specific extracellular matrix proteins are known to bind to the integrins and cause multiple signals to be sent to the stellate cell, inducing them to activate. The hypothesis to be tested in this series of experiments is that integrins (especially the fibronectin receptor alpha-5 beta-1) modulate and perpetuate the activation of hepatic stellate cells through their interaction with the extracellular matrix. To test this hypothesis, the following specific aims will be completed:1). Determine the mechanisms by which stellate cells control the expression of active integrin receptors on their cell surface. 2). Determine the mechanisms of integrin signaling during activation of stellate cells. 3). Determine if interrupting integrin signaling can block the perpetuation step of stellate cell-mediated fibrogenesis. These studies are designed to unravel the molecular mechanisms involved in integrinmediated activation of stellate cells. Understanding the complex array of integrin interactions, modulations, and signaling events may elucidate potential mechanisms that can be therapeutically targeted to stop the fibrogenesis that occurs in chronic liver disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIPID PEROXIDATION IN ALCOHOLIC LIVER DISEASE Principal Investigator & Institution: French, Samuel W.; Chief, Division of Anatomic Pathology; Harbor-Ucla Research & Educ Inst 1124 W Carson St Torrance, Ca 90502

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Timing: Fiscal Year 2001; Project Start 01-NOV-1990; Project End 31-MAY-2005 Summary: Role of Lipid Peroxidation in ALD: The long-term goal is to determine the pathogenesis of alcoholic liver disease (ALD). Specific Aims are: 1) To determine the role played by 26s proteasome peptidase inhibition in the protein retention in hepatocytes in experimental ALD in the rat and mouse. 2) To determine the role played by the 20s proteasome peptidase inhibition in the removal of oxidized proteins in hepatocytes in experimental ALD. 3) To determine at the individual liver cell level, using in situ assessment of the phosphorylation-ubiquitin- proteasome pathway, whether the proteasome function is damages in ALD. The studies will focus on correlations made between histopathology, immunohistochemistry and biochemical measurements made on the livers of rats and mouse fed ethanol intragastrically for 2-4 months when significant alterations of liver histology has developed. The basic concept to be tested is that oxidative stress and free radical induced injury initiates a change in protein turnover in the liver cell which shifts the balance between protein synthesis and protein elimination in the liver cell where the net result is protein retention and cell enlargement. Mice deficient in or over expressing CYP2E1 will be studies using the intragastric ethanol feeding model in order to better access the role of CYP2E1 in the pathogenesis of liver cell protein retention in experimental ALD. The mechanism which accounts for the up regulation of CYP2E1 and other proteins retained in the liver cytosol will be identified. In this way the pathogenesis o liver cell enlargement will be determined and the role that this phenomenon plays in ALD will be defined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIVER CENTER Principal Investigator & Institution: Bissell, Dwight M.; Professor; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 01-JUL-1985; Project End 31-MAY-2002 Summary: The liver plays a central and complex role in health, being responsible for synthesis of key molecules, maintenance of metabolic balance, and detoxification processes. Liver diseases are among the leading causes of death in the United States and their investigation spans basic science and clinical medicine. At the University of California, San Francisco, the liver is a major focus of study among scientists in fifteen Departments and two Schools (Medicine and Pharmacy) and is represented on three major campuses of the University (Moffitt-Long Hospital, San Francisco General Hospital, and the Veterans Affairs Medical Center). With the recent incorporation of Mt. Zion Medical Center among the UCSF campuses, it is anticipated that Center programs will eventually include investigators at that site as well. The Liver Center was established in 1975, assuming its current Core Center format in 1980, for the purposes of melding individual research programs into a consortium and of fostering interdisciplinary research through support of core facilities, funds for new initiatives, enrichment activities (including visiting scientists and mini-sabbatical programs), and the highly successful annual retreat. Center Core Facilities, among them Animals, Molecular Biology, Liver Cell Culture, Liver Perfusion, Microscopy, Biostatistics, and Mass Spectrometry, have provided important services to Center investigators during the present funding period. New research directions have emerged, and current areas of emphasis include basic and clinical studies in cell biology, drug metabolism and toxicity, hepatic fibrosis and cirrhosis, immunology and transplantation, metabolism, transport, bile secretion, and viral hepatitis. The research base has grown substantially, reflecting the favorable influences of several factors, including strong institutional commitment, continued successful operation of the liver transplantation program, and

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increasing interdisciplinary collaboration. Goals for the next funding period include further expansion of the use of molecular and genetic experimental approaches and the facilitation of clinical research, including the study of human materials. To this end, proposed major changes in core facilities include expansion of the Molecular Biology Core Facility, and establishment of a new Clinical and Biostatistics Core Facility. Dr. D.M. Bissell, currently a Center Associate Director, will assume the role of Co-Director. The Center enjoys the ongoing support of the leadership at UCSF, where it continues to be recognized for major contributions to digestive diseases research and serves as a national resource in providing rare animals or reagents and training in specialized techniques. It is anticipated that, during the next five years, the Center will facilitate increasing clinical and laboratory application of molecular approaches to address specific issues in human liver biology and disease, including studies of the pathogenesis of tumors and non-neoplastic disorders, development of diagnostic methods and reagents, and innovations in medical and surgical treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MEDIATORS OF PULMONARY VASODILATATION IN LIVER DISEASE Principal Investigator & Institution: Fallon, Michael B.; Associate Professor; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2004 Summary: Endothelial dysfunction underlies the vascular abnormalities of chronic liver disease and is characterized by changes in the levels and activity of endothelial nitric oxide synthase. How these changes occur and why there is variability in the vascular beds involved is incompletely characterized. The hepatopulmonary syndrome is one important vascular complication of liver disease where 15-20 percent of patients with cirrhosis develop pulmonary microvascular dilatation leading to hypoxemia. No effective medical therapies are available. Experimental biliary cirrhosis reproduces the pulmonary vascular and gas exchange abnormalities of human hepatopulmonary syndrome in association with an increase in pulmonary microvascular endothelial nitric oxide levels and activity. Pre-hepatic portal hypertension alone does not cause pulmonary vascular or endothelial nitric oxide synthase alterations, implying that mediators released during hepatic injury may trigger endothelial alterations in the lung. Hepatic and plasma endothelin-1 levels rise and correlate directly with the degree of intrapulmonary vasodilatation in experimental biliary cirrhosis and preliminary studies reveal that chronic low level endothelin-1 infusion in pre-hepatic portal hypertensive animals results in selective pulmonary microvascular dilatation. Although classically recognized as a vasoconstrictor, circulating endothelin-1 stimulates endothelial cell endothelial nitric oxide synthase activity and can cause vasodilatation. Our hypothesis is that endothelin-1, released into the circulation during liver injury, preferentially activates pulmonary vascular endothelial nitric oxide synthase and triggers pulmonary microvascular dilatation. To test this hypothesis our specific aims will 1) define the effects of chronic endothelin-1 infusion on the development of intrapulmonary vasodilatation and endothelial nitric oxide synthase expression and activity in normal, pre- hepatic portal hypertensive and biliary cirrhotic animals in vivo 2) assess the effects of exogenous emdothelin-1 on endothelial nitric oxide synthase expression and activity in isolated pulmonary vascular segments and endothelial cells from normal, pre-hepatic portal hypertensive and biliary cirrhotic animals and 3) directly measure the effects of exogenous endothelin-1 on pulmonary microvascular reactivity in normal, pre-hepatic portal hypertensive and biliary cirrhotic animals. Our long-term goal is to use an

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understanding of endothelial dysfunction in hepatopulmonary syndrome to develop specific medical therapies and as a paradigm for understanding the pathogenesis of other vascular complications of liver disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MITOCHONDRIAL GSH /SAM IN ALCOHOL INDUCED LIVER DAMAGE Principal Investigator & Institution: Fernandez-Checa, Jose C.; Fundacio Clinic C/Villarroel 170 Barcelona, Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant): Since we first discovered in 1987 the depletion of mitochondrial GSH (mGSH) status by chronic ethanol intake, considerable progress has been made regarding the molecular mechanism(s) of the defect and its functional impact in alcohol-induced liver damage (ALD). In addition to the altered regulation of mGSH by alcohol, S-adenosyl-L-methionine (SAM) depletion has been also reported and is thought to contribute to the progression of the disease. GSH and SAM may exhibit parallel features as both are found in mitochondria due to specific transport mechanisms. Thus, the present proposal will look at the specific regulation of mitochondrial SAM (mSAM) pool by alcohol and the temporal and functional relationship between mGSH and mSAM by alcohol. 1. - SAM levels and transport in rat liver mitochondria from alcohol-fed rats. Most studies have reported the status of total SAM levels in hepatocellular extracts in patients and experimental models of ALD. We wilt examine the status of mSAM levels and its mitoehondrial transport in chronic alcohol-fed rats. 2. Temporal and functional relationship between mitochondrial GSH and SAM depletion by alcohol: Role of Kupffer cells and liver steatosis. We will examine if mGSH depletion by alcohol precedes or follows that of SAM (total and mSAM) in mitochondria from alcohol fed rats and its relationship with pathology. The role of Kupffer cell activation and liver steatosis on alcohol-mediated mGSH and total SAM (cytosol and mSAM) depletion will be evaluated in alcohol-fed rats and in a model of non-alcohol: hepatic steatosis. 3. Mechanism whereby SAM feeding normalizes the alcohol-altered mitoehondrial membrane fluidity and mGSH transport. Increasing evidence indicate a critical role of cholesterol/phospholipid molar ratio in the regulation of mitochondrial membrane mieroviseosity and mGSH transport, in addition to these changes, we wilt examine the regulation and trafficking of cholesterol into mitoehondria, as well as the fatty acid composition of individual lipids of mitochondrial lipid classes from chronic alcohol-fed rats with or without SAM supplementation. 4. Regulation of MAT1A by glycosphingolipids and sphingomyelinases. TNF and shortchain ceramide have been reported to downregulate the expression of MAT1A. Since sphingomyelinases (SMases) are known to mediate some of the effects of TNF, we will examine the role of individual neutral or acidic SMase, in the regulation of MATIA in primary cultured rat hepatocytes and HepG2 cells exposed to exogenous neutral (NSMase) or acid (ASMase) SMases. In addition, we will assess the role of TNF on MATIA expression in ASMase knockout mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR MECHANISMS OF ETHANOL INDUCED LIVER FIBROGENES Principal Investigator & Institution: Ramirez, Francesco B.; Chief Science Officer; Pharmacology; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029

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Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 31-MAR-2003 Summary: Alcohol-induced liver cirrhosis is one of the major causes of death worldwide. Strong evidence has established that acetaldehyde, ethanol's first metabolite, is fibrogenic per e and enhances type I collagen production by hepatic stellate cells. Despite major efforts by several laboratories, relatively little is known pertaining the molecular events underlying this stimulatory effect. Thus, it is our long-term goal to integrate cellular and molecular events into a unified picture that explains how acetaldehyde stimulates type I collagen gene transcription in the liver. The specific aims of this proposal: 1) To characterize the cis-regulatory elements and trans-acting factors, active in hepatic stellate cells of human origin, mediating acetaldehyde-induced human alpha2(I) collagen gene up-regulation; 2) To elucidate key molecular mechanisms by which acetaldehyde modulates the activity and/or binding of the transcription factors that interact with the acetaldehyde- responsive element of the human alpha2(I) collagen gene; and 3) To determine whether acetaldehyde stimulates human alpha2(I) collagen gene expression directly, or through an autocrine loop involving enhanced production and/or activation of transforming growth factor-beta in human hepatic stellate cells. A better characterization of the molecular events underlying enhanced COL1A2 gene expression in hepatic stellate cells, will enhance our understanding of the pathophysiology of ethanol- induced liver fibrosis, and will allow in the near future, to develop new therapies aimed at counteracting the devastating effects of this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MULTICENTERED RANDOMIZED TRIAL OF HIGH-DOSE URSO IN PSC Principal Investigator & Institution: Lindor, Keith D.; Professor and Director; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Primary sclerosing cholangitis (PSC) is a progressive chronic cholestatic liver disease of unknown etiology that is commonly associated with chronic colitis. PSC, a common liver disease among adults, usually leads to advanced liver disease and liver failure, and as such, is an important indication for liver transplantation. Unfortunately, no effective medical therapy currently exists for PSC. The group of investigators has a longstanding track record of clinical trials in chronic cholestatic liver disease, particularly in primary sclerosing cholangitis. Recently we have generated promising results from a pilot study using high doses of ursodeoxycholic acid in the treatment of PSC. Lower doses of ursodeoxycholic acid in patients with PSC led to biochemical improvement but did not affect other clinically important endpoints in a previous study. Our pilot data is supported by data from another group showing in a small, randomized trial that high dose ursodeoxycholic acid led to biochemical, histologic, and cholangiographic improvement compared to placebo at two years. In this submission, we propose a large-scale multi-center placebo-controlled randomized trial with a minimum follow-up of four years for 150 patients with primary sclerosing cholangitis. Primary endpoints of the study will include histologic progression to cirrhosis, development of esophageal or gastric varices, need for liver transplantation, and survival. Secondary endpoints will include measurements of the effects of urosodeoxycholic acid (28-30 mg/kd/d) on liver biochemistries, histologic stage, cholangiographic features, Mayo risk score, and quality of life, using validated questionnaires. This study will be the largest ever conducted in PSC and the follow-up will be the most extensive. This will provide an invaluable resource for studying the natural history of this disease and as part of this study we will also collect serum, cells

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for extraction of DNA, bile, and tissue from the liver and colon as a resource for future studies. The multi-centered nature of this trial will allow recruitment of patients into this study from a diverse patient population, representative of the gender and racial distribution of this disease. Chances of successful completion of this study are enhanced by the large PSC patient population that the participating centers currently manage, recognition of these sites as referral centers for new patients with PSC, as well as a longstanding track record in clinical trials in cholestatic liver disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NATURAL HISTORY OF HEPATITIS C INFECTION IN HIV DISEASE Principal Investigator & Institution: Horsburgh, Charles Robert.; Boston Medical Center Gambro Bldg, 2Nd Fl, 660 Harrison Ave, Ste a Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Each year more than 20 percent of the 3.5 million Americans infected with hepatitis C progress to cirrhosis and ten to fifteen thousand develop end-stage liver disease. Because hepatitis C and HIV disease share common modes of transmission, coinfection occurs in 8-10 percent of all HIV-infected individuals overall and is present in over 70 percent of those with parenteral risk factors. There are few data available on the natural history of HIV and HCV co-infection in specific risk groups, as most previous studies have not assessed the impact of confounding variables such as alcohol use, continuing substance abuse, malnutrition, duration of HCV infection, and degree of HIV-related immune suppression. Moreover, current data regarding the impact of HIV on HCV infection are changing rapidly due to the widespread use of highly active antiretroviral therapy (HAART). New cases of HIV and HCV are expected to continue to occur in substance abusers, since HIV infection is increasing rapidly in inner-city populations. The purpose of this study is to examine the natural history of HIV and HCV co-infection in a large inner city cohort who are predominately minority and have a history of polysubstance abuse. We will compare three groups: 1) HIV and HCV infected, 2) HCV infected alone, and 3) HIV infected alone. Epidemiologic studies will be conducted to explore the risk factors associated with HCV progression, morbidity, and mortality, using both standard clinical parameters and novel surrogate markers of liver fibrosis. Additional targeted substudies will examine the important clinical question of whether therapy of either the HCV or HIV disease alters progression of liver disease. Finally, immunologic studies aimed at increasing our understanding of the pathogenesis of liver injury and why it may be accelerated in HIV disease will be performed. The central hypothesis of this proposal is that alterations in immune function associated with HIV infection are the main determinant of poorer hepatitis C outcomes. The specific aims of this grant are: 1) to identify the variable(s) that impact the progression of HCV infection in HIV-infected individuals; 2) to determine the effect of HAART on HCV in dually infected persons; and 3) to define the immunologic variables that predict more rapidly progressive liver disease. These studies are expected to improve our understanding of the natural history and pathogenesis of HCV in immunosuppressed hosts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NOVEL HEPATOCARCINOGENESIS

ANIMAL

MODELS

OF

HCV-RELATED

Principal Investigator & Institution: Chung, Raymond T.; Assistant Professor of Medicine; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114

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Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: (adapted from the application) Hepatitis C virus (HCV) infection and its complications are emerging as an extraordinarily important public health problem worldwide. Hepatocellular carcinoma (HCC) is now a firmly established and largely incurable complication of chronic HCV, and its prevalence in this country will continue to grow as a large cohort of patients infected decades ago comes to clinical attention. While most cases appear to arise in the setting of chronic inflammation, cirrhosis, and regeneration, the pathogenesis of HCV-related HCC remains unknown. It becomes apparent that a fundamental understanding of the mechanisms of HCV-related hepatocarcinogenesis is essential to effectively address this major sequel to chronic infection. Animal models of HCV-related hepatocarcinogenesis have been difficult to construct, in great part because of the obstacles to creation of a model permissive for infection. Transgenic mouse models permit the opportunity to examine the effects of selective expression of viral proteins. A recent report has suggested that transgenic mice expressing the HCV core protein alone develop HCC. We have created a transgenic mouse model that successfully expresses HCV core as well as the two envelope glycoproteins; however, these animals do not develop liver disease. The basis for these observed differences is unknown. We propose to explore the contributions of three major arms -to HCV-related HCC: (1) viral protein expression; (2) host genetic predisposition; and (3) the host immune response. To accomplish this, we will use novel transgenic mouse models to explore the direct contribution of both HCV structural to explore the mechanistic differences between our model and the core model. We will also cross our transgenic HCV structural protein mice with a recently developed mutant tumor suppressor gene mouse model that spontaneously develops HCC in a large portion of aging animals. This cross will allow us to "read out" the contribution of viral protein expression to HCC development (by increased frequency or acceleration of HCC formation), as well as to determine whether HCV-induced HCC requires a host genetic predisposition- Finally, we will create a novel, inducible transgenic model that expresses the full length HCV polyprotein to explore the contribution of activation of the host immune system to HCV-related hepatocarcinogenesis. Together, these models will help provide insights into the factors responsible for this devastating complication of chronic HCV infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENESIS COINFECTION

OF

HEPATIC

INJURY

WITH

HCV/HIV

Principal Investigator & Institution: Groopman, Jerome E.; Chief; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant) The primary objective of this proposal is to examine how the hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) envelope proteins may act collaboratively to trigger signaling events that contribute to hepatocyte inflammation and apoptosis. Coinfection with HIV and HCV confers a poor prognosis, with progressive hepatic dysfunction that often results in cirrhosis and death. Both intravenous drug users and hemophiliacs have a high incidence of coinfection and face this grim outcome. Why do coinfected hosts have such high rates of progressive liver disease? The pathogenesis of HCV-related hepatitis is believed to be due, in part, to immune-mediated inflammation as well as the effects of direct infection of hepatocytes. Our preliminary data suggest a novel third potential mechanism for hepatic inflammation and apoptosis. We observed in both HepG2 cells and primary

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hepatocytes that treatment with the HCV envelope protein E2, in conjunction with HIV gpl20, induced the inflammatory chemokine interleukin-8 (IL-8) and triggered apoptosis. These functional outcomes occurred at nanomolar concentrations of E2 and gp 120 that correspond to the Kd's for the cognate ligands binding to their respective receptors, CDS1 and CXCR4, and were associated with activation of specific signaling molecules, including the Src family Lyn kinase, RAFTK/Pyk2, Erkl/2 and p38 MAP kinases, and Fas-ligand. These data indicate that proinflammatory and apoptotic events may occur due to dual exposure to HCV and HIV envelope proteins via an "innocent bystander" mechanism. This proposal seeks to characterize the molecular mechanisms of IL-8 induction and the program of apoptosis caused by HCV E2 and HIV gpl20. A focused experimental approach is presented to delineate signaling events that originate at specific cell surface receptors, are transduced through intermediate signaling molecules, and converge on transcriptional activators of the MAP kinase family. Elucidating how these HCV and HIV envelope proteins may interact with hepatocytes could not only further our understanding of the pathogenesis of disease in coinfected hosts but also lead to targeted therapeutic strategies to improve the currently poor prognosis of such individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENESIS OF LIVER DISEASE IN HEPATITIS Principal Investigator & Institution: Chisari, Francis V.; Professor & Head; Scripps Research Institute 10550 N Torrey Pines Rd La Jolla, Ca 920371000 Timing: Fiscal Year 2003; Project Start 01-JUL-1983; Project End 31-DEC-2007 Summary: (provided by applicant): The hepatitis B virus (HBV) is a non-cytopathic, hepatotropic DNA virus that causes acute and chronic hepatitis and kills a million people each year from cirrhosis of the liver and hepatocellular carcinoma. Understanding the mechanisms responsible for viral clearance, persistence and disease pathogenesis during HBV infection is, thus, scientifically and medically important. We have previously shown that the immune response plays a key role in the outcome of HBV infection in humans; and we have used transgenic mice to identify immunological mechanisms that are probably responsible for viral clearance and liver disease. In the current funding interval, we used acutely infected chimpanzees in order to study the early host-virus interactions that occur at the site of infection and likely determine its outcome but, for practical and ethical reasons, aren't accessible in man. Those results indicate that the course and duration of HBV infection are clearly related to the kinetics and extent of viral spread, and to the kinetics, magnitude, quality and cytokine profile of the intrahepatic T cell response. In the next funding interval we will determine which of these factors actually decide the outcome of HBV infection by selectively regulating viral spread, the cellular immune response, inflammatory cytokines, and expression of a putatively immunosuppressive HBV protein in acutely infected chimpanzees. The results of these experiments should establish the basis for viral clearance, persistence and disease pathogenesis in acute and chronic HBV infection, and thereby identify new therapeutic strategies to, hopefully, cure this deadly disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PREDICTING OUTCOME--ALCOHOLIC LIVER TRANSPLANT PATIENTS Principal Investigator & Institution: Dimartini, Andrea F.; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260

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Timing: Fiscal Year 2001; Project Start 01-JUN-1998; Project End 31-MAY-2003 Summary: APPLICANT'S ABSTRACT: Alcoholic Cirrhosis is the most common reason for liver failure and the largest diagnostic category receiving liver transplantation. However, factors that shape policy, treatment choices, candidate selection, and public options are strongest against this group. Without guidance from rigorous research data, the future for alcohol cirrhotics pursuing transplantation is uncertain. To date, no studies of outcome in alcoholic cirrhotics have used alcohol research measures or models, as proposed herein. In the transplant literature there is a lack of consistency in relapse definitions, timing or methods of follow-up, or use of post-transplant factors to predict alcohol use. This proposed research will expand the primary aim of alcohol research which is to identify and explain the factors that shape alcohol use and its consequences in various populations. To investigate outcome in alcoholic cirrhotics undergoing liver transplantation, expertise in psychiatry, medicine, transplantation, and alcoholism is needed. The applicant, an M.D. board certified in psychiatry, has the basic requisite skills to embark on this line of research. Through five years of clinical work evaluating, treating, and following alcoholic cirrhotic patients pursuing transplantation the applicant has developed a high degree of clinical acumen as well as the necessary connections to one of the largest liver transplant teams in the U.S. This Mentored Clinical Scientist Development Award will allow the applicant the opportunity to consolidate clinical skills in conjunction with a structured educational program and mentored research. During the award period, the candidate will conduct a prospective longitudinal study of alcohol use following liver transplantation, while investigating pre-transplant and post-transplant factors hypothesized to influence return to drinking. This research experience will be complemented by career development activities supervised by pioneering researchers in addictions, transplantation, and psychiatric research. The proposed plan is designed to develop the candidate's expertise in: 1) longitudinal study design and analysis; 2) alcohol relapse identification and monitoring; 3) conceptual and analytic modeling of relapse factors; and 4) post-transplant alcohol use outcome, and will give her the necessary skills to become an independent academic researcher in addictions and transplantation research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROSTAGLANDIN THERAPY FOR ALCOHOLIC HEPATITIS Principal Investigator & Institution: Hill, Daniell B.; Associate Professor of Medicine; Medicine; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2001; Project Start 01-MAR-2000; Project End 31-OCT-2001 Summary: Alcoholic liver disease (ALD) is an important health problem. There is increasing evidence that many of the clinical manifestations and, at least, part of the liver injury in ALD are mediated by cytokines such as tumor necrosis factor (TNF), interleukin-6 (IL-6) and interleukin-8 (IL-8). Regulation of these cytokines has become a focal point for therapeutic intervention in many diseases including ALD. Nuclear factor kappa B (NFkappaB) is a transcription factor for these cytokines. NFkappaB is activated by reactive oxygen intermediates and endotoxin. We postulate that chronic alcohol abuse causes increased gut permeability and endotoxemia, depletion of many nutrient antioxidants, inadequate macrophage prostaglandin concentrations, generation of reactive oxygen intermediates, activation of NFkappaB, increased TNF production, increased IL-8 production with neutrophil infiltration, mitochondrial dysfunction with mitochondrial GSH depletion, increased susceptibility to hepatic TNF cytotoxicity, and liver injury. The overall goals of my laboratory are to further characterize cytokine mediated nutritional/metabolic events and mechanisms of cytokine induced liver

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injury, with the ultimate goal being the development of effective "anticytokine" therapy for ALD. The "anticytokine" therapy to be studied in this proposal is the prostaglandin E1 analogue misoprostol. We postulated that misoprostol will both inhibit cytokine production and improve gut permeability. The specific objectives of this proposal are: 1. Determine the dose of misoprostol that most effectively decreases ex vivo cytokine production when given orally for a 14 day period to normal volunteers. 2. Determine that the optimal dose of misoprostol that effectively decreases ex vivo cytokine production in normal volunteers also effectively decreases ex vivo cytokine production in patients with stable alcoholic cirrhosis and is well tolerated by them when given orally over a 14 day period. 3.A. Determined whether misoprostol treatment of patients with acute alcoholic hepatitis is well tolerated and effective in decreasing gut permeability, endotoxemia, plasma cytokine levels, ex vivo cytokine production and lipid peroxidation. 3.B. Determine the relationship between plasma cytokine levels and putative cytokine mediated clinical manifestations of alcoholic liver disease includings: measures of liver injury/function, neutrophilia/acute phase reactants, fever/metabolic rate and appetite/nutritional parameters. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROSTANOIDS AND LIVER MICROCIRCULATION IN STRESSES Principal Investigator & Institution: Zhang, Jian X.; Biology; University of North Carolina Charlotte Office of Research Services Charlotte, Nc 282230001 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAR-2006 Summary: (provided by applicant): Endotoxemia is a common but severe complication of cirrhosis frequently causing liver injury and even organ failure. The mechanism underlying the increased susceptibility of the cirrhotic liver to endotoxemia in the sequential stresses, however, is not completely understood. Studies have shown a hepatic upregulation of constrictor endothelin (ET) and a decreased release of vasodilator nitric oxide (NO) in the cirrhotic liver. Our preliminary studies have shown that in cirrhosis, constrictor prostanoids are released in response to ET, and the action of the prostanoids is modulated by NO. We also showed that endotoxemia as a secondary stress caused an additional upregulation in already increased ET gene expression in the cirrhotic rat liver, but endotoxin-induced expression of inducible nitric oxide synthase was blunted by the preexisting cirrhosis. We therefore hypothesize that liver cirrhosis as a pre-existing condition primes the hepatic microcirculation for predisposition to an imbalance between constrictor and dilator influences by sensitizing the ET/constrictor prostanoids pathway and decreasing production of NO. We further hypothesize that endotoxemia as a secondary stress further activates the pathway leading to dysregulation of the hepatic microcirculation and ultimately hepatocellular injury. To test these hypotheses, three specific aims are proposed: 1) determine whether cirrhosis as a pre-existing condition primes the hepatic microcirculation for predisposition of an imbalance between constrictor and dilator influences by sensitizing the ET-mediated release of vasoconstrictor prostanoids; 2) determine whether endotoxemia as a secondary stress enhances the pressor response mediated by the release of vasoconstrictor prostanoids in response to ET; 3) determine whether an overwhelming increase in ET accompanied by the sensitization of ET-induced release of prostanoids and an attenuated expression in iNOS following the sequential stresses result in an imbalanced regulation of vasoconstriction and vasodilation and dysregulation of the hepatic microcirculation. This proposal not only will allow us to evaluate the role of constrictor prostanoids in regulation of hepatic microcirculation in cirrhosis and endotoxin-induced sequential stresses, but also will provide invaluable information on

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therapeutic strategies to prevent hepatic microcirculatory failure under the double stressed conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTEOMICS AND BIOMARKERS FOR HEPATOCELLULAR CANCER Principal Investigator & Institution: Afdhal, Nezam H.; Associate Professor of Medicine; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 25-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Hepatitis C (HCV) is the commonest cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) in the United States. HCC occurs primarily in patients with advanced fibrosis and cirrhosis from HCV. Current screening techniques involve the use of serum alfafetoprotein and liver imaging with ultrasound performed in high risk patients on a 3 to 6 monthly basis. Early detection can improve outcomes with liver transplantation and perhaps non-surgical therapies. However screening is not very effective and many patients present with large tumors or multifocal HCC with a median survival of only 6 months. There is a definite clinical need for better non-invasive biomarkers for HCC which can lead to early detection and treatment. The specific aims of this exploratory R21 proposal are to utilize a proteomic approach to identify novel biomarkers for HCC and then evaluate these biomarkers in a cohort of patients with HCV at high risk for HCC. The initial step will be identification of a matching group of patients with a high risk of HCC and those who have developed HCC during the prospective COPILOT study. The COPILOT study provides a large cohort of patients with HCV and cirrhosis who are randomized to treatment with either low dose PEGylated interferon alfa 2b or colchicine and are followed for 4 years with rigorous clinical screening for HCC. The study is in year 2 and the incidence of HCC is approximately 5%. Serum from these patients prior to and after the development of HCC is stored and will be utilized for proteomic studies. Tissue from normal liver and HCC is available from these patients who have undergone liver transplant. A control disease serum bank from patients with HCC unrelated to HCV is also available at BIDMC. The serum and tissue will be examined by proteomics for identification of novel biomarkers using SELDI-TOF mass spectrometry. Careful clinical characterization and matching will assist in the bioinformatic approach necessary to identify candidate biomarkers. Novel proteins and peptide biomarkers will be sequenced and identified and an ELISA will be developed for any promising candidate biomarkers. The candidate biomarker ELISA will then be validated in the large HCV serum bank at BIDMC of patients with all stages of HCV and those in the COPILOT trial. These studies may lead to identification of more specific and sensitive biomarkers for HCC in HCV which can then be validated further in prospective clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF PULMONARY VASCULAR TONE DURING CIRRHOSIS Principal Investigator & Institution: Carter, Ethan P.; Associate Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2005 Summary: The cellular mechanisms governing the regulation of pulmonary vascular tone are complex and incompletely understood, particularly during pathphysiological

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conditions. One such pathophysiological condition is hepatopulmonary syndrome. Hepatopulmonary syndrome is a clinical triad of advanced liver disease (usually cirrhosis), pulmonary gas exchange abnormalities (i.e. shunting) leading to severe systemic arterial hypoxemia, and widespread pulmonary vasodilations in the absence of intrinsic cardiopulmonary disease. This syndrome occurs in 15 - 30 percent of cirrhotic individuals and vastly complicates their treatment. Nitric oxide (NO) has been postulated to be central to the development of hepatopulmonary syndrome. An animal model of hepatopulmonary syndrome recently has been developed in rats that has proven useful for investigating to pathogenesis of hepatopulmonary syndrome. These animals have intrapulmonary shunting and hypoxemia. The mechanisms linking NO to the development of hepatopulmonary syndrome have not been defined. This proposal investigates the underlying mechanisms of hepatopulmonary syndrome using a comprehensive approach of in vivo and in vitro experimental strategies. We provide preliminary data demonstrating that in addition to elevated NO and eNOS, expression in lung of the vasocontrictor endothelin (ET-1) is decreased in cirrhotic rats. Evidence is also provided showing that vascular smooth muscle potassium channels are activated during cirrhosis. These are the first data ever, providing a mechanism for the pulmonary vasodilation and blunted hypoxic pressor response during cirrhosis. Additional data is shown demonstrating that during cirrhosis the stress response gene heme oxygenase-1 (HO-1) is significantly upregulated in lung and liver and decreased in kidney. HO-1 enzymatic activity liberates CO, a known vasodilator that can act via cGMP-dependent and -independent pathways. Therefore, it is possible that the tissuespecific regulation of the HO-1/CO axis contributes to the pulmonary vasodilation and renal vasoconstriction during cirrhosis. Finally, to investigate the role of NO in alterations to ET-1, potassium channels, and HO-1, cirrhotic rats were chronically treated with a NO inhibitor. This treatment resulted in a complete reversal of the cirrhotic associated changes to gene expression. Taken together, our data suggest that during cirrhosis, NO is central to the development of hepatopulmonary syndrome acting not only as a vasodilator but also as a regulator of gene expression of ET-1, potassium channels, and HO-1. We will test the hypotheses that: (1) chronic NO elevation during cirrhosis renders the pulmonary circulation unresponsive to hypoxia via direct vasodilatory actions and indirect modifications to gene expression; (2) factors released by the cirrhotic liver regulate pulmonary vascular tone; (3) HO-1 derived CO contributes to the pulmonary vasodilation during cirrhosis. This project will not only define the cellular basis for hepatopulmonary syndrome, but will also contribute to our understanding of how pulmonary vascular tone is controlled at the most basic level. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RETINOID METABOLISM IN STELLATE CELLS Principal Investigator & Institution: Bosron, William F.; Professor; Biochem and Molecular Biology; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2001; Project Start 25-SEP-2000; Project End 31-AUG-2003 Summary: This is an R21 developmental grant application to support a collaborative international project (PA-96-033). A collaboration between two United States investigators, Drs. W. Bosron and N. Kedishvili, with two Italian investigators, Drs. A. Casini and A. galli has been established. Drs. W. Bosron and N. Kedishvili have expertise in the characterization of dehydrogenases and hydrolases involved in retinoid metabolism. Drs. Casini and Galli have expertise in the preparation and culture of stellate cells and the characterization of biochemical events associated with stellate cell

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activation leading to alcohol-induced hepatic fibrosis. The overall goal of the research proposal is to identify the metabolic pathways of retinyl ester metabolism in hepatic stellate cells when they become activated to form myofibroblast-like cells. Hepatic stellate cells are the main reservoir of Vitamin A in liver. When animals are chronically exposed to alcohol or other hepatotoxins, the stellate cells become activated and transform into myofibroblast-like cells. These transformed cells are the sites of collagen synthesis and extracellular matrix formation in alcohol-induced hepatic fibrosis. One of the earliest events in stellate cell activation is the hydrolysis in retinyl palmitate esters. Multiple retinyl ester hydrolase and retinol dehydrogenase activities have been reported in human, rabbit and rat liver. However, the specific enzymes and genes involved in retinyl ester metabolism during the activation of hepatic stellate cells have not been identified. The specific aims are to develop methods to prepare stellate cells from rat, rabbit and/or human liver to identify the isoenzymes of retinyl ester hydrolases and retinol dehydrogenases present during stellate cell activation. The enzyme activation will be measured in cells. The catalytic and molecular properties of the retinyl palmitate hydrolases and retinol dehydrogenases will be characterized. The studies should provide new information on the role of retinoid metabolism in alcohol-induced liver disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RETROVIRAL ETIOLOGY OF PRIMARY BILIARY CIRRHOSIS Principal Investigator & Institution: Mason, Andrew L.; Associate Professor; Ochsner Clinic Foundation 1514 Jefferson Hwy New Orleans, La 70121 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-DEC-2002 Summary: Primary biliary cirrhosis (PBC) is an idiopathic multisystem autoimmune disorder that primarily effects women. Patients with PBC have a pluriglandular syndrome resulting in cirrhosis and sicca syndrome, and a demonstrable autoimmune response to specific mitochondrial oxo-acid dehydrogenase E2 proteins. PBC patients are also prone to develop other autoimmune diseases such as Sjogren's syndrome, thyroiditis, and systemic lupus erythematosus. These autoimmune disorders have all been linked to rettroviral infection as by Western blot studies 30 to 35 percent of patients have indeterminate serum reactivity to HIV proteins and 85 to 05 percent have serum reactivity to human intracisternal A type particle (HIAP-I) which was isolated from salivary glands of patients with Sjogren's syndrome and also visualized by electron microscopy. Likewise, 15 percent of PBC patients have been reported to have false positive HIV ELISA reactivity and in preliminary studies, retrovirus particles have been observed by electron microscopy in the biliary epithelial cells of PBC patients but not controls. Using representational difference analysis, we have isolated and cloned novel retroviral nucleic acid sequences from the liver of a PBC patients. These clones have been used to screen a cDNA library made from bilary epithelium cells isolated from three transplant recipients with PBC. We have now identified more than ten qunique cDNA clones with sequence homology to HIV, SIV, HTLV-1, and IAP as well as the E2 mitochondrial autoantigens. To date, our RTPCR studies have revealed that all the RDA and 3 of 3 novel clones tested to data are not unique to PBC patients, suggesting that they may be derived from endogenous retroviruses. Also, we have conducted Western blot studies which reveal that approximately 74 percent of PBC patients sera have indeterminate reactivity to HIAP proteins and 35 percent of patients react to HIV p24 gag, compared to less than 5 percent of liver disease controls. This suggests that the putative PBC retrovirus shares antigenic determinants with HIV-I and HIAP-I but is a separate virus. In order to further characterize the agent associated with PBC, we plan to

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identify specific retroviral proteins and nucleic sequences with the ultimate goal of investigating the role this virus plays in the eitology of PBC. Our specific aims are to (1) Clone full length PBC retrovirus from hepatic tissue and PBC cDNA libraries; (2) Isolate the PBC retrovirus in lymphoblastoid and hepatic cell lines by co-culture with infected hepatic tissue; (3) Assess the prevalence of retroviral infection in PBC patients and controls by nucleic acid hybridization techniques and western blot experiments of recombinant or purified viral proteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF CD40-CD40 LIGAND IN PRIMARY BILIARY CIRRHOSIS Principal Investigator & Institution: Mayo, Marlyn J.; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2001; Project Start 15-MAY-2000; Project End 31-MAR-2003 Summary: (adapted from the application) Primary biliary cirrhosis is a chronic autoimmune liver disease characterized by inflammatory destruction of small and medium sized intrahepatic bile ducts, leading to cholestasis, then fibrosis, cirrhosis, and its complications. Although the etiology is unknown, T cells that surround the bile ductules are the likely mediators of bile duct destruction. Other cell types within the portal infiltrate, including macrophages and B cells, probably contribute to this autoimmune process. However, the manner in which these cells communicate and collaborate to cause bile duct lesions is not understood. The hypothesis of this proposed project is that T cells orchestrate the immune attack on cholangiocytes via signaling to other cells in the liver through CD40 ligand. Specifically, expression of CD40 ligand by activated T cells in the liver stimulates B cells to increase production of immunoglobulins; activates macrophages to produce IL-12, which leads to a shift of T helper cells to the Th1 phenotype and subsequent IL-2 and IFN-gamma production; and induces cholangiocytes to undergo apoptosis at an increased rate. This hypothesis will be tested by a correlative analysis of the level of expression of CD40 ligand in the liver of PBC patients with the potential consequences of CD40-CD40 ligand interaction; such as upregulation of immunoglobulin and cytokine production, and apoptosis of cholangiocytes. Expression of CD40 and CD40 ligand will be localized in the liver with immunohistochernistry. These patient-oriented studies will be supplemented by in vitro experiments designed to study CD40-ligand induced apoptosis in cholangiocytes. These studies will provide insight into the role of T cells in the pathogenesis of PBC and provide information useful in developing new treatment modalities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SMAD3 AS AN INHIBITOR OF ATHEROGENESIS Principal Investigator & Institution: Jain, Mukesh K.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): Recent studies have highlighted the importance of inflammation as a contributor to the pathogenesis of a number of chronic disease states such as rheumatoid arthritis, cirrhosis, glomerulosclerosis, inflammatory bowel disease and atherosclerosis. The infiltration of monocytes/macrophages is a characteristic feature seen in chronic inflammatory disease states. Indeed, experimental, clinical, and pathologic studies have established an essential role for the monocyte in the development of atherosclerotic lesions. As such, identification of mechanism(s) regulating monocyte/macrophage activation are of considerable interest. Transforming

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growth factor beta (TGFb1) is a potent inhibitor of inflammation and immune cell activation. Definitive evidence for this role is derived from the fact that mice deficient in this factor succumb to a systemic inflammatory wasting syndrome. TGFb1 is expressed in human atherosclerotic lesions and its levels correlate inversely with the severity of clinical disease. The mechanism(s) by which TGFb1 is able to inhibit immune cells remains poorly understood. Recently, a family of proteins termed Smads have been identified as effectors of TGFb1 signaling. We hypothesized that members of this family may regulate TGFb1?s inhibitory effects on monocytes. Indeed, we found that one of these factors, termed Smad3, was able to recapitulate the inhibitory properties of TGFb1 with respect to monocyte/macrophage activation. These studies also suggest that inhibition occurs through a novel mechanism involving competition for rate-limiting quantities of critical cellular regulatory factors (co-activator competition). Thus, the goals of this study are to define the role of Smad3 in monocyte biology. First, we will dissect the molecular mechanisms governing Smad3 mediated inhibition in macrophages. Second, we will overexpress Smad3 in macrophages and assess effects on specific effector functions such as elaboration of cytokines, matrix degrading enzymes and lipid uptake. Third, we will assess the effect of Smad3 deficiency on the development of atherosclerosis in mice. Collectively, these studies should provide insight into the role of Smad3 in mononuclear cell biology both in vitro and in vivo. Furthermore, these results may serve as the basis of novel strategies to limit mononuclear cell activation and inflammation in a number of human disease states, including atherosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURAL ANALYSIS OF THE HEPATITIS C CORE PROTEIN Principal Investigator & Institution: Allaire, Marc; Brookhaven Science AssocBrookhaven Lab Brookhaven National Lab Upton, Ny 11973 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JAN-2006 Summary: (provided by applicant): Hepatitis C virus (HCV) infection is recognized as a worldwide health problem affecting over 170 million individuals. In the United States, over 4 million peoples have been infected and 12,000 deaths yearly are due to hepatitis C. HCV is the most common reason for liver transplantation and accounts for one-third of hepatocellular carcinoma. Prevention of the HCV infection is impeded by the lack of protective vaccines and current therapies against HCV are unsatisfactory. There is clearly an urgent need for the development of new drugs. The molecular mechanisms of viral replication and viral assembly of HCV are poorly understood. It has been shown recently that nucleocapsid-like particles of HCV can be assembled from the HCV core protein that are identical to the HCV nucleocapsid from sera of infected patients. The aim of this proposal is to characterize the HCV core and capsid using macromolecular crystallography and to characterize the packaging signal on the viral RNA. The HCV core protein is the viral subunit of the HCV capsid. It appeared in the last few years that this protein is also very important for the pathogenesis of the disease by inducing cancer, cirrhosis and inflammation of the liver tissue. The resolution of the threedimensional structure of this protein and the capsid will not only help us to characterize the protein-protein interactions between the proteins subunits, the interaction between the subunits and the nucleic acid but also to resolve the surface of the capsid that interacts with several host factors responsible for different aspects of the pathogenesis of the disease. Altogether, the determination of the structure of the capsid will facilitate the development of research programs that aim to inhibit the assembly of the virus, a novel and very promising target for drug development.

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

Project Title: STUDIES OF THE NATURAL HISTORY OF HEPATITIS C IN LIVER Principal Investigator & Institution: Carithers, Robert L.; Director of Hepatology Section; Medicine; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2003 Summary: Chronic hepatitis C virus infection has emerged as the most important form of viral hepatitis in the United States. Although the disease often remains indolent for many years, approximately 20 percent of patients with chronic hepatitis C progress to cirrhosis within 20 years. As a consequence, liver failure from chronic hepatitis C has become the leading indication for liver transplantation both in the United States and Europe. Despite remarkable progress in our understanding of many aspects of this disease, the mechanism of hepatocellular injury in patients with chronic hepatitis C is not well understood. Unfortunately, neither efficient cell culture systems nor animal models are available to study the pathogenesis of the liver disease. Given these limitations, we have systematically examined the evolution of liver injury in patients with recurrent hepatitis C after liver transplantation. By correlating the degree of injury to the transplanted organ with detailed analyses of viral replication we hope to provide insights into the pathogenesis of liver cell injury in these chronically infected patients. This proposal is designed to examine the hypothesis that differing patterns of mutation in the genomic sequence of HCV RNA have a profound influence on the severity of liver injury in patients with recurrent hepatitis C after liver transplantation. Our Specific Aim 1 is to prospectively determine the relationship between evolution of HCV quasispecies and hepatocellular injury in patients with recurrent hepatitis C. In Specific Aim 2 we plan to intensively investigate the clonal evolution of quasispecies and to determine the tissue origin of these viral strains both in patients with severe recurrent hepatitis C and in those with mild hepatocellular injury after liver transplantation. We plan to test the hypothesis that the primary site of quasispecies replication is critical to the development of hepatocellular injury. We propose that emergence of nonpathogenic strains of virus after liver transplantation result from continuous extrahepatic replication of HCV, whereas pathogenic strains of HCV originate from intrahepatic replication of the virus. In Specific Aim 3 we plan to assess in impact of HCV genotype, circulating levels of virus, and evolution of HCV quasispecies on the long term evolution of histologic injury in the transplanted liver. By carefully correlating the evolution of the virus with the degree of hepatocellular injury experienced by patients who develop recurrent hepatitis C after liver transplantation, we hope to provide insights into to the pathogenesis of this important liver disease. From these detailed analyses we also hope to isolate pathogenic strains of virus which can later be tested in cell culture systems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STUDY OF T CELL CHARACTERISTICS AND ADHESION MOLECULES Principal Investigator & Institution: Bergasa, Nora V.; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: Primary biliary cirrhosis (PBC) is chronic liver disease of unknown etiology. Histologically, PBC is characterized by a progressive immunologically mediated inflammation known as chronic nonsuppurative destructive cholangitis (CNSDC) that leads to bile duct destruction, ductopenia and biliary cirrhosis. At present there is no

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cure for PBC. The most common symptoms associated with PBC are fatigue and pruritus. More than 90% of patients with PBC are women. The average age of diagnosis is about 50 years. Asymptomatic patients have a four-fold increase in mortality when compared to the U.S.A. population matched for age and the median survival from the onset of symptoms is 7.5 to 9 years. PBC is considered a model autoimmune disease; it is associated with hypergammaglobulinemia, autoantibodies, defects of immune regulation, and an increased incidence of other autoimmune conditions (thyroiditis, Sjogren's syndrome, scleroderma). The liver injury is characterized by a rich inflammatory infiltrate composed of CD4+ and CD8+ cells, cytokines, adhesion molecules and other immunologic mediators. The consequence of CNSDC is biliary cirrhosis and liver failure. The only treatment approved to treat PBC is ursodeoxycholic acid (UDCA), which appears to delay the time to liver transplantation but does not cure for the disease. Thus, the need for the provision of effective and safe treatments for PBC is clear. Patients with PBC may benefit from treatment with an appropriate immunosuppressive drug. Mycophenolate mofetil meets the criteria of a superior immunosuppressive agent. In this proposal we are going to explore immune mediators of PBC including T cells and adhesion molecules in patients with PBC and the effect of treatment with MMF in combination with UDCA on these factors in patients who are participants in a clinical trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE CNS AND CIRRHOSIS:PSYCHOBIOLOGICAL APPROACHES Principal Investigator & Institution: Stewart, Charmaine; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-DEC-2002 Summary: (provided by applicant): Hepatic encephalopathy (HE) is one of the most common manifestations of decompensated cirrhosis. Approximately 70% of patients with cirrhosis also have subacute hepatic encephalopathy (SHE), as demonstrated on neuropsychological testing. The use of transjugular intrahepatic portosystemic shunts (TIPS), which acts as a side-to-side shunt, has become common to manage complications of cirrhosis. However, TIPS are associated with adverse effects, including worsening of existing HE or the precipitation of overt HE and liver failure. Liver transplantation has become the ideal management for patients who have decompensated liver disease. The principal hypothesis of this proposal is that changes of HE and SHE can be determined by neuropsychological testing and changes in cerebral blood flow (CBF). The Specific Aims are the following: (1) Determine the changes in cognitive function in patients with cirrhosis; (2) Identify changes in CBF and neurotransmitter activity, as assessed by central benzodiazepine receptor binding and serotonin transporter binding after TIPS insertion; (3) Identify changes in CBF and neurotransmitter activity, as assessed by central benzodiazepine receptor binding and serotonin transporter binding after liver transplantation; and (4) Correlate the neuropsychological changes with cognitive function and central benzodiazepine receptor binding and serotonin transporter binding. These Specific Aims will be pursued in 60 subjects: group I will be 20 cirrhotics who will undergo TIPS; group II will be 20 cirrhotic patients who are scheduled to undergo liver transplantation; and group III will be 20 age and sex matched cirrhotic controls. All groups will be studied with a battery of neuropsychological tests and stimulated CBF, using 1502 labeled water, while half of groups I and II will be tested with 11C flumazenil PET or (11C)(+)McN5652 positron emission tomography (PET), in order to determine central benzodiazepine receptor binding and serotonin transporter binding, respectively, before and one month after undergoing TIPS or liver

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transplantation. The control group will be studied with 11C flumazenil PET or (11C)(+)McN5652 PET at baseline and 1 month, thereafter. In aggregate, these studies will provide a platform to elucidate cognitive and biological mechanisms underlying hepatic encephalopathy with the ultimate goal of enhancing diagnosis and management. Additionally, the proposed studies will be guided by a team of mentors and sponsors and supplemented by a didactic curriculum, all to lay the foundation for eventual independent clinical investigator status. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF LEPTIN IN LIVER FIBROGENESIS Principal Investigator & Institution: Anania, Frank A.; Assistant Professor; Medicine; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Non-alcoholic steatohepatitis or non-alcoholic fatty liver (NAFL) is a growing clinical problem that may account for a newly recognized etiology for cryptogenic cirrhosis. Leptin, a 16-kilodalton protein resulting from the transcription of the obese gene, is a hormone associated with weight and satiety control. NAFL, along with obesity, type II diabetes mellitus, and hyperlipidemia, are conditions characterized by high circulating concentrations of the hormone leptin. The overall goal of this proposal is to demonstrate the biological consequences of leptin as a novel mediator of liver fibrosis, the precursor to cirrhosis. Preliminary data indicate leptin has profibrogenic activity in the principal collagen producing cells of the liver, hepatic stellate cells (HSCs). In vivo data indicate that leptin is also required for liver fibrosis induced by carbon tetrachloride (CCl4) in lean, but not obese, mice. The preliminary data and the current proposal meet the long-term objectives of this laboratory: to understand basic mechanisms underlying chronic liver fibrosis. In this proposal, it is hypothesized that leptin is a profibrogenic cytokine in activated hepatic stellate cells and increases (2(I) collagen expression by phosphorylated signal transduction and activator of transcription (pSTAT) enhancing AP-1 binding to the alpha2(I) collagen promoter. Three aims are outlined to test this hypothesis. First to (a) further characterize leptin as a novel profibrogenic cytokine by examining genes responsible for increased extracellular matrix (ECM) production in fibrotic liver; and (b) to elucidate the specific signal transduction pathway(s) responsible for the effect of leptin on (2(I) collagen expression in HSCs. Second to (a) characterize leptin-associated alpha2(I) collagen mRNA stabilization; to (b) identify specific cis-acting elements along the human alpha2(I) collagen promoter affected by leptin signaling that are responsible for increased collagen gene expression by employing deletion mutant and site-directed mutagenesis; and (c) to identify, by DNase I protection analysis and electrophoretic mobility shift assay, specific transcription factors associated with leptin altered collagen gene expression. Third, to exploit rodent animal models of obesity, and their lean littermates, to determine the mechanisms by which leptin may be required for liver fibrosis in wildtype mice exposed to CC14 but not in identically treated db/db or ob/ob mice; and whether leptin is required in a common bile duct ligation (CBDL) injury model using fa/fa, or Zucker Diabetic Fatty (ZDF) rats and their lean littermates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: URSODIOL-METHOTREXATE FOR PRIMARY BILIARY CIRRHOSIS Principal Investigator & Institution: Combes, Burton; Professor of Internal Medicine; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105

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Timing: Fiscal Year 2001; Project Start 01-APR-1993; Project End 31-MAR-2004 Summary: The major thrust of this randomized, double-blinded clinical trial is to determine whether treatment of patients with Primary Biliary Cirrhosis (PBC) with Ursodiol (Ursodeoxycholic Acid-UDCA) plus methotrexate (MTX) is more effective than treatment with UDCA alone. PBC is a chronic cholestatic liver disease, predominantly of women, in which interlobular and septal bile ducts undergo inflammation and destruction. Once initiated, the disease persists and progresses at varying rates. Neither the initiating nor perpetuating mechanisms are well understood. Current concepts of pathogenesis include (1) destruction of bile ducts is maintained and perhaps initiated by autoimmune mechanisms; (2) hydrophobic bile acids which accumulate in serum and liver cause functional and cytotoxic liver injury; (3) cytokines and lymphokines released at sites of inflammation may contribute to cell damage and fibrosis. A considerable body of evidence indicates that UDCA when fed orally leads to improvement in liver tests, in pruritus and in liver histology. There exist differences in opinion as to whether development of complications of liver disease, liver transplantation or transplant-free survival is affected. UDCA a relatively non-toxic bile acid, when administered orally, alters the composition of the bile acid pool in factor of its enrichment with UDCA and appears to protect against the cytotoxic effects of endogenous bile acids that accumulate as a result of bile duct destruction. MTX is being shown to improve liver tests, symptoms and liver histology in a small number of precirrhotic patients with PBC. The mechanism of action is unknown but felt to be related to antiinflammatoryimmunosuppressive effects of MTX. The current trial explores whether MTX improves the therapeutic effects of UDCA in PBC. Patients with PBC whose serum bilirubin is less than 3 mg percent, who have been on UDCA for at least 6 months, and who satisfy a series of inclusion and exclusion criteria are stratified into 2 groups on the basis of liver histologic stage (Ludwig classification), i.e. early (Stages I or II) versus late (Stages III or IV). They are then randomized to receive either methotrexate or its placebo as a second drug while continuing to receive UDCA. The relative value of the two treatment arms is assessed by comparing their effects on symptoms, results of laboratory tests, development of complications of liver disease, histologic changes in liver, liver transplantation, and on transplant-free survival. The safety of each therapeutic regimen is also being determined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CIRRHOSIS

XENOGENEIC

HEPATOCYTE

TRANSPLANTATION

FOR

Principal Investigator & Institution: Fox, Ira J.; Professor; Surgery; University of Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-DEC-2006 Summary: (provided by applicant): The vast majority of patients awaiting organ transplantation have end-stage chronic liver disease secondary to cirrhosis. Hepatocyte transplantation has several important advantages over organ transplantation and was recently shown to prolong the survival and improve the physiologic abnormalities associated with cirrhosis and end-stage liver disease in rodents. The number of human livers available for hepatocyte isolation and later transplantation, however, is limited. One possible solution to the human donor availability issue is transplantation of hepatocytes from pigs. Two major concerns regarding the use of porcine hepatocytes in man relate to the degree to which xenogeneic hepatocytes can restore normal liver physiology to patients with liver dysfunction and the immunological response to liver cells or their products. Preliminary studies indicate that immunosuppression may not be

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needed to improve the survival or function of allogeneic rat or pig hepatocytes transplanted in cirrhotic rats. However, specific antibody and cellular immune responses to pig hepatocytes vary by species and the specific physiologic compatibility and function of pig liver proteins in man is unknown. We now propose to extend our observations in a primate model that will serve as a prelude to clinical application. The aims of this proposal are: 1) To test the degree to which porcine hepatocyte transplantation can improve liver function in cirrhotic non-human primates; 2) To examine whether pig hepatocytes are susceptible to rejection mediated by anti-swine antibodies and test whether the primate immune response to porcine hepatocytes is significantly different in cirrhotic versus non-cirrhotic recipients; and 3) To determine whether porcine hepatocyte transplantation leads to systemic complications that include a) immune complex formation, b) activation of the coagulation/complement system and c) immune sensitization that may preclude later allotransplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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

A comparison of Child-Pugh, APACHE II and APACHE III scoring systems in predicting hospital mortality of patients with liver cirrhosis. by Chatzicostas C, Roussomoustakaki M, Notas G, Vlachonikolis IG, Samonakis D, Romanos J, Vardas E, Kouroumalis EA.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156886

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A systematic review of the diagnostic accuracy of physical examination for the detection of cirrhosis. by de Bruyn G, Graviss EA.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64783

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Cirrhosis mortality and per capita consumption of distilled spirits, United States, 1949-94: trend analysis. by Roizen R, Kerr WC, Fillmore KM.; 1999 Sep 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28217

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Combinatorial Autoantibodies to Dihydrolipoamide Acetyltransferase, the Major Autoantigen of Primary Biliary Cirrhosis. by Cha S, Leung PS, Gershwin ME, Fletcher MP, Ansari AA, Coppel RL.; 1993 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46121

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. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.

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Different degrees of malnutrition and immunological alterations according to the aetiology of cirrhosis: a prospective and sequential study. by Caly WR, Strauss E, Carrilho FJ, Laudanna AA.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=270012

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Identification of Helicobacter pylori and Other Helicobacter Species by PCR, Hybridization, and Partial DNA Sequencing in Human Liver Samples from Patients with Primary Sclerosing Cholangitis or Primary Biliary Cirrhosis. by Nilsson HO, Taneera J, Castedal M, Glatz E, Olsson R, Wadstrom T.; 2000 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86342

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Pharmacokinetics of Dirithromycin in Patients with Mild or Moderate Cirrhosis. by Mazzei T, Surrenti C, Novelli A, Biagini MR, Fallani S, Cassetta MI, Conti S, Surrenti E.; 1999 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89323

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Primary biliary cirrhosis and autoimmune cholangitis are not associated with coeliac disease in Crete. by Chatzicostas C, Roussomoustakaki M, Drygiannakis D, Niniraki M, Tzardi M, Koulentaki M, Dimoulios P, Mouzas I, Kouroumalis E.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102761

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Quantitative and functional analysis of PDC-E2 --specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. by Kita H, Matsumura S, He XS, Ansari AA, Lian ZX, Van de Water J, Coppel RL, Kaplan MM, Gershwin ME.; 2002 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150963

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Reactivity of Primary Biliary Cirrhosis Sera with Escherichia coli Dihydrolipoamide Acetyltransferase (E2p): Characterization of the Main Immunogenic Region. by Fussey SP, Ali ST, Guest JR, James OF, Bassendine MF, Yeaman SJ.; 1990 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54029

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Recurrent Bacteremic Peritonitis Caused by Enterococcus cecorum in a Patient with Liver Cirrhosis. by Hsueh PR, Teng LJ, Chen YC, Yang PC, Ho SW, Luh KT.; 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86842

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 cirrhosis, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “cirrhosis” (or

6

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

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synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for cirrhosis (hyperlinks lead to article summaries): •

A 38-year-old African-American woman with an unusually rapid progression of “Primary Biliary Cirrhosis”: a missed opportunity! Author(s): van Leeuwen DJ, Sood G, Ferrante D, Lazenby AJ, Sellers MJ. Source: Seminars in Liver Disease. 2002 November; 22(4): 395-406. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12447711&dopt=Abstract

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A case of well-differentiated hepatocellular carcinoma arising in primary biliary cirrhosis. Author(s): Yano Y, Yoon S, Seo Y, Ninomiya T, Nagano H, Nakaji M, Hayashi Y, Kasuga M. Source: The Kobe Journal of Medical Sciences. 2003; 49(1-2): 39-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12796567&dopt=Abstract

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A diagnostic significance of early renal impairment with liver cirrhosis through the determination of urinary enzymes. Author(s): Zhou Z, Li S, Dai W, Li M, Wang Y. Source: Chinese Medical Sciences Journal = Chung-Kuo I Hsueh K'o Hsueh Tsa Chih / Chinese Academy of Medical Sciences. 1999 September; 14(3): 162. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12903816&dopt=Abstract

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A fatal case of toxic epidermal necrolysis associated with liver cirrhosis. Author(s): Uzum K, Caksen H, Gunduz Z, Ustunbas HB, Kandemir O. Source: The Journal of Emergency Medicine. 2003 January; 24(1): 92-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554048&dopt=Abstract

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A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis. Author(s): Chagnon P, Michaud J, Mitchell G, Mercier J, Marion JF, Drouin E, RasquinWeber A, Hudson TJ, Richter A. Source: American Journal of Human Genetics. 2002 December; 71(6): 1443-9. Epub 2002 November 04. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12417987&dopt=Abstract

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A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis. Author(s): Lucena JF, Herrero JI, Quiroga J, Sangro B, Garcia-Foncillas J, Zabalegui N, Sola J, Herraiz M, Medina JF, Prieto J. Source: Gastroenterology. 2003 April; 124(4): 1037-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12671900&dopt=Abstract

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A patient with hepatitis C-related cirrhosis and hepatocellular carcinoma who was cured with an orthotopic liver transplantation and interferon therapy. Author(s): Shibata M, Yanaga K, Morizane T, Yanagawa T, Hirakawa M, Ueno Y, Esquivel CO, Mitamura K. Source: Journal of Gastroenterology. 2003; 38(6): 598-602. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858850&dopt=Abstract

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A patient with primary biliary cirrhosis complicated with slowly progressive insulindependent diabetes mellitus. Author(s): Nakasone H, Kinjo K, Yamashiro M, Kamiyama T, Kamiyama S, Miyazato H, Matsushita T, Arakawa Y, Ohshiro T, Toma S, Chinen K, Yamashiro M, Miyagi M, Makishi T, Hokama A, Sakugawa H, Kinjo F, Saito A. Source: Intern Med. 2003 June; 42(6): 496-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857047&dopt=Abstract

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A patient with Takayasu's arteritis treated with corticosteroids who developed primary biliary cirrhosis. Author(s): Ito S, Ohkoshi S, Aoyagi T, Suzuki K, Takahashi T, Nomoto M, Nakano M, Arakawa M, Asakura H, Gejyo F. Source: Intern Med. 2003 May; 42(5): 443-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12793718&dopt=Abstract

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A randomized controlled trial of ursodeoxycholic acid in patients with alcoholinduced cirrhosis and jaundice. Author(s): Pelletier G, Roulot D, Davion T, Masliah C, Causse X, Oberti F, Raabe JJ, Van Lemmens C, Labadie H, Serfaty L; URSOMAF Group. Source: Hepatology (Baltimore, Md.). 2003 April; 37(4): 887-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12668982&dopt=Abstract

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A role of autoantibody-mediated platelet destruction in thrombocytopenia in patients with cirrhosis. Author(s): Kajihara M, Kato S, Okazaki Y, Kawakami Y, Ishii H, Ikeda Y, Kuwana M. Source: Hepatology (Baltimore, Md.). 2003 June; 37(6): 1267-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12774004&dopt=Abstract

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A scoring system for primary biliary cirrhosis and its application for variant forms of autoimmune liver disease. Author(s): Yamamoto K, Terada R, Okamoto R, Hiasa Y, Abe M, Onji M, Tsuji T. Source: Journal of Gastroenterology. 2003; 38(1): 52-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12560922&dopt=Abstract

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A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Author(s): Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, Lok AS. Source: Hepatology (Baltimore, Md.). 2003 August; 38(2): 518-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12883497&dopt=Abstract

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A study of hepatopulmonary syndrome among patients of cirrhosis of liver and portal hypertension. Author(s): Hira HS, Kumar J, Tyagi SK, Jain SK. Source: Indian J Chest Dis Allied Sci. 2003 July-September; 45(3): 165-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12866633&dopt=Abstract

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A trial on regeneration therapy of rat liver cirrhosis by controlled release of hepatocyte growth factor. Author(s): Oe S, Fukunaka Y, Hirose T, Yamaoka Y, Tabata Y. Source: Journal of Controlled Release : Official Journal of the Controlled Release Society. 2003 March 7; 88(2): 193-200. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628327&dopt=Abstract

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Accumulating CD57 + CD3 + natural killer T cells are related to intrahepatic bile duct lesions in primary biliary cirrhosis. Author(s): Harada K, Isse K, Tsuneyama K, Ohta H, Nakanuma Y. Source: Liver International : Official Journal of the International Association for the Study of the Liver. 2003 April; 23(2): 94-100. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12654131&dopt=Abstract

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Advanced intrahepatic cholangiocarcinoma in hepatitis C virus-related decompensated cirrhosis: case report and review of the literature. Author(s): Polizos A, Kelekis N, Sinani C, Patsiaoura K, Papadamou G, Dalekos GN. Source: European Journal of Gastroenterology & Hepatology. 2003 March; 15(3): 331-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12610331&dopt=Abstract

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Alcohol consumption and liver cirrhosis mortality with and without mention of alcohol--the case of Canada. Author(s): Ramstedt M. Source: Addiction (Abingdon, England). 2003 September; 98(9): 1267-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12930214&dopt=Abstract

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Alterations of RB1, p53 and Wnt pathways in hepatocellular carcinomas associated with hepatitis C, hepatitis B and alcoholic liver cirrhosis. Author(s): Edamoto Y, Hara A, Biernat W, Terracciano L, Cathomas G, Riehle HM, Matsuda M, Fujii H, Scoazec JY, Ohgaki H. Source: International Journal of Cancer. Journal International Du Cancer. 2003 September 1; 106(3): 334-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12845670&dopt=Abstract

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Anterior uveitis and Sjogren's syndrome in a patient with primary biliary cirrhosis. Author(s): Tekeli O, Ozdemir O. Source: Can J Ophthalmol. 2002 October; 37(6): 359-60. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12422919&dopt=Abstract

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Anti-mitochondrial antibodies in primary biliary cirrhosis. Author(s): Neuberger J, Bradwell AR. Source: Journal of Hepatology. 2002 December; 37(6): 712-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12445409&dopt=Abstract

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Antimitochondrial antibodies in primary biliary cirrhosis: the role of xenobiotics. Author(s): Long SA, Van de Water J, Gershwin ME. Source: Autoimmunity Reviews. 2002 February; 1(1-2): 37-42. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849056&dopt=Abstract

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Ascites and hepatorenal syndrome in cirrhosis: pathophysiological basis of therapy and current management. Author(s): Arroyo V, Colmenero J. Source: Journal of Hepatology. 2003; 38 Suppl 1: S69-89. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591187&dopt=Abstract

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Assessment of insulin sensitivity based on a fasting blood sample in men with liver cirrhosis before and after liver transplantation. Author(s): Perseghin G, Caumo A, Mazzaferro V, Pulvirenti A, Piceni Sereni L, Romito R, Lattuada G, Coppa J, Costantino F, Regalia E, Luzi L. Source: Transplantation. 2003 August 27; 76(4): 697-702. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12973112&dopt=Abstract

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Assessment of portal hemodynamics by ultrasound color Doppler and laser Doppler velocimetry in liver cirrhosis. Author(s): Vyas K, Gala B, Sawant P, Das HS, Kulhalli PM, Mahajan SS. Source: Indian J Gastroenterol. 2002 September-October; 21(5): 176-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12416745&dopt=Abstract

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Association of coeliac disease with primary biliary cirrhosis in Poland. Author(s): Habior A, Lewartowska A, Orlowska J, Zych W, Sankowska M, Bauer A, Butruk E. Source: European Journal of Gastroenterology & Hepatology. 2003 February; 15(2): 15964. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12560760&dopt=Abstract

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Association of single nucleotide polymorphisms of the interleukin-10 promoter gene and susceptibility to primary biliary cirrhosis: immunogenetic differences in Italian and Japanese patients. Author(s): Matsushita M, Tanaka A, Kikuchi K, Kitazawa E, Kawaguchi N, Kawashima Y, Kato T, Fujikawa H, Quaranta S, Rosina F, Gershwind ME, Miyakawa H. Source: Autoimmunity. 2002 December; 35(8): 531-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765479&dopt=Abstract

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Autoantibodies to the transcriptional factor SOX13 in primary biliary cirrhosis compared with other diseases. Author(s): Fida S, Myers MA, Whittingham S, Rowley MJ, Ozaki S, Mackay IR. Source: Journal of Autoimmunity. 2002 December; 19(4): 251-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12473246&dopt=Abstract

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Autonomic neuropathy in patients with hepatic cirrhosis. Author(s): Bajaj BK, Agarwal MP, Ram BK. Source: Postgraduate Medical Journal. 2003 July; 79(933): 408-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12897221&dopt=Abstract

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Auxiliary partial orthotopic living donor liver transplantation for alcoholic liver cirrhosis: a case report. Author(s): Kobayashi T, Sato Y, Ichida T, Yamamoto S, Oya H, Nakatsuka H, Watanabe T, Kameyama H, Hatakeyama K. Source: Transplantation Proceedings. 2003 February; 35(1): 345-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591433&dopt=Abstract

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Breast carcinoma metastases to the liver simulating cirrhosis. Author(s): Burkill GJ, King LJ, Scurr E, Healy JC. Source: Radiology. 2002 December; 225(3): 917; Author Reply 917-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12461279&dopt=Abstract

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Calcified portal vein aneurysm and porto-hepatic venous shunt in a patient with liver cirrhosis. Author(s): So NM, Lam WW. Source: Clinical Radiology. 2003 September; 58(9): 742-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12943650&dopt=Abstract

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Can quantitative tests of liver function discriminate between different etiologies of liver cirrhosis? Author(s): Herold C, Regn S, Ganslmayer M, Ocker M, Hahn EG, Schuppan D. Source: Digestive Diseases and Sciences. 2002 December; 47(12): 2669-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12498283&dopt=Abstract

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Capillarization of hepatic sinusoid by liver endothelial cell-reactive autoantibodies in patients with cirrhosis and chronic hepatitis. Author(s): Xu B, Broome U, Uzunel M, Nava S, Ge X, Kumagai-Braesch M, Hultenby K, Christensson B, Ericzon BG, Holgersson J, Sumitran-Holgersson S. Source: American Journal of Pathology. 2003 October; 163(4): 1275-89. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14507637&dopt=Abstract

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Cardiac output determined by echocardiography in patients with cirrhosis: comparison with the indicator dilution technique. Author(s): Andersen UB, Moller S, Bendtsen F, Henriksen JH. Source: European Journal of Gastroenterology & Hepatology. 2003 May; 15(5): 503-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12702907&dopt=Abstract

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Central and noncentral blood volumes in cirrhosis: relationship to anthropometrics and gender. Author(s): Moller S, Henriksen JH, Bendtsen F. Source: American Journal of Physiology. Gastrointestinal and Liver Physiology. 2003 June; 284(6): G970-9. Epub 2003 February 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12606306&dopt=Abstract

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Central nervous system alterations in liver cirrhosis: the role of portal-systemic shunt and portal hypoperfusion. Author(s): Del Piccolo F, Sacerdoti D, Amodio P, Bombonato G, Bolognesi M, Mapelli D, Gatta A. Source: Metabolic Brain Disease. 2003 March; 18(1): 51-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603082&dopt=Abstract

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Central nervous system alterations in liver cirrhosis: the role of portal-systemic shunt and portal hypoperfusion. Author(s): Del Piccolo F, Sacerdoti D, Amodio P, Bombonato G, Bolognesi M, Mapelli D, Gatta A. Source: Metabolic Brain Disease. 2002 December; 17(4): 347-58. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12602511&dopt=Abstract

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Cholangiocarcinoma in liver cirrhosis. Author(s): Hui CK, Yuen MF, Tso WK, Ng IO, Chan AO, Lai CL. Source: Journal of Gastroenterology and Hepatology. 2003 March; 18(3): 337-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603537&dopt=Abstract

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Chronic parkinsonism associated with cirrhosis: a distinct subset of acquired hepatocerebral degeneration. Author(s): Burkhard PR, Delavelle J, Du Pasquier R, Spahr L. Source: Archives of Neurology. 2003 April; 60(4): 521-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12707065&dopt=Abstract

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Cirrhosis as a risk factor for sepsis and death: analysis of the National Hospital Discharge Survey. Author(s): Foreman MG, Mannino DM, Moss M. Source: Chest. 2003 September; 124(3): 1016-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970032&dopt=Abstract

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Cirrhosis in a young woman from Central America. Author(s): Julapalli V, Duchini A. Source: Medgenmed [electronic Resource] : Medscape General Medicine. 2003 February 3; 5(1): 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12827076&dopt=Abstract

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Cirrhosis with steatohepatitis following longterm stilboestrol treatment. Author(s): Cooper L, Palmer M, Oien K. Source: Journal of Clinical Pathology. 2003 August; 56(8): 639. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12890826&dopt=Abstract

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Cirrhosis: new research provides a basis for rational and targeted treatments. Author(s): Iredale JP. Source: Bmj (Clinical Research Ed.). 2003 July 19; 327(7407): 143-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12869458&dopt=Abstract

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Clinical and neurohumoral response to posture, physical exercise, and ascites treatment in Child-Pugh C liver cirrhosis: randomized prospective trial. Author(s): Degoricija V, Zjacic-Rotkvic V, Marout J, Sefer S, Troskot B. Source: Croatian Medical Journal. 2003 April; 44(2): 178-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12698509&dopt=Abstract

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Clinical significance of basal ganglia alterations at brain MRI and 1H MRS in cirrhosis and role in the pathogenesis of hepatic encephalopathy. Author(s): Spahr L, Burkhard PR, Grotzsch H, Hadengue A. Source: Metabolic Brain Disease. 2002 December; 17(4): 399-413. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12602516&dopt=Abstract

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Colonic wall thickening in patients with cirrhosis and portal hypertension. Author(s): Quilez C, Palazon JM, Arenas J, Alonso S, Sanchez J, Belda G, Perez-Mateo M. Source: Rev Esp Enferm Dig. 2003 April; 95(4): 269-72, 265-8. English, Spanish. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828526&dopt=Abstract

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Comparison of Doppler ultrasonography and the hepatic venous pressure gradient in assessing portal hypertension in liver cirrhosis. Author(s): Choi YJ, Baik SK, Park DH, Kim MY, Kim HS, Lee DK, Kwon SO, Kim YJ, Park JW. Source: Journal of Gastroenterology and Hepatology. 2003 April; 18(4): 424-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12653891&dopt=Abstract

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Complications of cirrhosis. Author(s): Mendez C, Marsano L, Wright R. Source: J Ky Med Assoc. 2003 September; 101(9): 403-14. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14556436&dopt=Abstract

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Concomitant hepatocellular adenoma and adenomatous hyperplasia in a patient without cirrhosis. Author(s): Hsu CY, Chu CH, Lin SC, Yang FS, Yang TL, Chang KM. Source: World Journal of Gastroenterology : Wjg. 2003 March; 9(3): 627-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12632534&dopt=Abstract

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Consistently low hepatitis B virus DNA saves patients from hepatocellular carcinogenesis in HBV-related cirrhosis. A nested case-control study using 96 untreated patients. Author(s): Ikeda K, Arase Y, Kobayashi M, Someya T, Saitoh S, Suzuki Y, Suzuki F, Tsubota A, Akuta N, Kumada H. Source: Intervirology. 2003; 46(2): 96-104. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12684548&dopt=Abstract

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Construction and expression of a humanized M2 autoantigen trimer and its application in the diagnosis of primary biliary cirrhosis. Author(s): Jiang XH, Zhong RQ, Yu SQ, Hu Y, Li WW, Kong XT. Source: World Journal of Gastroenterology : Wjg. 2003 June; 9(6): 1352-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12800255&dopt=Abstract

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Continuous versus intermittent portal triad clamping during hepatectomy in cirrhosis. Results of a prospective, randomized clinical trial. Author(s): Capussotti L, Nuzzo G, Polastri R, Giuliante F, Muratore A, Giovannini I. Source: Hepatogastroenterology. 2003 July-August; 50(52): 1073-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12845985&dopt=Abstract

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Correlation between histopathological findings of the liver and IgA class antibodies to 2-oxo-acid dehydrogenase complex in primary biliary cirrhosis. Author(s): Masuda J, Omagari K, Ohba K, Hazama H, Kadokawa Y, Kinoshita H, Hayashida K, Hayashida K, Ishibashi H, Nakanuma Y, Kohno S. Source: Digestive Diseases and Sciences. 2003 May; 48(5): 932-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12772793&dopt=Abstract

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Correlation between ultrasonographic and pathologic diagnoses of hepatitis B and C virus-related cirrhosis. Author(s): Hung CH, Lu SN, Wang JH, Lee CM, Chen TM, Tung HD, Chen CH, Huang WS, Changchien CS. Source: Journal of Gastroenterology. 2003; 38(2): 153-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640529&dopt=Abstract

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Costs and clinical outcomes of primary prophylaxis of variceal bleeding in patients with hepatic cirrhosis: a decision analytic model. Author(s): Saab S, DeRosa V, Nieto J, Durazo F, Han S, Roth B. Source: The American Journal of Gastroenterology. 2003 April; 98(4): 763-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12738453&dopt=Abstract

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Cryptogenic cirrhosis: clinicopathologic findings at and after liver transplantation. Author(s): Ayata G, Gordon FD, Lewis WD, Pomfret E, Pomposelli JJ, Jenkins RL, Khettry U. Source: Human Pathology. 2002 November; 33(11): 1098-104. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454814&dopt=Abstract

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CT detection of hepatocellular carcinoma in advanced liver cirrhosis: correlation of helical CT and explanted liver. Author(s): Lim JH, Kim MJ, Chiang LW, Lim HK, Park CK, Paik SW, Koh KC, Joh JW. Source: Taehan Kan Hakhoe Chi = the Korean Journal of Hepatology. 2002 June; 8(2): 201-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12499806&dopt=Abstract

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Current aspects of antibiotic prophylaxis for upper gastrointestinal bleeding in cirrhosis patients. Author(s): Almeida D, Parana R. Source: The Brazilian Journal of Infectious Diseases : an Official Publication of the Brazilian Society of Infectious Diseases. 2002 October; 6(5): 266-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495610&dopt=Abstract

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Current pharmacotherapy in the management of cirrhosis: focus on the hyperdynamic circulation. Author(s): Vaughan RB, Chin-Dusting JP. Source: Expert Opinion on Pharmacotherapy. 2003 May; 4(5): 625-37. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12739989&dopt=Abstract

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Cyclospora cayetanensis associated with diarrhea in a patient with idiopathic compensated hepatic cirrhosis. Author(s): Yazar S, Yaman O, Demirtas F, Yalcin S, Yucesoy M, Sahin I. Source: Acta Gastroenterol Belg. 2002 October-December; 65(4): 241-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12619434&dopt=Abstract

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Decompensated hepatitis B virus-related cirrhosis successfully treated with lamivudine allowing surgery for hepatocellular carcinoma. Author(s): Nakanishi S, Michitaka K, Miyake T, Hidaka S, Yoshino I, Konishi I, Iuchi H, Horiike N, Onji M. Source: Intern Med. 2003 May; 42(5): 416-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12793712&dopt=Abstract

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Decreased muscle strength and contents of Mg and Na,K-pumps in chronic alcoholics occur independently of liver cirrhosis. Author(s): Aagaard NK, Andersen H, Vilstrup H, Clausen T, Jakobsen J, Dorup I. Source: Journal of Internal Medicine. 2003 March; 253(3): 359-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603504&dopt=Abstract

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Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis. Author(s): Colucci M, Binetti BM, Branca MG, Clerici C, Morelli A, Semeraro N, Gresele P. Source: Hepatology (Baltimore, Md.). 2003 July; 38(1): 230-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12830006&dopt=Abstract

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Developing a prediction rule to assess hepatic malignancy in patients with cirrhosis. Author(s): Carlos RC, Kim HM, Hussain HK, Francis IR, Nghiem HV, Fendrick AM. Source: Ajr. American Journal of Roentgenology. 2003 April; 180(4): 893-900. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12646426&dopt=Abstract

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Diagnostic accuracy of alpha(1)-acid glycoprotein fucosylation for liver cirrhosis in patients undergoing hepatic biopsy. Author(s): Ryden I, Pahlsson P, Lindgren S. Source: Clinical Chemistry. 2002 December; 48(12): 2195-201. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12446476&dopt=Abstract

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Differential expression of toll-like receptors 2 and 4 in patients with liver cirrhosis. Author(s): Manigold T, Bocker U, Hanck C, Gundt J, Traber P, Antoni C, Rossol S. Source: European Journal of Gastroenterology & Hepatology. 2003 March; 15(3): 275-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12610323&dopt=Abstract

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Differential gene expression in distinct virologic types of hepatocellular carcinoma: association with liver cirrhosis. Author(s): Iizuka N, Oka M, Yamada-Okabe H, Mori N, Tamesa T, Okada T, Takemoto N, Hashimoto K, Tangoku A, Hamada K, Nakayama H, Miyamoto T, Uchimura S, Hamamoto Y. Source: Oncogene. 2003 May 15; 22(19): 3007-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12771952&dopt=Abstract

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Disappearance of hepatic encephalopathy and improvement of liver function after surgical treatment of portal-systemic shunt in a patient with liver cirrhosis. Author(s): Moriya K, Kojima H, Matsumura M, Sakurai S, Imazu H, Uemura M, Honda H, Fukui H. Source: Hepatogastroenterology. 2003 July-August; 50(52): 1128-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12845996&dopt=Abstract

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Discussion on the true impact of fatigue in primary biliary cirrhosis: a population study. Author(s): Kingham JG. Source: Gastroenterology. 2003 February; 124(2): 582; Author Reply 582. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12557171&dopt=Abstract

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Does a betaretrovirus infection trigger primary biliary cirrhosis? Author(s): Xu L, Shen Z, Guo L, Fodera B, Keogh A, Joplin R, O'Donnell B, Aitken J, Carman W, Neuberger J, Mason A. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 July 8; 100(14): 8454-9. Epub 2003 June 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12832623&dopt=Abstract

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Dramatic reduction of the alpha-fetoprotein level after lamivudine treatment of patients with chronic hepatitis B virus infection and cirrhosis. Author(s): Yao FY. Source: Journal of Clinical Gastroenterology. 2003 May-June; 36(5): 440-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12702990&dopt=Abstract

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Drug use for non-hepatic associated conditions in patients with liver cirrhosis. Author(s): Lucena MI, Andrade RJ, Tognoni G, Hidalgo R, Sanchez de la Cuesta F; Spanish Collaborative Study Group on Therapeutic Management of Liver Diseases. Source: European Journal of Clinical Pharmacology. 2003 May; 59(1): 71-6. Epub 2003 April 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12684727&dopt=Abstract

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Dysfunction of the hypothalamic-pituitary-glandular axes and relation to Child-Pugh classification in male patients with alcoholic and virus-related cirrhosis. Author(s): Zietz B, Lock G, Plach B, Drobnik W, Grossmann J, Scholmerich J, Straub RH. Source: European Journal of Gastroenterology & Hepatology. 2003 May; 15(5): 495-501. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12702906&dopt=Abstract

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Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients. Author(s): Fattovich G, Pantalena M, Zagni I, Realdi G, Schalm SW, Christensen E; European Concerted Action on Viral Hepatitis (EUROHEP). Source: The American Journal of Gastroenterology. 2002 November; 97(11): 2886-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12425564&dopt=Abstract

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Effect of hepatitis C virus infection and abstinence from alcohol on survival in patients with alcoholic cirrhosis. Author(s): Serra MA, Escudero A, Rodriguez F, del Olmo JA, Rodrigo JM. Source: Journal of Clinical Gastroenterology. 2003 February; 36(2): 170-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544203&dopt=Abstract

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Effects of orthotopic liver transplantation on vasoactive systems and renal function in patients with advanced liver cirrhosis. Author(s): Cassinello C, Moreno E, Gozalo A, Ortuno B, Cuenca B, Solis-Herruzo JA. Source: Digestive Diseases and Sciences. 2003 January; 48(1): 179-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12645807&dopt=Abstract

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Efficacy of colchicine in patients with primary biliary cirrhosis poorly responsive to ursodiol and methotrexate. Author(s): Lee YM, Kaplan MM. Source: The American Journal of Gastroenterology. 2003 January; 98(1): 205-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12526960&dopt=Abstract

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Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis. Author(s): Mao TK, Kimura Y, Kenny TP, Branchi A, Gishi RG, Van de Water J, Kung HJ, Friedman SL, Gershwin ME. Source: Autoimmunity. 2002 December; 35(8): 521-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765478&dopt=Abstract

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Elevated nitric oxide levels in patients with chronic liver disease and cirrhosis correlate with disease stage and parameters of hyperdynamic circulation. Author(s): Arkenau HT, Stichtenoth DO, Frolich JC, Manns MP, Boker KH. Source: Zeitschrift Fur Gastroenterologie. 2002 November; 40(11): 907-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12436367&dopt=Abstract

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Emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis: a Cochrane meta-analysis. Author(s): D'Amico G, Pietrosi G, Tarantino I, Pagliaro L. Source: Gastroenterology. 2003 May; 124(5): 1277-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12730868&dopt=Abstract

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Endoscopic screening for esophageal varices in cirrhosis: Is it ever cost effective? Author(s): Spiegel BM, Targownik L, Dulai GS, Karsan HA, Gralnek IM. Source: Hepatology (Baltimore, Md.). 2003 February; 37(2): 366-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12540787&dopt=Abstract

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Enhanced intrahepatic inducible nitric oxide synthase expression and nitrotyrosine accumulation in primary biliary cirrhosis and autoimmune hepatitis. Author(s): Sanz-Cameno P, Medina J, Garcia-Buey L, Garcia-Sanchez A, Borque MJ, Martin-Vilchez S, Gamallo C, Jones EA, Moreno-Otero R. Source: Journal of Hepatology. 2002 December; 37(6): 723-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12445411&dopt=Abstract

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Enhanced renal ammonia excretion following volume expansion in patients with well compensated cirrhosis of the liver. Author(s): Jalan R, Kapoor D. Source: Gut. 2003 July; 52(7): 1041-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12801964&dopt=Abstract

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Enhanced vasodilatation to endothelin antagonism in patients with compensated cirrhosis and the role of nitric oxide. Author(s): Helmy A, Newby DE, Jalan R, Hayes PC, Webb DJ. Source: Gut. 2003 March; 52(3): 410-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12584225&dopt=Abstract

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Epistaxis: an overlooked cause of massive haematemesis in cirrhosis. Author(s): Johal SS, Austin AS, Ryder SD. Source: Bmj (Clinical Research Ed.). 2003 February 22; 326(7386): 440-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12595387&dopt=Abstract

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Escherichia coli myonecrosis in alcoholic cirrhosis. Author(s): Levy V, Reed C, Abbott SL, Israelski D. Source: Journal of Clinical Gastroenterology. 2003 May-June; 36(5): 443-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12702991&dopt=Abstract

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Ethnic differences in cirrhosis of the liver in a British city: alcoholic cirrhosis in South Asian men. Author(s): Douds AC, Cox MA, Iqbal TH, Cooper BT. Source: Alcohol and Alcoholism (Oxford, Oxfordshire). 2003 March-April; 38(2): 148-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12634262&dopt=Abstract

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Evaluation and follow-up of patients with cirrhosis and oesophageal varices. Author(s): de Franchis R. Source: Journal of Hepatology. 2003 March; 38(3): 361-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12586304&dopt=Abstract

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Evaluation of a new scoring system for primary biliary cirrhosis and its related variant forms. Author(s): Imura J, Fujimori T. Source: Journal of Gastroenterology. 2003; 38(1): 106-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12560933&dopt=Abstract

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Evaluation of nitric oxide (NO) levels in hepatitis C virus (HCV) infection: relationship to schistosomiasis and liver cirrhosis among Egyptian patients. Author(s): Hassan MI, Kassim SK, Ali HS, Sayed el-DA, Khalifa A. Source: Disease Markers. 2002; 18(3): 137-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12515909&dopt=Abstract

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Evaluation of the albumin-gamma-glutamyltransferase isoenzyme as a diagnostic marker of hepatocellular carcinoma-complicating liver cirrhosis. Author(s): Pompili M, Addolorato G, Pignataro G, Rossi C, Zuppi C, Covino M, Grieco A, Gasbarrini G, Rapaccini GL. Source: Journal of Gastroenterology and Hepatology. 2003 March; 18(3): 288-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603529&dopt=Abstract

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Expression and coordinated regulation of matrix metalloproteinases in chronic hepatitis C and hepatitis C virus-induced liver cirrhosis. Author(s): Lichtinghagen R, Bahr MJ, Wehmeier M, Michels D, Haberkorn CI, Arndt B, Flemming P, Manns MP, Boeker KH. Source: Clinical Science (London, England : 1979). 2003 September; 105(3): 373-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12760742&dopt=Abstract

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Expression and DNA-binding activity of signal transducer and activator of transcription 3 in alcoholic cirrhosis compared to normal liver and primary biliary cirrhosis in humans. Author(s): Starkel P, Bishop K, Horsmans Y, Strain AJ. Source: American Journal of Pathology. 2003 February; 162(2): 587-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12547716&dopt=Abstract

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Expression of nitric oxide synthase isoforms in human liver cirrhosis. Author(s): Mohammed NA, Abd El-Aleem S, Appleton I, Maklouf MM, Said M, McMahon RF. Source: The Journal of Pathology. 2003 August; 200(5): 647-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12898602&dopt=Abstract

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Expression of telomerase activity and oxidative stress in human hepatocellular carcinoma with cirrhosis. Author(s): Liu DY, Peng ZH, Qiu GQ, Zhou CZ. Source: World Journal of Gastroenterology : Wjg. 2003 August; 9(8): 1859-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918139&dopt=Abstract

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Expression of uncoupling protein-2 in biliary epithelial cells in primary biliary cirrhosis. Author(s): Taniguchi E, Harada M, Kawaguchi T, Koga H, Kumemura H, Hanada S, Shishido S, Baba S, Kumashiro R, Ueno T, Sakisaka S, Sata M. Source: Liver. 2002 December; 22(6): 451-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12445169&dopt=Abstract

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Expression of Wilms' tumor suppressor in the liver with cirrhosis: relation to hepatocyte nuclear factor 4 and hepatocellular function. Author(s): Berasain C, Herrero JI, Garcia-Trevijano ER, Avila MA, Esteban JI, Mato JM, Prieto J. Source: Hepatology (Baltimore, Md.). 2003 July; 38(1): 148-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829997&dopt=Abstract

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Factors predicting hyperkalemia in patients with cirrhosis receiving spironolactone. Author(s): Abbas Z, Mumtaz K, Salam A, Jafri W. Source: J Coll Physicians Surg Pak. 2003 July; 13(7): 382-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12887837&dopt=Abstract

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Familial clustering of (mostly) HCV-related cirrhosis. A case-control study. Author(s): Pagliaro L, Pasta L, D'Amico G, Madonia S, Pietrosi G. Source: Journal of Hepatology. 2002 December; 37(6): 762-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12445416&dopt=Abstract

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Fatal spontaneous gallbladder variceal bleeding in a patient with alcoholic cirrhosis. Author(s): Chu EC, Chick W, Hillebrand DJ, Hu KQ. Source: Digestive Diseases and Sciences. 2002 December; 47(12): 2682-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12498285&dopt=Abstract

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Fibrosing cholestatic hepatitis developing after liver transplantation: case report of a patient with HCV-related cirrhosis. Author(s): Takahashi T, Ashizawa S, Matsumoto H, Furuta K, Omura T, Sato K, Kakita A. Source: Transplantation Proceedings. 2003 February; 35(1): 392-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591455&dopt=Abstract

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Five-year survival predictive factors in patients with excessive alcohol intake and cirrhosis. Effect of alcoholic hepatitis, smoking and abstinence. Author(s): Pessione F, Ramond MJ, Peters L, Pham BN, Batel P, Rueff B, Valla DC. Source: Liver International : Official Journal of the International Association for the Study of the Liver. 2003 February; 23(1): 45-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640727&dopt=Abstract

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Focal nodular hyperplasia-like areas in cirrhosis. Author(s): Quaglia A, Tibballs J, Grasso A, Prasad N, Nozza P, Davies SE, Burroughs AK, Watkinson A, Dhillon AP. Source: Histopathology. 2003 January; 42(1): 14-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12493020&dopt=Abstract

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Focal overexpression of insulin-like growth factor 2 by hepatocytes and cholangiocytes in viral liver cirrhosis. Author(s): Sedlaczek N, Hasilik A, Neuhaus P, Schuppan D, Herbst H. Source: British Journal of Cancer. 2003 March 10; 88(5): 733-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12618883&dopt=Abstract

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Functional significance of hepatic arterial flow reserve in patients with cirrhosis. Author(s): Zipprich A, Steudel N, Behrmann C, Meiss F, Sziegoleit U, Fleig WE, Kleber G. Source: Hepatology (Baltimore, Md.). 2003 February; 37(2): 385-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12540789&dopt=Abstract

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Functional status of patients with primary biliary cirrhosis. Author(s): Parik-Patel A, Gold EB, Utts J, Worman H, Krivy KE, Gershwin ME. Source: The American Journal of Gastroenterology. 2002 November; 97(11): 2871-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12425562&dopt=Abstract

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Gastroduodenal and intestinal permeability in primary biliary cirrhosis. Author(s): Di Leo V, Venturi C, Baragiotta A, Martines D, Floreani A. Source: European Journal of Gastroenterology & Hepatology. 2003 September; 15(9): 967-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12923368&dopt=Abstract

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Gross chylous ascites in cirrhosis with massive portal vein thrombosis: diagnostic value of lymphoscintigraphy. A case report and review of the literature. Author(s): Archimandritis AJ, Zonios DI, Karadima D, Vlachoyiannopoulos PG, Kiriaki D, Hatzis GS. Source: European Journal of Gastroenterology & Hepatology. 2003 January; 15(1): 81-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544699&dopt=Abstract

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Habitual betel quid chewing as a risk factor for cirrhosis: a case-control study. Author(s): Tsai JF, Jeng JE, Chuang LY, Ho MS, Ko YC, Lin ZY, Hsieh MY, Chen SC, Chuang WL, Wang LY, Yu ML, Dai CY, Ho C. Source: Medicine; Analytical Reviews of General Medicine, Neurology, Psychiatry, Dermatology, and Pediatrics. 2003 September; 82(5): 365-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14530785&dopt=Abstract

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Hand involvement in primary biliary cirrhosis in an 85-year-old woman. Author(s): Stone M, Inman RD, Salonen D. Source: The Journal of Rheumatology. 2003 July; 30(7): 1628-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858471&dopt=Abstract

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Helical CT screening for hepatocellular carcinoma in patients with cirrhosis: frequency and causes of false-positive interpretation. Author(s): Brancatelli G, Baron RL, Peterson MS, Marsh W. Source: Ajr. American Journal of Roentgenology. 2003 April; 180(4): 1007-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12646446&dopt=Abstract

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Helicobacter pylori infection in patients with liver cirrhosis: facts and fictions. Author(s): Zullo A, Hassan C, Morini S. Source: Dig Liver Dis. 2003 March; 35(3): 197-205. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12779075&dopt=Abstract

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Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Author(s): Abraldes JG, Tarantino I, Turnes J, Garcia-Pagan JC, Rodes J, Bosch J. Source: Hepatology (Baltimore, Md.). 2003 April; 37(4): 902-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12668985&dopt=Abstract

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Hepatic amino-acid metabolism in liver cirrhosis and in the long-term course after liver transplantation. Author(s): Tietge UJ, Bahr MJ, Manns MP, Boker KH. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 2003 January; 16(1): 1-8. Epub 2002 December 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12545334&dopt=Abstract

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Hepatic cirrhosis with sarcoid granulomas. Differential diagnosis and liver transplantation: a case report. Author(s): Gavilan F, Pereda T, Sousa JM, Serrano J, Gomez MA, Garcia I, Tamayo MJ, Martin C, Reig M, Hinojosa R, Perez-Bernal J, Canas E, Bernardos A. Source: Transplantation Proceedings. 2003 March; 35(2): 713-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12644107&dopt=Abstract

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Hepatic venous pressure gradient measurements to assess response to primary prophylaxis in patients with cirrhosis: a decision analytical study. Author(s): Hicken BL, Sharara AI, Abrams GA, Eloubeidi M, Fallon MB, Arguedas MR. Source: Alimentary Pharmacology & Therapeutics. 2003 January; 17(1): 145-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12492744&dopt=Abstract

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Hepatitis C virus RNA quantitation in hepatic veins and peripheral blood in patients with liver cirrhosis: evidence for low level intrahepatic hepatitis C virus replication in advanced liver disease. Author(s): Puoti C, Castellacci R, Bellis L, Montagnese R, Corvisieri P, Festuccia P, Mellozzi M, Villani AR. Source: Dig Liver Dis. 2002 November; 34(11): 802-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546516&dopt=Abstract

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Hepatitis C virus serotypes in Romanian patients with chronic hepatitis and cirrhosis. Author(s): Iancu LS, Pandele GI, Stanciu C, Luca V. Source: Rev Med Chir Soc Med Nat Iasi. 2002 January-March; 106(1): 79-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12635365&dopt=Abstract

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Hepatocellular carcinoma in a patient with primary biliary cirrhosis and seronegativity for markers of hepatitis B virus and hepatitis C virus: report of a case. Author(s): Sunagawa H, Takayama H, Yamashiro T, Sasaki H, Sashida Y, Matsuura K, Kayou M. Source: Surgery Today. 2003; 33(3): 219-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12658391&dopt=Abstract

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Hepatocyte growth factor gene transfer into the liver via the portal vein using electroporation attenuates rat liver cirrhosis. Author(s): Matsuno Y, Iwata H, Umeda Y, Takagi H, Mori Y, Kosugi A, Matsumoto K, Nakamura T, Hirose H. Source: Gene Therapy. 2003 September; 10(18): 1559-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12907947&dopt=Abstract

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Hepatoma in a 40-year old male with hereditary hemochromatosis in the absence of cirrhosis. Implications of molecular diagnosis. Author(s): Brage A, Tome S, Figueruela B, Abdulkader I, Martinez J, Varo E. Source: Rev Esp Enferm Dig. 2002 August; 94(8): 493-9. English, Spanish. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12486854&dopt=Abstract

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HFE mutations and chronic hepatitis C: H63D and C282Y heterozygosity are independent risk factors for liver fibrosis and cirrhosis. Author(s): Erhardt A, Maschner-Olberg A, Mellenthin C, Kappert G, Adams O, Donner A, Willers R, Niederau C, Haussinger D. Source: Journal of Hepatology. 2003 March; 38(3): 335-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12586300&dopt=Abstract

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High seroprevalence and clinical significance of hepatitis B and C infection in hospitalized patients with alcoholic cirrhosis. Author(s): Saigal S, Kapoor D, Tandon N, Thakur V, Guptan RC, Agarwal SR, Sarin SK. Source: J Assoc Physicians India. 2002 August; 50: 1002-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12421019&dopt=Abstract

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Hip arthroplasty in patients with cirrhosis of the liver. Author(s): Hsieh PH, Chen LH, Lee MS, Chen CH, Yang WE, Shih CH. Source: The Journal of Bone and Joint Surgery. British Volume. 2003 August; 85(6): 81821. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12931797&dopt=Abstract

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Hyperdynamic circulation in liver cirrhosis: not peripheral vasodilatation but 'splanchnic steal'. Author(s): Newby DE, Hayes PC. Source: Qjm : Monthly Journal of the Association of Physicians. 2002 December; 95(12): 827-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454326&dopt=Abstract

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Hypothalamic digoxin and hemispheric chemical dominance: relation to alcoholic addiction, alcoholic cirrhosis, and acquired hepatocerebral degeneration. Author(s): Kurup RK, Kurup PA. Source: The International Journal of Neuroscience. 2003 August; 113(8): 1105-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12888425&dopt=Abstract

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Hypothalamic digoxin and isoprenoid pathway dysfunction relation to alcoholic addiction, alcoholic cirrhosis, and acquired hepatocerebral degeneration--relation to hemispheric chemical dominance. Author(s): Kurup RK, Kurup PA. Source: The International Journal of Neuroscience. 2003 April; 113(4): 547-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12856482&dopt=Abstract

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Identification of beta-subunit of bacterial RNA-polymerase--a non-species-specific bacterial protein--as target of antibodies in primary biliary cirrhosis. Author(s): Roesler KW, Schmider W, Kist M, Batsford S, Schiltz E, Oelke M, Tuczek A, Dettenborn T, Behringer D, Kreisel W. Source: Digestive Diseases and Sciences. 2003 March; 48(3): 561-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757171&dopt=Abstract

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IGF1 gene transfer into skeletal muscle using recombinant adeno-associated virus in a rat model of liver cirrhosis. Author(s): Zaratiegui M, Castilla-Cortazar I, Garcia M, Quiroga J, Prieto J, Novo FJ. Source: J Physiol Biochem. 2002 September; 58(3): 169-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603011&dopt=Abstract

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Immunogenicity and safety of an adjuvanted influenza vaccine in patients with decompensated cirrhosis. Author(s): Gaeta GB, Stornaiuolo G, Precone DF, Amendola A, Zanetti AR. Source: Vaccine. 2002 December 20; 20 Suppl 5: B33-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12477416&dopt=Abstract

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Impaired accommodation of proximal stomach in patients with alcoholic liver cirrhosis. Author(s): Izbeki F, Kiss I, Wittmann T, Varkonyi TT, Legrady P, Lonovics J. Source: Scandinavian Journal of Gastroenterology. 2002 December; 37(12): 1403-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12523589&dopt=Abstract

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Impaired hepatic mitochondrial oxidation using the 13C-methionine breath test in patients with macrovesicular steatosis and patients with cirrhosis. Author(s): Spahr L, Negro F, Leandro G, Marinescu O, Goodman KJ, Rubbia-Brandt L, Jordan M, Hadengue A. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 January; 9(1): Cr6-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12552242&dopt=Abstract

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Improved diagnosing of small hepatocellular carcinomas by echo-enhanced power Doppler sonography in patients with cirrhosis. Author(s): Rickes S, Schulze S, Neye H, Ocran KW, Wermke W. Source: European Journal of Gastroenterology & Hepatology. 2003 August; 15(8): 893900. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12867800&dopt=Abstract

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Improvement of regional cerebral blood flow after treatment with branched-chain amino acid solutions in patients with cirrhosis. Author(s): Iwasa M, Matsumura K, Watanabe Y, Yamamoto M, Kaito M, Ikoma J, Gabazza EC, Takeda K, Adachi Y. Source: European Journal of Gastroenterology & Hepatology. 2003 July; 15(7): 733-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12811303&dopt=Abstract

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Increase of S-100 protein-positive stellate cells in the anterior pituitary of chronic alcoholic patients with fatty liver or fatty cirrhosis. Author(s): Ishikawa T, Tachibana T, Ishikawa H, Miyaishi S, Ishizu H. Source: Acta Medica Okayama. 2003 April; 57(2): 53-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12866744&dopt=Abstract

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Increased arterial compliance in cirrhosis is related to decreased arterial C-type natriuretic peptide, but not to atrial natriuretic peptide. Author(s): Henriksen JH, Gulberg V, Gerbes AL, Bendtsen F, Moller S. Source: Scandinavian Journal of Gastroenterology. 2003 May; 38(5): 559-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12795471&dopt=Abstract

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Increased carbon monoxide production in patients with cirrhosis with and without spontaneous bacterial peritonitis. Author(s): De las Heras D, Fernandez J, Gines P, Cardenas A, Ortega R, Navasa M, Barbera JA, Calahorra B, Guevara M, Bataller R, Jimenez W, Arroyo V, Rodes J. Source: Hepatology (Baltimore, Md.). 2003 August; 38(2): 452-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12883490&dopt=Abstract

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Increased incidence of fungal infections in advanced primary biliary cirrhosis. Author(s): Samonakis DN, Chatzicostas C, Vardas E, Roussomoustakaki M, Kouroumalis EA. Source: Journal of Clinical Gastroenterology. 2003 April; 36(4): 369. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12642749&dopt=Abstract

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Increased mortality after liver transplantation for hepatocellular carcinoma in hepatitis B-associated cirrhosis. Author(s): Jonas S, Steinmuller T, Tullius SG, Thelen A, Settmacher U, Berg T, Radtke C, Neuhaus P. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 2003 January; 16(1): 33-6. Epub 2002 December 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12545339&dopt=Abstract

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Increased risk for hepatitis B-related liver cirrhosis in relatives of patients with hepatocellular carcinoma in northern Taiwan. Author(s): Yu MW, Chang HC, Chen PJ, Liu CJ, Liaw YF, Lin SM, Lee SD, Lin SC, Lin CL, Chen CJ. Source: International Journal of Epidemiology. 2002 October; 31(5): 1008-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12435776&dopt=Abstract

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Increased serum leptin concentrations correlate with soluble tumour necrosis factor receptor levels in patients with cirrhosis. Author(s): Lin SY, Wang YY, Sheu WH. Source: Clinical Endocrinology. 2002 December; 57(6): 805-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12460331&dopt=Abstract

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Increased serum reverse triiodothyronine levels at diagnosis of hepatocellular carcinoma in patients with compensated HCV-related liver cirrhosis. Author(s): Sorvillo F, Mazziotti G, Carbone A, Morisco F, Cioffi M, Rotondi M, Stornaiuolo G, Amato G, Gaeta GB, Caporaso N, Carella C. Source: Clinical Endocrinology. 2003 February; 58(2): 207-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12580937&dopt=Abstract

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Increased urinary excretion of aquaporin 2 in patients with liver cirrhosis. Author(s): Ivarsen P, Frokiaer J, Aagaard NK, Hansen EF, Bendtsen F, Nielsen S, Vilstrup H. Source: Gut. 2003 August; 52(8): 1194-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865281&dopt=Abstract

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Increased urotensin II plasma levels in patients with cirrhosis and portal hypertension. Author(s): Heller J, Schepke M, Neef M, Woitas R, Rabe C, Sauerbruch T. Source: Journal of Hepatology. 2002 December; 37(6): 767-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12445417&dopt=Abstract

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Induced hyperammonemia alters neuropsychology, brain MR spectroscopy and magnetization transfer in cirrhosis. Author(s): Balata S, Damink SW, Ferguson K, Marshall I, Hayes PC, Deutz NE, Williams R, Wardlaw J, Jalan R. Source: Hepatology (Baltimore, Md.). 2003 April; 37(4): 931-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12668989&dopt=Abstract

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Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis. Author(s): Arguedas MR, DeLawrence TG, McGuire BM. Source: Digestive Diseases and Sciences. 2003 August; 48(8): 1622-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12924658&dopt=Abstract

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Insulin-like growth factor binding protein-3 in patients with liver cirrhosis. Author(s): Sidlova K, Pechova M, AKotaska K, Prusa R. Source: Physiological Research / Academia Scientiarum Bohemoslovaca. 2002; 51(6): 587-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12511182&dopt=Abstract

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Interstitial laser coagulation with temporary hepatic artery occlusion for patients with cirrhosis and irresectable hepatoma. Author(s): Verhoef C, Kuiper JW, Heisterkamp J, de Man RA, Pattynama PM, IJzermans JN. Source: The British Journal of Surgery. 2003 August; 90(8): 950-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12905547&dopt=Abstract

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Intestinal absorption of the bile acid analogue 75Se-homocholic acid-taurine is increased in primary biliary cirrhosis, and reverts to normal during ursodeoxycholic acid administration. Author(s): Lanzini A, De Tavonatti MG, Panarotto B, Scalia S, Mora A, Benini F, Baisini O, Lanzarotto F. Source: Gut. 2003 September; 52(9): 1371-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12912872&dopt=Abstract

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Intrahepatic heterogeneity of hepatic venous pressure gradient in human cirrhosis again. Author(s): Keiding S, Vilstrup H. Source: Scandinavian Journal of Gastroenterology. 2002 November; 37(11): 1344. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12465737&dopt=Abstract

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Is cirrhosis of the liver reversible? The ultimate that a hepatologist wishes. Author(s): Acharya SK, Batra Y. Source: Trop Gastroenterol. 2003 January-March; 24(1): 1-2. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974205&dopt=Abstract

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Is hepatitis A vaccination necessary in Indian patients with cirrhosis of liver? Author(s): Xavier S, Anish K. Source: Indian J Gastroenterol. 2003 March-April; 22(2): 54-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12696823&dopt=Abstract

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Is hyperammonemia really the true cause of altered neuropsychology, brain MR spectroscopy and magnetization transfer after an oral amino acid load in cirrhosis? Author(s): Riggio O, Efrati C, Masini A, Angeloni S, Merli M. Source: Hepatology (Baltimore, Md.). 2003 September; 38(3): 777; Author Reply 778. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939607&dopt=Abstract

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Is laparoscopy an advantage in the diagnosis of cirrhosis in chronic hepatitis C virus infection? Author(s): Wietzke-Braun P, Braun F, Schott P, Ramadori G. Source: World Journal of Gastroenterology : Wjg. 2003 April; 9(4): 745-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12679924&dopt=Abstract

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Is obesity a risk factor for cirrhosis-related death or hospitalization? A populationbased cohort study. Author(s): Ioannou GN, Weiss NS, Kowdley KV, Dominitz JA. Source: Gastroenterology. 2003 October; 125(4): 1053-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14517789&dopt=Abstract

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Isolated cecal varices as the source of massive lower GI bleeding in a patient with cirrhosis. Author(s): Klein SD, Hellinger JC, Silverstein ML, Cai Q. Source: The American Journal of Gastroenterology. 2003 January; 98(1): 220-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12526971&dopt=Abstract

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Lack of association between HFE gene mutations and hepatocellular carcinoma in patients with cirrhosis. Author(s): Boige V, Castera L, de Roux N, Ganne-Carrie N, Ducot B, Pelletier G, Beaugrand M, Buffet C. Source: Gut. 2003 August; 52(8): 1178-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865278&dopt=Abstract

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Lack of optimal T-cell reactivity against the hepatitis C virus is associated with the development of fibrosis/cirrhosis during chronic hepatitis. Author(s): Sreenarasimhaiah J, Jaramillo A, Crippin J, Lisker-Melman M, Chapman WC, Mohanakumar T. Source: Human Immunology. 2003 February; 64(2): 224-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559624&dopt=Abstract

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Lack of portosystemic bacterial translocation in patients with liver cirrhosis after placement of transjugular shunt. Author(s): Cohnen M, Luthen R, Daubener W, Modder U. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2003 May; 22(5): 310-2. Epub 2003 May 07. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12734723&dopt=Abstract

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Levels of BAFF in serum in primary biliary cirrhosis and autoimmune diabetes. Author(s): Mackay IR, Groom J, Mackay CR. Source: Autoimmunity. 2002 December; 35(8): 551-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765482&dopt=Abstract

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Liver cirrhosis: an unfavorable factor for nonoperative management of blunt splenic injury. Author(s): Fang JF, Chen RJ, Lin BC, Hsu YB, Kao JL, Chen MF. Source: The Journal of Trauma. 2003 June; 54(6): 1131-6; Discussion 1136. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12813334&dopt=Abstract

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Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy? Author(s): Adam R, Azoulay D, Castaing D, Eshkenazy R, Pascal G, Hashizume K, Samuel D, Bismuth H. Source: Annals of Surgery. 2003 October; 238(4): 508-18; Discussion 518-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14530722&dopt=Abstract

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Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence. Author(s): Ercolani G, Grazi GL, Ravaioli M, Del Gaudio M, Gardini A, Cescon M, Varotti G, Cetta F, Cavallari A. Source: Annals of Surgery. 2003 April; 237(4): 536-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12677151&dopt=Abstract

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Liver transplantation for primary biliary cirrhosis. Author(s): Neuberger J. Source: Autoimmunity Reviews. 2003 January; 2(1): 1-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848968&dopt=Abstract

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Liver transplantation for primary biliary cirrhosis: a long-term pathologic study. Author(s): Khettry U, Anand N, Faul PN, Lewis WD, Pomfret EA, Pomposelli J, Jenkins RL, Gordon FD. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2003 January; 9(1): 87-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12514778&dopt=Abstract

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Longitudinal bone loss in postmenopausal women with primary biliary cirrhosis and well-preserved liver function. Author(s): Ormarsdottir S, Ljunggren O, Mallmin H, Olsson R, Prytz H, Loof L. Source: Journal of Internal Medicine. 2002 December; 252(6): 537-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12472915&dopt=Abstract

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Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Author(s): Hui JM, Kench JG, Chitturi S, Sud A, Farrell GC, Byth K, Hall P, Khan M, George J. Source: Hepatology (Baltimore, Md.). 2003 August; 38(2): 420-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12883486&dopt=Abstract

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Long-term survival and cause-specific mortality in patients with cirrhosis of the liver: a nationwide cohort study in Denmark. Author(s): Sorensen HT, Thulstrup AM, Mellemkjar L, Jepsen P, Christensen E, Olsen JH, Vilstrup H. Source: Journal of Clinical Epidemiology. 2003 January; 56(1): 88-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12589875&dopt=Abstract

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Low dose amiodarone causing pseudo-alcoholic cirrhosis. Author(s): Singhal A, Ghosh P, Khan SA. Source: Age and Ageing. 2003 March; 32(2): 224-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615569&dopt=Abstract

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Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis. Author(s): Bellis L, Berzigotti A, Abraldes JG, Moitinho E, Garcia-Pagan JC, Bosch J, Rodes J. Source: Hepatology (Baltimore, Md.). 2003 February; 37(2): 378-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12540788&dopt=Abstract

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Low serum total thyroxine and free triiodothyronine in patients with hepatic encephalopathy due to non-alcoholic cirrhosis. Author(s): Kayacetin E, Kisakol G, Kaya A. Source: Swiss Medical Weekly : Official Journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology. 2003 April 5; 133(13-14): 210-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12811678&dopt=Abstract

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Management of patients with decompensated HBV cirrhosis. Author(s): Fontana RJ. Source: Seminars in Liver Disease. 2003 February; 23(1): 89-100. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12616454&dopt=Abstract

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Mechanisms of hyperinsulinaemia in Child's disease grade B liver cirrhosis investigated in free living conditions. Author(s): Greco AV, Mingrone G, Mari A, Capristo E, Manco M, Gasbarrini G. Source: Gut. 2002 December; 51(6): 870-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12427792&dopt=Abstract

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MELD scoring system is useful for predicting prognosis in patients with liver cirrhosis and is correlated with residual liver function: a European study. Author(s): Botta F, Giannini E, Romagnoli P, Fasoli A, Malfatti F, Chiarbonello B, Testa E, Risso D, Colla G, Testa R. Source: Gut. 2003 January; 52(1): 134-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12477775&dopt=Abstract

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Methotrexate therapy for primary biliary cirrhosis. Author(s): Bach N, Bodian C, Bodenheimer H, Croen E, Berk PD, Thung SN, Lindor KD, Therneau T, Schaffner F. Source: The American Journal of Gastroenterology. 2003 January; 98(1): 187-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12526956&dopt=Abstract

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Minilaparoscopy for early diagnosis of cirrhosis: is the endoscopist's eye better than the histopathologist's? Author(s): Manns MP, Schneider A, Meier PN. Source: Endoscopy. 2003 January; 35(1): 74-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12510230&dopt=Abstract

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Minilaparoscopy in the diagnosis of cirrhosis: superiority in patients with ChildPugh A and macronodular disease. Author(s): Helmreich-Becker I, Schirmacher P, Denzer U, Hensel A, Meyer zum Buschenfelde KH, Lohse AW. Source: Endoscopy. 2003 January; 35(1): 55-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12510227&dopt=Abstract

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Minimal hepatic encephalopathy and extrapyramidal signs in patients with cirrhosis. Author(s): Jover R, Company L, Gutierrez A, Zapater P, Perez-Serra J, Girona E, Aparicio JR, Perez-Mateo M. Source: The American Journal of Gastroenterology. 2003 July; 98(7): 1599-604. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873585&dopt=Abstract

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Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis. Author(s): Shimoda S, Nakamura M, Ishibashi H, Kawano A, Kamihira T, Sakamoto N, Matsushita S, Tanaka A, Worman HJ, Gershwin ME, Harada M. Source: Gastroenterology. 2003 June; 124(7): 1915-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12806624&dopt=Abstract

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MR imaging features of primary sclerosing cholangitis: patterns of cirrhosis in relationship to clinical severity of disease. Author(s): Bader TR, Beavers KL, Semelka RC. Source: Radiology. 2003 March; 226(3): 675-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12616016&dopt=Abstract

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Multibacterial sepsis in an alcohol abuser with hepatic cirrhosis. Author(s): Matsukawa Y, Kitamura N, Kaneko M, Yoshioka D, Miki T, Nishinarita S, Horie T, Hosokawa N, Iwasaki Y, Kumasaka K, Kawano K. Source: Intern Med. 2003 February; 42(2): 208-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12636245&dopt=Abstract

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Myeloperoxidase-positive inflammatory cells participate in bile duct damage in primary biliary cirrhosis through nitric oxide-mediated reactions. Author(s): Wu CT, Eiserich JP, Ansari AA, Coppel RL, Balasubramanian S, Bowlus CL, Gershwin ME, Van De Water J. Source: Hepatology (Baltimore, Md.). 2003 October; 38(4): 1018-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14512889&dopt=Abstract

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Neostigmine and polyethylene glycol electrolyte solution for the therapy of acute hepatic encephalopathy with liver cirrhosis and ascites. Author(s): Kiba T, Numata K, Saito S. Source: Hepatogastroenterology. 2003 May-June; 50(51): 823-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828094&dopt=Abstract

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New weapon for primary biliary cirrhosis from Japan. Author(s): Zeniya M. Source: Journal of Gastroenterology. 2003; 38(6): 619-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858848&dopt=Abstract

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Nitric oxide in patients with cirrhosis and bacterial infections. Author(s): Such J, Frances R, Perez-Mateo M. Source: Metabolic Brain Disease. 2002 December; 17(4): 303-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12602507&dopt=Abstract

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Nitric oxide inhibition in cirrhosis and ascites. Author(s): Cardenas A. Source: The American Journal of Gastroenterology. 2003 July; 98(7): 1666-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873610&dopt=Abstract

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Nitric oxide mediates the reduced vasoconstrictor response to angiotensin II in patients with preascitic cirrhosis. Author(s): Helmy A, Newby DE, Jalan R, Johnston NR, Hayes PC, Webb DJ. Source: Journal of Hepatology. 2003 January; 38(1): 44-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12480559&dopt=Abstract

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Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. Author(s): Clark JM, Diehl AM. Source: Jama : the Journal of the American Medical Association. 2003 June 11; 289(22): 3000-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12799409&dopt=Abstract

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Nonalcoholic steatohepatitis-related cirrhosis with subacute liver failure: an autopsy case. Author(s): Kuwabara H, Yoshii Y, Mori H, Fujiwara S, Eiraku S, Kojima H, Miyaji K, Hongo Y, Katsu K. Source: Digestive Diseases and Sciences. 2003 August; 48(8): 1668-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12924667&dopt=Abstract

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Non-invasive predictors of the presence of large oesophageal varices in patients with cirrhosis. Author(s): Thomopoulos KC, Labropoulou-Karatza C, Mimidis KP, Katsakoulis EC, Iconomou G, Nikolopoulou VN. Source: Dig Liver Dis. 2003 July; 35(7): 473-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870732&dopt=Abstract

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Normalization of markedly elevated alpha-fetoprotein in a virologic nonresponder with HCV-related cirrhosis. Author(s): Stein DF, Myaing M. Source: Digestive Diseases and Sciences. 2002 December; 47(12): 2686-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12498286&dopt=Abstract

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Novel differential gene expression in human cirrhosis detected by suppression subtractive hybridization. Author(s): Shackel NA, McGuinness PH, Abbott CA, Gorrell MD, McCaughan GW. Source: Hepatology (Baltimore, Md.). 2003 September; 38(3): 577-88. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939584&dopt=Abstract

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Nucleolar hypertrophy correlates with hepatocellular carcinoma development in cirrhosis due to HBV infection. Author(s): Trere D, Borzio M, Morabito A, Borzio F, Roncalli M, Derenzini M. Source: Hepatology (Baltimore, Md.). 2003 January; 37(1): 72-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12500191&dopt=Abstract

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Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Author(s): Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, Rossi Fanelli F, Abbiati R; Italian BCAA Study Group. Source: Gastroenterology. 2003 June; 124(7): 1792-801. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12806613&dopt=Abstract

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Off-pump coronary artery bypass grafting in a patient with liver cirrhosis. Author(s): Yamamoto T, Takazawa K, Hariya A, Ishikawa N, Dohi S, Matsushita S. Source: Jpn J Thorac Cardiovasc Surg. 2002 December; 50(12): 526-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12561096&dopt=Abstract

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Oral amino acid load mimicking hemoglobin results in reduced regional cerebral perfusion and deterioration in memory tests in patients with cirrhosis of the liver. Author(s): Jalan R, Olde Damink SW, Lui HF, Glabus M, Deutz NE, Hayes PC, Ebmeier K. Source: Metabolic Brain Disease. 2003 March; 18(1): 37-49. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12603081&dopt=Abstract

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Oral antioxidant supplementation for fatigue associated with primary biliary cirrhosis: results of a multicentre, randomized, placebo-controlled, cross-over trial. Author(s): Prince MI, Mitchison HC, Ashley D, Burke DA, Edwards N, Bramble MG, James OF, Jones DE. Source: Alimentary Pharmacology & Therapeutics. 2003 January; 17(1): 137-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12492743&dopt=Abstract

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Osteopontin is involved in the formation of epithelioid granuloma and bile duct injury in primary biliary cirrhosis. Author(s): Harada K, Ozaki S, Sudo Y, Tsuneyama K, Ohta H, Nakanuma Y. Source: Pathology International. 2003 January; 53(1): 8-17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12558864&dopt=Abstract

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Osteoporosis in primary biliary cirrhosis. Author(s): Newton J, Jones D. Source: Panminerva Medica. 2002 December; 44(4): 335-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12434115&dopt=Abstract

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Osteoporosis: still a typical complication of primary biliary cirrhosis? Author(s): Solerio E, Isaia G, Innarella R, Di Stefano M, Farina M, Borghesio E, Framarin L, Rizzetto M, Rosina F. Source: Dig Liver Dis. 2003 May; 35(5): 339-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12846406&dopt=Abstract

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Oxidant stress is a significant feature of primary biliary cirrhosis. Author(s): Aboutwerat A, Pemberton PW, Smith A, Burrows PC, McMahon RF, Jain SK, Warnes TW. Source: Biochimica Et Biophysica Acta. 2003 March 20; 1637(2): 142-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12633902&dopt=Abstract

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Oxidative breakdown of octanoic acid is maintained in patients with cirrhosis despite advanced disease. Author(s): van de Casteele M, Luypaerts A, Geypens B, Fevery J, Ghoos Y, Nevens F. Source: Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society. 2003 April; 15(2): 113-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12680910&dopt=Abstract

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Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis. Author(s): Riordan SM, Skinner N, Nagree A, McCallum H, McIver CJ, Kurtovic J, Hamilton JA, Bengmark S, Williams R, Visvanathan K. Source: Hepatology (Baltimore, Md.). 2003 May; 37(5): 1154-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12717397&dopt=Abstract

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Pharmacokinetics and pharmacodynamic action of budesonide in early- and latestage primary biliary cirrhosis. Author(s): Hempfling W, Grunhage F, Dilger K, Reichel C, Beuers U, Sauerbruch T. Source: Hepatology (Baltimore, Md.). 2003 July; 38(1): 196-202. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12830002&dopt=Abstract

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Phenylalanine kinetics in cirrhosis. Author(s): Short KR. Source: American Journal of Physiology. Endocrinology and Metabolism. 2003 August; 285(2): E447; Author Reply E448. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12857679&dopt=Abstract

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Platelet abnormalities in patients with hepatic cirrhosis. Author(s): Agarwal MP, Singh S, Dwivedi S, Madan N, Sikka M. Source: Trop Doct. 2003 April; 33(2): 110-1. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12680551&dopt=Abstract

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Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis. Author(s): Giannini E, Botta F, Borro P, Risso D, Romagnoli P, Fasoli A, Mele MR, Testa E, Mansi C, Savarino V, Testa R. Source: Gut. 2003 August; 52(8): 1200-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865282&dopt=Abstract

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Poor sensitivity of sonography in detection of hepatocellular carcinoma in advanced liver cirrhosis: accuracy of pretransplantation sonography in 118 patients. Author(s): Liu WC, Lim JH, Park CK, Kim MJ, Kim SH, Lee SJ, Lee WJ, Lim HK. Source: European Radiology. 2003 July; 13(7): 1693-8. Epub 2003 February 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12835987&dopt=Abstract

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Portal hypertension and portal hypertensive gastropathy in patients with liver cirrhosis: a haemodynamic study. Author(s): Merkel C, Schipilliti M, Bighin R, Bellini B, Angeli P, Bolognesi M, Vescovi F, Gatta A. Source: Dig Liver Dis. 2003 April; 35(4): 269-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12801039&dopt=Abstract

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Portal pressure response to losartan compared with propranolol in patients with cirrhosis. Author(s): De BK, Bandyopadhyay K, Das TK, Das D, Biswas PK, Majumdar D, Mandal SK, Ray S, Dasgupta S. Source: The American Journal of Gastroenterology. 2003 June; 98(6): 1371-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818283&dopt=Abstract

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Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Author(s): Benjaminov FS, Prentice M, Sniderman KW, Siu S, Liu P, Wong F. Source: Gut. 2003 September; 52(9): 1355-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12912870&dopt=Abstract

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Portopulmonary hypertension: an increasingly important complication of cirrhosis. Author(s): Blendis L, Wong F. Source: Gastroenterology. 2003 August; 125(2): 622-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891571&dopt=Abstract

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Predicting progression to cirrhosis in chronic hepatitis C virus infection. Author(s): Freeman AJ, Law MG, Kaldor JM, Dore GJ. Source: Journal of Viral Hepatitis. 2003 July; 10(4): 285-93. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823595&dopt=Abstract

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Predictors and implications of severe hypersplenism in patients with cirrhosis. Author(s): Liangpunsakul S, Ulmer BJ, Chalasani N. Source: The American Journal of the Medical Sciences. 2003 September; 326(3): 111-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14501224&dopt=Abstract

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Primary biliary cirrhosis and hepatocellular carcinoma. Author(s): Findor J, He XS, Sord J, Terg R, Gershwin ME. Source: Autoimmunity Reviews. 2002 August; 1(4): 220-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848999&dopt=Abstract

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Primary biliary cirrhosis and ulcerative colitis: a case report and review of literature. Author(s): Xiao WB, Liu YL. Source: World Journal of Gastroenterology : Wjg. 2003 April; 9(4): 878-80. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12679954&dopt=Abstract

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Primary biliary cirrhosis associated with HLA-DRw3. Author(s): Ercilla G, Pares A, Arriaga F, Bruguera M, Castillo R, Rodes J, Vives J. Source: Tissue Antigens. 1979 November; 14(5): 449-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12731577&dopt=Abstract

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Primary biliary cirrhosis at Hospital Kuala Lumpur: a study of 17 cases seen between 1992 and 1999. Author(s): Kananathan R, Suresh RL, Merican I. Source: Med J Malaysia. 2002 March; 57(1): 56-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14569718&dopt=Abstract

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Primary biliary cirrhosis in an 86-year-old male. Author(s): Lal SK, Pedrosa M, Orlander J, Klein MA. Source: Digestive Diseases and Sciences. 2003 August; 48(8): 1627-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12924659&dopt=Abstract

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Primary biliary cirrhosis in antimitochondrial antibody-negative patients: Chang Gung Memorial Hospital experience. Author(s): Tsou YK, Yeh CT. Source: Chang Gung Med J. 2003 May; 26(5): 323-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12934848&dopt=Abstract

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Primary biliary cirrhosis. Author(s): Talwalkar JA, Lindor KD. Source: Lancet. 2003 July 5; 362(9377): 53-61. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12853201&dopt=Abstract

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Primary biliary cirrhosis: a Mount Sinai perspective. Author(s): Bach N, Odin JA. Source: The Mount Sinai Journal of Medicine, New York. 2003 September; 70(4): 242-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12968197&dopt=Abstract

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Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: a cause of resistance to ursodeoxycholic treatment. Author(s): Floreani A, Baragiotta A, Guido M. Source: Dig Liver Dis. 2003 February; 35(2): 128-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12747633&dopt=Abstract

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Primary hepatic neuroendocrine carcinoma coexisting with hepatocellular carcinoma in hepatitis C liver cirrhosis: report of a case. Author(s): Ishida M, Seki K, Tatsuzawa A, Katayama K, Hirose K, Azuma T, Imamura Y, Abraham A, Yamaguchi A. Source: Surgery Today. 2003; 33(3): 214-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12658390&dopt=Abstract

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Progastrin and its products from patients with chronic viral hepatitis and liver cirrhosis. Author(s): Konturek SJ, Gonciarz M, Gonciarz Z, Bielanski W, Mazur W, Mularczyk A, Konturek PC, Goetze JP, Rehfeld JF. Source: Scandinavian Journal of Gastroenterology. 2003 June; 38(6): 643-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12825873&dopt=Abstract

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Prognosis of hepatocellular carcinoma associated with Child class B and C cirrhosis in relation to treatment: a multivariate analysis of 411 patients at a single center. Author(s): Ueno S, Tanabe G, Nuruki K, Oketani M, Komorizono Y, Hokotate H, Fukukura Y, Baba Y, Imamura Y, Aikou T. Source: Journal of Hepato-Biliary-Pancreatic Surgery. 2002; 9(4): 469-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12483269&dopt=Abstract

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Prognostic factors of hepatic resection for hepatocellular carcinoma with cirrhosis: univariate and multivariate analysis. Author(s): Yeh CN, Chen MF, Lee WC, Jeng LB. Source: Journal of Surgical Oncology. 2002 December; 81(4): 195-202. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12451624&dopt=Abstract

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Prognostic significance of the hepatopulmonary syndrome in patients with cirrhosis. Author(s): Schenk P, Schoniger-Hekele M, Fuhrmann V, Madl C, Silberhumer G, Muller C. Source: Gastroenterology. 2003 October; 125(4): 1042-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14517788&dopt=Abstract

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Prospective analysis of risk factors for hepatocellular carcinoma on patients with cirrhosis. Author(s): Di Costanzo GG. Source: Hepatology (Baltimore, Md.). 2003 October; 38(4): 1061; Author Reply 1061. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14512897&dopt=Abstract

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Protein metabolism in liver cirrhosis: from albumin to muscle myofibrils. Author(s): Tessari P. Source: Current Opinion in Clinical Nutrition and Metabolic Care. 2003 January; 6(1): 79-85. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12496684&dopt=Abstract

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Quantitative lung perfusion scintigraphy and detection of intrapulmonary shunt in liver cirrhosis. Author(s): Hosono M, Machida K, Honda N, Takahashi T, Kashimada A, Osada H, Murata O, Ohtawa N, Nishimura K. Source: Ann Nucl Med. 2002 December; 16(8): 577-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12593425&dopt=Abstract

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Radiofrequency ablation for treatment of hepatocellular carcinoma with cirrhosis. Author(s): Lo HW, Tsai YJ, Chen PH, Chen HY, Ker CG, Juan CC. Source: Hepatogastroenterology. 2003 May-June; 50(51): 645-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828052&dopt=Abstract

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Recombinant human interleukin-11 improves thrombocytopenia in patients with cirrhosis. Author(s): Ghalib R, Levine C, Hassan M, McClelland T, Goss J, Stribling R, Seu P, Patt YZ. Source: Hepatology (Baltimore, Md.). 2003 May; 37(5): 1165-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12717398&dopt=Abstract

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Recurrence of primary biliary cirrhosis after liver transplantation. Author(s): Salguero O, Moreno JM, Seijas MC, Rubio E, Salas C, Laporta R, CuervasMons V. Source: Transplantation Proceedings. 2003 March; 35(2): 721-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12644111&dopt=Abstract

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Recurrence of primary biliary cirrhosis after orthotopic liver transplantation. Author(s): Kurdow R, Marks HG, Kraemer-Hansen H, Luttges J, Kremer B, HenneBruns D. Source: Hepatogastroenterology. 2003 March-April; 50(50): 322-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12749212&dopt=Abstract

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Recurrent pleural effusion complicating liver cirrhosis. Author(s): Assouad J, Barthes Fle P, Shaker W, Souilamas R, Riquet M. Source: The Annals of Thoracic Surgery. 2003 March; 75(3): 986-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12645728&dopt=Abstract

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Recurrent primary biliary cirrhosis. Author(s): Neuberger J. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2003 June; 9(6): 539-46. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783392&dopt=Abstract

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Reduced diffusion in liver cirrhosis is related to impairment of protein liver synthesis. Author(s): Drenth JP, Jansen JB, Dekhuijzen PN. Source: Scandinavian Journal of Gastroenterology. 2002 November; 37(11): 1338-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12465735&dopt=Abstract

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Reduced hepatic glycogen stores in patients with liver cirrhosis. Author(s): Krahenbuhl L, Lang C, Ludes S, Seiler C, Schafer M, Zimmermann A, Krahenbuhl S. Source: Liver International : Official Journal of the International Association for the Study of the Liver. 2003 April; 23(2): 101-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12654132&dopt=Abstract

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Regression of hepatic fibrosis and cirrhosis in patients with chronic hepatitis C treated with interferon-based therapy. Author(s): Metwally MA, Zein CO, Zein NN. Source: Gastroenterology. 2003 May; 124(5): 1561. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12760398&dopt=Abstract

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Renal functional reserve is well maintained in patients with advanced liver cirrhosis and ascites. Author(s): Woitas RP, Flommersfeld S, Stoffel-Wagner B, Schiedermaier P, Brensing KA, Spengler U, Sauerbruch T. Source: Scandinavian Journal of Gastroenterology. 2002 November; 37(11): 1321-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12465732&dopt=Abstract

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Resolution of liver cirrhosis and prevention of hepatocellular carcinoma by interferon therapy against chronic hepatitis C. Author(s): Omata M, Yoshida H. Source: Scandinavian Journal of Gastroenterology. Supplement. 2003; (237): 47-51. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12797682&dopt=Abstract

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Reversal of cirrhosis: evidence-based medicine? Author(s): Desmet VJ, Roskams T. Source: Gastroenterology. 2003 August; 125(2): 629-30; Author Reply 630-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891578&dopt=Abstract

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Review article: albumin for circulatory support in patients with cirrhosis. Author(s): Gines P, Guevara M, De Las Heras D, Arroyo V. Source: Alimentary Pharmacology & Therapeutics. 2002 December; 16 Suppl 5: 24-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12423450&dopt=Abstract

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Review article: is there an optimal therapeutic regimen for antimitochondrial antibody-negative primary biliary cirrhosis (autoimmune cholangitis)? Author(s): Gisbert JP, Jones EA, Pajares JM, Moreno-Otero R. Source: Alimentary Pharmacology & Therapeutics. 2003 January; 17(1): 17-27. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12492729&dopt=Abstract

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Review article: volume expansion in patients with cirrhosis. Author(s): Henriksen JH, Kiszka-Kanowitz M, Bendtsen F. Source: Alimentary Pharmacology & Therapeutics. 2002 December; 16 Suppl 5: 12-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12423449&dopt=Abstract

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Rhinocerebral mucormycosis in a patient with cirrhosis and chronic renal failure. Author(s): Georgopoulou S, Kounougeri E, Katsenos C, Rizos M, Michalopoulos A. Source: Hepatogastroenterology. 2003 May-June; 50(51): 843-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828101&dopt=Abstract

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Risk factors for nonhepatic surgery in patients with cirrhosis. Author(s): del Olmo JA, Flor-Lorente B, Flor-Civera B, Rodriguez F, Serra MA, Escudero A, Lledo S, Rodrigo JM. Source: World Journal of Surgery. 2003 June; 27(6): 647-52. Epub 2003 May 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12732995&dopt=Abstract

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Risk factors for symptomatic gallstones in patients with liver cirrhosis: a case-control study. Author(s): Acalovschi M, Blendea D, Feier C, Letia AI, Ratiu N, Dumitrascu DL, Veres A. Source: The American Journal of Gastroenterology. 2003 August; 98(8): 1856-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12907344&dopt=Abstract

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Safety and efficacy of estrogen therapy in preventing bone loss in primary biliary cirrhosis. Author(s): Menon KV, Angulo P, Boe GM, Lindor KD. Source: The American Journal of Gastroenterology. 2003 April; 98(4): 889-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12738473&dopt=Abstract

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Safety and efficacy of Mangafodipir trisodium in patients with liver lesions and cirrhosis. Author(s): Marti-Bonmati L, Fog AF, de Beeck BO, Kane P, Fagertun H. Source: European Radiology. 2003 July; 13(7): 1685-92. Epub 2002 December 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12835986&dopt=Abstract

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Scintigraphic diagnosis of pleuroperitoneal communication in cirrhosis secondary to polycythemia vera. Author(s): Ameredes HT, Joyce JM, Fecher A, Landreneau R, Keenan R, Jackson T. Source: Clinical Nuclear Medicine. 2003 April; 28(4): 332-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12642720&dopt=Abstract

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Screening for hepatocellular carcinoma in patients with hepatitis C cirrhosis: a costutility analysis. Author(s): Arguedas MR, Chen VK, Eloubeidi MA, Fallon MB. Source: The American Journal of Gastroenterology. 2003 March; 98(3): 679-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12650806&dopt=Abstract

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Septic arthritis due to Streptococcus bovis in a patient with cirrhosis of enolic etiology. Author(s): Marin E, Navas C, Martin-Vivaldi J, Garcia-Tapia A, Martin-Herrera L. Source: Rev Esp Enferm Dig. 2003 July; 95(7): 506-8, 503-5. English, Spanish. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12952512&dopt=Abstract

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Serum aminotransferase levels and platelet count as predictive factor of fibrosis and cirrhosis in patients with chronic hepatitis C infection. Author(s): Khokhar N. Source: J Pak Med Assoc. 2003 March; 53(3): 101-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12779023&dopt=Abstract

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Serum concentrations of insulin-like growth factor-I (IGF-I) in patients with liver cirrhosis. Author(s): Vyzantiadis T, Theodoridou S, Giouleme O, Harsoulis P, Evgenidis N, Vyzantiadis A. Source: Hepatogastroenterology. 2003 May-June; 50(51): 814-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828091&dopt=Abstract

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Serum insulin-like growth factor I evaluation as a useful tool for predicting the risk of developing hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis: a prospective study. Author(s): Mazziotti G, Sorvillo F, Morisco F, Carbone A, Rotondi M, Stornaiuolo G, Precone DF, Cioffi M, Gaeta GB, Caporaso N, Carella C. Source: Cancer. 2002 December 15; 95(12): 2539-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12467068&dopt=Abstract

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Severe recurrent hepatitis C after liver retransplantation for hepatitis C virus-related graft cirrhosis. Author(s): Berenguer M, Prieto M, Palau A, Rayon JM, Carrasco D, Juan FS, LopezLabrador FX, Moreno R, Mir J, Berenguer J. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2003 March; 9(3): 228-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12619018&dopt=Abstract

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Should HCV-related cirrhosis be a contraindication for retransplantation? Author(s): Biggins SW, Terrault NA. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2003 March; 9(3): 236-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12619019&dopt=Abstract

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Similarity between hepatic graft-versus-host disease and primary biliary cirrhosis. Author(s): Wakae T, Takatsuka H, Seto Y, Iwata N, Mori A, Okada M, Fujimori Y, Okamoto T, Kakishita E, Hara H. Source: Hematology (Amsterdam, Netherlands). 2002 October; 7(5): 305-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12850818&dopt=Abstract

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Small hepatocellular carcinoma in cirrhosis: randomized comparison of radiofrequency thermal ablation versus percutaneous ethanol injection. Author(s): Lencioni RA, Allgaier HP, Cioni D, Olschewski M, Deibert P, Crocetti L, Frings H, Laubenberger J, Zuber I, Blum HE, Bartolozzi C. Source: Radiology. 2003 July; 228(1): 235-40. Epub 2003 May 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12759473&dopt=Abstract

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Small hepatocellular carcinomas in patients with liver cirrhosis: potentials and limitations of contrast-enhanced power Doppler sonography. Author(s): Gritzmann N. Source: European Journal of Gastroenterology & Hepatology. 2003 August; 15(8): 881-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12867798&dopt=Abstract

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Small intestinal motility disturbances and bacterial overgrowth in patients with liver cirrhosis and portal hypertension. Author(s): Gunnarsdottir SA, Sadik R, Shev S, Simren M, Sjovall H, Stotzer PO, Abrahamsson H, Olsson R, Bjornsson ES. Source: The American Journal of Gastroenterology. 2003 June; 98(6): 1362-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818282&dopt=Abstract

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Smoking and liver cancer in China: case-control comparison of 36,000 liver cancer deaths vs. 17,000 cirrhosis deaths. Author(s): Chen ZM, Liu BQ, Boreham J, Wu YP, Chen JS, Peto R. Source: International Journal of Cancer. Journal International Du Cancer. 2003 October 20; 107(1): 106-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12925964&dopt=Abstract

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Sources of glucose production in cirrhosis by 2H2O ingestion and 2H NMR analysis of plasma glucose. Author(s): Perdigoto R, Furtado AL, Porto A, Rodrigues TB, Geraldes CF, Jones JG. Source: Biochimica Et Biophysica Acta. 2003 March 20; 1637(2): 156-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12633904&dopt=Abstract

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Specific psychiatric morbidity in liver cirrhosis in a Nigerian general hospital setting. Author(s): Aghanwa HS, Ndububa D. Source: General Hospital Psychiatry. 2002 November-December; 24(6): 436-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490347&dopt=Abstract

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Spontaneous bacterial peritonitis in patients with hepatic cirrhosis: evaluation of a treatment protocol at specialized units. Author(s): Dinis-Ribeiro M, Cortez-Pinto H, Marinho R, Valente A, Raimundo M, Salgado MJ, Ramalho F, Alexandrino P, Carneiro-de-Moura M. Source: Rev Esp Enferm Dig. 2002 August; 94(8): 473-81. English, Spanish. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12486852&dopt=Abstract

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Stool antigen for the diagnosis of Helicobacter pylori infection in cirrhosis: comparative usefulness of three different methods. Author(s): Calvet X, Quesada M, Rosello M, Salceda F, Sanfeliu I, Dalmau B, Gil M. Source: Alimentary Pharmacology & Therapeutics. 2003 March 1; 17(5): 727-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12641523&dopt=Abstract

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Successful treatment of hepatitis C in a patient with advanced AIDS and decompensated cirrhosis. Author(s): Johanson FD, Balliram DB. Source: Aids Read. 2003 October; 13(10): 494-6, 500-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14596227&dopt=Abstract

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T cell immunity and primary biliary cirrhosis. Author(s): Ishibashi H, Nakamura M, Shimoda S, Gershwin ME. Source: Autoimmunity Reviews. 2003 January; 2(1): 19-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848971&dopt=Abstract

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T2 hyperintensity along the cortico-spinal tract in cirrhosis relates to functional abnormalities. Author(s): Cordoba J, Raguer N, Flavia M, Vargas V, Jacas C, Alonso J, Rovira A. Source: Hepatology (Baltimore, Md.). 2003 October; 38(4): 1026-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14512890&dopt=Abstract

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The effect of immunosuppressive regimens on the recurrence of primary biliary cirrhosis after liver transplantation. Author(s): Levitsky J, Hart J, Cohen SM, Te HS. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2003 July; 9(7): 733-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12827561&dopt=Abstract

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The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis. A randomized trial. Author(s): Rasaratnam B, Kaye D, Jennings G, Dudley F, Chin-Dusting J. Source: Annals of Internal Medicine. 2003 August 5; 139(3): 186-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12899586&dopt=Abstract

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The influence of sulindac on patients with primary biliary cirrhosis that responds incompletely to ursodeoxycholic acid: a pilot study. Author(s): Leuschner M, Holtmeier J, Ackermann H, Leuschner U. Source: European Journal of Gastroenterology & Hepatology. 2002 December; 14(12): 1369-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12468960&dopt=Abstract

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The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis. Author(s): Olde Damink SW, Jalan R, Deutz NE, Redhead DN, Dejong CH, Hynd P, Jalan RA, Hayes PC, Soeters PB. Source: Hepatology (Baltimore, Md.). 2003 June; 37(6): 1277-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12774005&dopt=Abstract

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The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Author(s): Moore KP, Wong F, Gines P, Bernardi M, Ochs A, Salerno F, Angeli P, Porayko M, Moreau R, Garcia-Tsao G, Jimenez W, Planas R, Arroyo V. Source: Hepatology (Baltimore, Md.). 2003 July; 38(1): 258-66. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12830009&dopt=Abstract

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The relationship between internally deposited alpha-particle radiation and subsitespecific liver cancer and liver cirrhosis: an analysis of published data. Author(s): Sharp GB. Source: Journal of Radiation Research. 2002 December; 43(4): 371-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12674201&dopt=Abstract

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Therapeutic role of vasopressin receptor antagonism in patients with liver cirrhosis. Author(s): Ferguson JW, Therapondos G, Newby DE, Hayes PC. Source: Clinical Science (London, England : 1979). 2003 July; 105(1): 1-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12639215&dopt=Abstract

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Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-blind multicenter trial. Author(s): Gerbes AL, Gulberg V, Gines P, Decaux G, Gross P, Gandjini H, Djian J; VPA Study Group. Source: Gastroenterology. 2003 April; 124(4): 933-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12671890&dopt=Abstract

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TIPS in refractory ascites in cirrhosis: not only survival is the clue. Author(s): Ockenga J, Schuetz T, Lochs H. Source: Gastroenterology. 2003 September; 125(3): 997-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974267&dopt=Abstract

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Trans-catheter arterial chemoembolisation for hepatocellular carcinoma in patients with viral cirrhosis: role of combined staging systems, Cancer Liver Italian Program (CLIP) and Model for End-stage Liver Disease (MELD), in predicting outcome after treatment. Author(s): Testa R, Testa E, Giannini E, Botta F, Malfatti F, Chiarbonello B, Fumagalli A, Polegato S, Podesta E, Romagnoli P, Risso D, Cittadini G, De Caro G. Source: Alimentary Pharmacology & Therapeutics. 2003 June 15; 17(12): 1563-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823161&dopt=Abstract

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Transjugular intrahepatic porto-systemic shunt to relieve refractory ascites in a patient with cirrhosis and portal hypertension. Author(s): Joseph G, George OK, Jayanthi V. Source: Indian Heart J. 2002 November-December; 54(6): 731-2. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12674194&dopt=Abstract

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Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in cirrhosis. Author(s): Gines P, Uriz J, Calahorra B, Garcia-Tsao G, Kamath PS, Del Arbol LR, Planas R, Bosch J, Arroyo V, Rodes J. Source: Gastroenterology. 2002 December; 123(6): 1839-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454841&dopt=Abstract

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Transplantation for hepatocellular carcinoma and cirrhosis: sensitivity of magnetic resonance imaging. Author(s): Krinsky GA, Lee VS, Theise ND, Weinreb JC, Morgan GR, Diflo T, John D, Teperman LW, Goldenberg AS. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2002 December; 8(12): 1156-64. Erratum In: Liver Transpl. 2003 February; 9(2): 205. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12474156&dopt=Abstract

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Transverse myelitis occurring in association with primary biliary cirrhosis and Sjogren's syndrome. Author(s): Anantharaju A, Baluch M, Van Thiel DH. Source: Digestive Diseases and Sciences. 2003 April; 48(4): 830-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12741480&dopt=Abstract

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Treatment strategies for hepatocellular carcinoma in cirrhosis. Author(s): Helton WS, Di Bisceglie A, Chari R, Schwartz M, Bruix J. Source: Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract. 2003 March-April; 7(3): 401-11. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12654567&dopt=Abstract

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Treatment with ursodeoxycholic acid is associated with weight gain in patients with primary biliary cirrhosis. Author(s): Siegel JL, Jorgensen R, Angulo P, Lindor KD. Source: Journal of Clinical Gastroenterology. 2003 August; 37(2): 183-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12869893&dopt=Abstract

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Tumor location, cirrhosis, and surgical history contribute to tumor movement in the liver, as measured during stereotactic irradiation using a real-time tumor-tracking radiotherapy system. Author(s): Kitamura K, Shirato H, Seppenwoolde Y, Shimizu T, Kodama Y, Endo H, Onimaru R, Oda M, Fujita K, Shimizu S, Miyasaka K. Source: International Journal of Radiation Oncology, Biology, Physics. 2003 May 1; 56(1): 221-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12694842&dopt=Abstract

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Two cases of spontaneous epidural abscess in patients with cirrhosis. Author(s): Cross RK Jr, Howell C. Source: Southern Medical Journal. 2003 March; 96(3): 291-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12659363&dopt=Abstract

•

Ultrasonography and liver cirrhosis. Author(s): Varas Lorenzo MJ. Source: Rev Esp Enferm Dig. 2003 April; 95(4): 248-50, 245-7. English, Spanish. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12826002&dopt=Abstract

•

Ultrasonography in patients with chronic liver disease: its usefulness in the diagnosis of cirrhosis. Author(s): Macias Rodriguez MA, Rendon Unceta P, Navas Relinque C, Tejada Cabrera M, Infantes Hernandez JM, Martin Herrera L. Source: Rev Esp Enferm Dig. 2003 April; 95(4): 258-64, 251-7. English, Spanish. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12826003&dopt=Abstract

•

Unsuspected primary hepatic angiosarcoma associated with portal vein thrombosis complicating cirrhosis. Author(s): Pimentel Cauduro SK, Petrovic LM, Sodeman TC, Ishitani MB, Menon KV, Hay JE. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2002 November; 8(11): 1080-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12424726&dopt=Abstract

Studies

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Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators. Author(s): D'Amico G, De Franchis R; Cooperative Study Group. Source: Hepatology (Baltimore, Md.). 2003 September; 38(3): 599-612. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939586&dopt=Abstract

•

Ursodeoxycholic acid therapy and the risk of colorectal adenoma in patients with primary biliary cirrhosis: an observational study. Author(s): Serfaty L, De Leusse A, Rosmorduc O, Desaint B, Flejou JF, Chazouilleres O, Poupon RE, Poupon R. Source: Hepatology (Baltimore, Md.). 2003 July; 38(1): 203-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12830003&dopt=Abstract

•

Use of activated recombinant human factor VII (rhFVIIa) for colonic polypectomies in patients with cirrhosis and coagulopathy. Author(s): Anantharaju A, Mehta K, Mindikoglu AL, Van Thiel DH. Source: Digestive Diseases and Sciences. 2003 July; 48(7): 1414-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870806&dopt=Abstract

•

Utility of the MELD score for assessing 3-month survival in patients with liver cirrhosis: one more positive answer. Author(s): Giannini E, Botta F, Testa R. Source: Gastroenterology. 2003 September; 125(3): 993-4; Author Reply 994-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974262&dopt=Abstract

•

Utility of the MELD score for assessing 3-month survival in patients with liver cirrhosis: one more positive answer. Author(s): Heuman DM, Mihas A. Source: Gastroenterology. 2003 September; 125(3): 992-3; Author Reply 994-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974261&dopt=Abstract

•

What features of the pathological morphology of the liver increase the accuracy of diagnostic imaging for cirrhosis? Author(s): Kage M. Source: Journal of Gastroenterology. 2003; 38(2): 202-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640540&dopt=Abstract

•

What is the real prevalence of the D virus infection in chronic hepatitis and liver cirrhosis in Romania? Author(s): Grigorescu M, Pascu O, Acalovschi M, Radu C. Source: Rom J Gastroenterol. 2003 September; 12(3): 179-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14502316&dopt=Abstract

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CHAPTER 2. NUTRITION AND CIRRHOSIS Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and cirrhosis.

Finding Nutrition Studies on Cirrhosis 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 “cirrhosis” (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.

122 Cirrhosis

The following is a typical result when searching for recently indexed consumer information on cirrhosis: •

A rare association of primary biliary cirrhosis and pernicious anemia. Author(s): First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan. Source: Aoyama, H Sakugawa, H Nakasone, H Nakayoshi, T Kinjo, A Tamayose, M Higa, H Uema, E Chinen, T Tomiyama, R Uchima, N Kugai, Y Kinjo, F Saito, A Kinjo, M J-Gastroenterol. 2002; 37(7): 560-3 0944-1174

•

Acute effects of nitric oxide synthase inhibition on systemic, hepatic, and renal hemodynamics in patients with cirrhosis and ascites. Author(s): Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital, Geneva, Switzerland. [email protected] Source: Spahr, Laurent Martin, Pierre Yves Giostra, Emile Niederberger, Michel Lang, Ursula Capponi, Allessandro Hadengue, Antoine J-Investig-Med. 2002 Mar; 50(2): 11624 1081-5589

•

Alcohol-related cirrhosis with pancreatitis. The role of oxidative stress in the progression of the disease. Author(s): Department of Virology and Immunology, Maria Curie-Sklodowska University, Akademicka, Lublin, Poland. Source: Szuster Ciesielska, A Daniluk, J Kandefer Szerszen, M Arch-Immunol-Ther-Exp(Warsz). 2001; 49(2): 139-46 0004-069X

•

Autoreactive responses to pyruvate dehydrogenase complex in the pathogenesis of primary biliary cirrhosis. Author(s): Centre for Liver Research, School of Biochemistry and Genetics, University of Newcastle, Newcastle-upon-Tyne, UK. [email protected] Source: Yeaman, S J Kirby, J A Jones, D E Immunol-Revolume 2000 April; 174: 238-49 0105-2896

•

Biliary epithelial expression of pyruvate dehydrogenase complex in primary biliary cirrhosis: an immunohistochemical and immunoelectron microscopic study. Author(s): Second Department of Pathology, Kanazawa University School of Medicine, Japan. Source: Nakanuma, Y Tsuneyama, K Kono, N Hoso, M Van de Water, J Gershwin, M E Hum-Pathol. 1995 January; 26(1): 92-8 0046-8177

•

Calcitriol for bone loss in patients with primary biliary cirrhosis. Author(s): Third Department of Internal Medicine, Osaka, Japan. Source: Shiomi, S Masaki, K Habu, D Takeda, T Nishiguchi, S Kuroki, T Ochi, H JGastroenterol. 1999 April; 34(2): 241-5 0944-1174

•

Changes in hepatic nitrogen metabolism in isolated perfused liver during the development of thioacetamide-induced cirrhosis in rats. Author(s): Department of Veterinary Physiology, College of Agriculture, Osaka Prefecture University, Japan. [email protected] Source: Masumi, S Moriyama, M Kannan, Y Ohta, M Koshitani, O Sawamoto, O Sugano, T Toxicology. 1999 July 1; 135(1): 21-31 0300-483X

•

Cirrhosis of liver with ascites treatment based on principles of ayurved. Author(s): Bhatia Hospital. Source: Patel, J C Indian-J-Med-Sci. 2001 September; 55(9): 481-2 0019-5359

Nutrition

123

•

Clinical and biochemical features and therapy responses in primary biliary cirrhosis and primary biliary cirrhosis-autoimmune hepatitis overlap syndrome. Author(s): Department of Gastroenterology, Ege University Hospital Izmir, Turkey. [email protected] Source: Gunsar, F Akarca, U S Ersoz, G Karasu, Z Yuce, G Batur, Y Hepatogastroenterology. 2002 Sep-October; 49(47): 1195-200 0172-6390

•

Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis. Author(s): Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, H:S Rigshopitalet, Blegdamsvej 9, Dep. 77.01., Copenhagen, Denmark, DK-2100. [email protected] Source: Rambaldi, A Gluud, C Cochrane-Database-Syst-Revolume 2001; (3): CD002148 1469-493X

•

Comparative immunoreactivity of anti-trifluoroacetyl (TFA) antibody and anti-lipoic acid antibody in primary biliary cirrhosis: searching for a mimic. Author(s): Division of Rheumatology/Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA. Source: Sasaki, M Ansari, A Pumford, N van de Water, J Leung, P S Humphries, K M Szweda, L I Nakanuma, Y Roche, T E Coppel, R L Bach, J F Gershwin, M E JAutoimmun. 2000 August; 15(1): 51-60 0896-8411

•

Comparative metabolism and structure of BCKD-E2 in primary biliary cirrhosis. Author(s): Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis 95616. Source: Turchany, J M Leung, P S Iwayama, T Jefferson, D M Ishida, J Yamaguchi, M Munoz, S Danner, D J Dickson, E R Gershwin, M E J-Autoimmun. 1993 August; 6(4): 459-66 0896-8411

•

Early administration of vapreotide for variceal bleeding in patients with cirrhosis. Source: Eloubeidi, Mohamad A Arguedas, Miguel R Gastrointest-Endosc. 2002 January; 55(1): 135-7 0016-5107

•

Effect of resovist on rats with different severities of liver cirrhosis. Author(s): Drug Discovery Institute, Nihon Schering K.K., Yodogawa-ku, Osaka, Japan. [email protected] Source: Kato, Naoki Ihara, Shinya Tsujimoto, Taichi Miyazawa, Tomoaki Invest-Radiol. 2002 May; 37(5): 292-8 0020-9996

•

Effects of zinc deficiency/zinc supplementation on ammonia metabolism in patients with decompensated liver cirrhosis. Author(s): Department of Medicine I, Okayama University Medical School, Japan, Source: Yoshida, Y Higashi, T Nouso, K Nakatsukasa, H Nakamura, S I Watanabe, A Tsuji, T Acta-Med-Okayama. 2001 December; 55(6): 349-55 0386-300X

•

Endoscopic sclerotherapy (ethanolamine oleate injection) for acute rectal varices bleeding in a patient with liver cirrhosis. Author(s): First Department of Internal Medicine, Mie University School of Medicine, Edobashi, 2-174, Tsu, 514-8507, Japan. Source: Yamanaka, T Shiraki, K Ito, T Sugimoto, K Sakai, T Ohmori, S Takase, K Nakano, T Oohashi, Y Okuda, Y Hepatogastroenterology. 2002 Jul-August; 49(46): 941-3 0172-6390

124 Cirrhosis

•

Evaluation of 13C-phenylalanine and 13C-tyrosine breath tests for the measurement of hepatocyte functional capacity in patients with liver cirrhosis. Author(s): Department of Medicinal Chemistry, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan. Source: Ishii, T Furube, M Hirano, S Takatori, K Iida, K Kajiwara, M Chem-Pharm-Bull(Tokyo). 2001 December; 49(12): 1507-11 0009-2363

•

Hepatic cirrhosis increases sensitivity of kidney to endotoxin in rats. Author(s): Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, P.R. China. [email protected] Source: Liu, Jian June Wang, Ji Yao Zhang, Chi Nilsson, Ake Duan, Rui Dong Med-SciMonit. 2002 February; 8(2): BR56-60 1234-1010

•

Impact factors on development of cirrhosis and subsequent hepatocellular carcinoma. Author(s): University of North Carolina-Chapel Hill, Lineberger Comprehensive Cancer Center, School of Medicine, Chapel Hill, North Carolina, USA. Source: Holmes McNary, M Compend-Contin-Educ-Dent. 2001 July; 22(3): 19-33

•

Improved liver tests and greater biliary enrichment with high dose ursodeoxycholic acid in early stage primary biliary cirrhosis. Author(s): Department of Internal Medicine and Gastroenterology, University of Bologna, S. Drsola-Malpighi Hospital, Italy. Source: Roda, E Azzaroli, F Nigro, G Piazza, F Jaboli, F Ferrara, F Liva, S Giovanelli, S Miracolo, A Colecchia, A Festi, D Mazzeo, C Bacchi, l Roda, A Mazzella, G Dig-LiverDis. 2002 July; 34(7): 523-7 1590-8658

•

Molecular basis of mitochondrial autoreactivity in primary biliary cirrhosis. Source: Mackay, I R Gershwin, M E Immunol-Today. 1989 September; 10(9): 315-8 01675699

•

Pathogenesis of ascites and renal salt retention in cirrhosis. Author(s): Department of Medicine, University of Texas Southwestern Medical School, Dallas 75235, USA. Source: Palmer, B F J-Investig-Med. 1999 May; 47(5): 183-202 1081-5589

•

Plasma and liver carnitine status of children with chronic liver disease and cirrhosis. Author(s): Ege University, Department of Pediatric Gastroenterology and Nutrition, Izmir, Turkey. [email protected] Source: Selimoglu, M A Aydogdu, S Yagci, R V HuseyiNovember, A Pediatr-Int. 2001 August; 43(4): 391-5 1328-8067

•

Possible role of endogenous retinoid (Vitamin A) toxicity in the pathophysiology of primary biliary cirrhosis. Author(s): Department of Internal Medicine, Iowa Methodist Medical Center, 1215 Pleasant St., Suite 300, Des Moines, IA 50309, USA. Source: Erickson, J M Mawson, A R J-Theor-Biol. 2000 September 7; 206(1): 47-54 00225193

•

Primary biliary cirrhosis associated with type A gastritis and chronic thyroiditis. Author(s): Department of Gastroenterology, Saiseikai Kanazawa Hospital, Kanazawa, Japan. Source: Wakabayashi, T Ohno, H Hayakawa, Y Kawashima, A Sawabu, N JGastroenterol. 1999 June; 34(3): 415-9 0944-1174

Nutrition

125

•

Segmental transcatheter arterial chemoembolization treatment in patients with cirrhosis and inoperable hepatocellular carcinomas. Author(s): Institute of Radiology, IRCCS Maggiore Hospital, University of Milan, Milan, Italy. Source: Saccheri, S Lovaria, A Sangiovanni, A Nicolini, A De Fazio, C Ronchi, G Fasani, P Del Ninno, E Colombo, M J-Vasc-Interv-Radiol. 2002 October; 13(10): 995-9 1051-0443

•

Selenium status in patients with liver cirrhosis. Source: Akesson, B. Johansson, U. Selenium in biology and medicine : proceedings of the Third International Symposium on Selenium in Biology and Medicine, held May 27June 1, 1984, Xiangshan (Fragrance Hills) Hotel Beijing, People's Republic of China. New York : Van Nostrand Reinhold, c1987. page 968-975. ISBN: 0442221088

•

Slow metabolism and long half life of methadone in a patient with lung cancer and cirrhosis. Author(s): Pharmacie, Hopital Paul-Guiraud, 54, avenue de la Republique, 94806 Villejuif Cedex. [email protected] Source: Beauverie, P Furlan, V Edel, Y A Ann-Med-Interne-(Paris). 2001 November; 152 Suppl 7: 50-2 0003-410X

•

Specific reactivity of recombinant human PDC-E1 alpha in primary biliary cirrhosis. Author(s): Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis 95616. Source: Iwayama, T Leung, P S Coppel, R L Roche, T E Patel, M S Mizushima, Y Nakagawa, T Dickson, R Gershwin, M E J-Autoimmun. 1991 October; 4(5): 769-78 08968411

•

Ursodeoxycholic acid enhances fractional calcium absorption in primary biliary cirrhosis. Author(s): Department of Medicine, Calderdale Royal Hospital, Halifax, UK. Source: Verma, A Maxwell, J D Ang, L Davis, T Hodges, S Northfield, T C Zaidi, M Pazianas, M Osteoporos-Int. 2002 August; 13(8): 677-82 0937-941X

The following information is typical of that found when using the “Full IBIDS Database” to search for “cirrhosis” (or a synonym): •

A rare association of primary biliary cirrhosis and pernicious anemia. Author(s): First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan. Source: Aoyama, H Sakugawa, H Nakasone, H Nakayoshi, T Kinjo, A Tamayose, M Higa, H Uema, E Chinen, T Tomiyama, R Uchima, N Kugai, Y Kinjo, F Saito, A Kinjo, M J-Gastroenterol. 2002; 37(7): 560-3 0944-1174

•

Acute effects of nitric oxide synthase inhibition on systemic, hepatic, and renal hemodynamics in patients with cirrhosis and ascites. Author(s): Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital, Geneva, Switzerland. [email protected] Source: Spahr, Laurent Martin, Pierre Yves Giostra, Emile Niederberger, Michel Lang, Ursula Capponi, Allessandro Hadengue, Antoine J-Investig-Med. 2002 Mar; 50(2): 11624 1081-5589

•

Alcohol-related cirrhosis with pancreatitis. The role of oxidative stress in the progression of the disease. Author(s): Department of Virology and Immunology, Maria Curie-Sklodowska University, Akademicka, Lublin, Poland.

126 Cirrhosis

Source: Szuster Ciesielska, A Daniluk, J Kandefer Szerszen, M Arch-Immunol-Ther-Exp(Warsz). 2001; 49(2): 139-46 0004-069X •

Autoreactive responses to pyruvate dehydrogenase complex in the pathogenesis of primary biliary cirrhosis. Author(s): Centre for Liver Research, School of Biochemistry and Genetics, University of Newcastle, Newcastle-upon-Tyne, UK. [email protected] Source: Yeaman, S J Kirby, J A Jones, D E Immunol-Revolume 2000 April; 174: 238-49 0105-2896

•

Biliary epithelial expression of pyruvate dehydrogenase complex in primary biliary cirrhosis: an immunohistochemical and immunoelectron microscopic study. Author(s): Second Department of Pathology, Kanazawa University School of Medicine, Japan. Source: Nakanuma, Y Tsuneyama, K Kono, N Hoso, M Van de Water, J Gershwin, M E Hum-Pathol. 1995 January; 26(1): 92-8 0046-8177

•

Calcitriol for bone loss in patients with primary biliary cirrhosis. Author(s): Third Department of Internal Medicine, Osaka, Japan. Source: Shiomi, S Masaki, K Habu, D Takeda, T Nishiguchi, S Kuroki, T Ochi, H JGastroenterol. 1999 April; 34(2): 241-5 0944-1174

•

Changes in hepatic nitrogen metabolism in isolated perfused liver during the development of thioacetamide-induced cirrhosis in rats. Author(s): Department of Veterinary Physiology, College of Agriculture, Osaka Prefecture University, Japan. [email protected] Source: Masumi, S Moriyama, M Kannan, Y Ohta, M Koshitani, O Sawamoto, O Sugano, T Toxicology. 1999 July 1; 135(1): 21-31 0300-483X

•

Cirrhosis of liver with ascites treatment based on principles of ayurved. Author(s): Bhatia Hospital. Source: Patel, J C Indian-J-Med-Sci. 2001 September; 55(9): 481-2 0019-5359

•

Clinical and biochemical features and therapy responses in primary biliary cirrhosis and primary biliary cirrhosis-autoimmune hepatitis overlap syndrome. Author(s): Department of Gastroenterology, Ege University Hospital Izmir, Turkey. [email protected] Source: Gunsar, F Akarca, U S Ersoz, G Karasu, Z Yuce, G Batur, Y Hepatogastroenterology. 2002 Sep-October; 49(47): 1195-200 0172-6390

•

Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis. Author(s): Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, H:S Rigshopitalet, Blegdamsvej 9, Dep. 77.01., Copenhagen, Denmark, DK-2100. [email protected] Source: Rambaldi, A Gluud, C Cochrane-Database-Syst-Revolume 2001; (3): CD002148 1469-493X

•

Comparative immunoreactivity of anti-trifluoroacetyl (TFA) antibody and anti-lipoic acid antibody in primary biliary cirrhosis: searching for a mimic. Author(s): Division of Rheumatology/Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA. Source: Sasaki, M Ansari, A Pumford, N van de Water, J Leung, P S Humphries, K M Szweda, L I Nakanuma, Y Roche, T E Coppel, R L Bach, J F Gershwin, M E JAutoimmun. 2000 August; 15(1): 51-60 0896-8411

Nutrition

127

•

Comparative metabolism and structure of BCKD-E2 in primary biliary cirrhosis. Author(s): Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis 95616. Source: Turchany, J M Leung, P S Iwayama, T Jefferson, D M Ishida, J Yamaguchi, M Munoz, S Danner, D J Dickson, E R Gershwin, M E J-Autoimmun. 1993 August; 6(4): 459-66 0896-8411

•

Early administration of vapreotide for variceal bleeding in patients with cirrhosis. Source: Eloubeidi, Mohamad A Arguedas, Miguel R Gastrointest-Endosc. 2002 January; 55(1): 135-7 0016-5107

•

Effect of resovist on rats with different severities of liver cirrhosis. Author(s): Drug Discovery Institute, Nihon Schering K.K., Yodogawa-ku, Osaka, Japan. [email protected] Source: Kato, Naoki Ihara, Shinya Tsujimoto, Taichi Miyazawa, Tomoaki Invest-Radiol. 2002 May; 37(5): 292-8 0020-9996

•

Effects of zinc deficiency/zinc supplementation on ammonia metabolism in patients with decompensated liver cirrhosis. Author(s): Department of Medicine I, Okayama University Medical School, Japan, Source: Yoshida, Y Higashi, T Nouso, K Nakatsukasa, H Nakamura, S I Watanabe, A Tsuji, T Acta-Med-Okayama. 2001 December; 55(6): 349-55 0386-300X

•

Endoscopic sclerotherapy (ethanolamine oleate injection) for acute rectal varices bleeding in a patient with liver cirrhosis. Author(s): First Department of Internal Medicine, Mie University School of Medicine, Edobashi, 2-174, Tsu, 514-8507, Japan. Source: Yamanaka, T Shiraki, K Ito, T Sugimoto, K Sakai, T Ohmori, S Takase, K Nakano, T Oohashi, Y Okuda, Y Hepatogastroenterology. 2002 Jul-August; 49(46): 941-3 0172-6390

•

Evaluation of 13C-phenylalanine and 13C-tyrosine breath tests for the measurement of hepatocyte functional capacity in patients with liver cirrhosis. Author(s): Department of Medicinal Chemistry, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan. Source: Ishii, T Furube, M Hirano, S Takatori, K Iida, K Kajiwara, M Chem-Pharm-Bull(Tokyo). 2001 December; 49(12): 1507-11 0009-2363

•

Hepatic cirrhosis increases sensitivity of kidney to endotoxin in rats. Author(s): Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, P.R. China. [email protected] Source: Liu, Jian June Wang, Ji Yao Zhang, Chi Nilsson, Ake Duan, Rui Dong Med-SciMonit. 2002 February; 8(2): BR56-60 1234-1010

•

Impact factors on development of cirrhosis and subsequent hepatocellular carcinoma. Author(s): University of North Carolina-Chapel Hill, Lineberger Comprehensive Cancer Center, School of Medicine, Chapel Hill, North Carolina, USA. Source: Holmes McNary, M Compend-Contin-Educ-Dent. 2001 July; 22(3): 19-33

•

Improved liver tests and greater biliary enrichment with high dose ursodeoxycholic acid in early stage primary biliary cirrhosis. Author(s): Department of Internal Medicine and Gastroenterology, University of Bologna, S. Drsola-Malpighi Hospital, Italy. Source: Roda, E Azzaroli, F Nigro, G Piazza, F Jaboli, F Ferrara, F Liva, S Giovanelli, S Miracolo, A Colecchia, A Festi, D Mazzeo, C Bacchi, l Roda, A Mazzella, G Dig-LiverDis. 2002 July; 34(7): 523-7 1590-8658

128 Cirrhosis

•

Molecular basis of mitochondrial autoreactivity in primary biliary cirrhosis. Source: Mackay, I R Gershwin, M E Immunol-Today. 1989 September; 10(9): 315-8 01675699

•

Pathogenesis of ascites and renal salt retention in cirrhosis. Author(s): Department of Medicine, University of Texas Southwestern Medical School, Dallas 75235, USA. Source: Palmer, B F J-Investig-Med. 1999 May; 47(5): 183-202 1081-5589

•

Plasma and liver carnitine status of children with chronic liver disease and cirrhosis. Author(s): Ege University, Department of Pediatric Gastroenterology and Nutrition, Izmir, Turkey. [email protected] Source: Selimoglu, M A Aydogdu, S Yagci, R V HuseyiNovember, A Pediatr-Int. 2001 August; 43(4): 391-5 1328-8067

•

Possible role of endogenous retinoid (Vitamin A) toxicity in the pathophysiology of primary biliary cirrhosis. Author(s): Department of Internal Medicine, Iowa Methodist Medical Center, 1215 Pleasant St., Suite 300, Des Moines, IA 50309, USA. Source: Erickson, J M Mawson, A R J-Theor-Biol. 2000 September 7; 206(1): 47-54 00225193

•

Primary biliary cirrhosis associated with type A gastritis and chronic thyroiditis. Author(s): Department of Gastroenterology, Saiseikai Kanazawa Hospital, Kanazawa, Japan. Source: Wakabayashi, T Ohno, H Hayakawa, Y Kawashima, A Sawabu, N JGastroenterol. 1999 June; 34(3): 415-9 0944-1174

•

Segmental transcatheter arterial chemoembolization treatment in patients with cirrhosis and inoperable hepatocellular carcinomas. Author(s): Institute of Radiology, IRCCS Maggiore Hospital, University of Milan, Milan, Italy. Source: Saccheri, S Lovaria, A Sangiovanni, A Nicolini, A De Fazio, C Ronchi, G Fasani, P Del Ninno, E Colombo, M J-Vasc-Interv-Radiol. 2002 October; 13(10): 995-9 1051-0443

•

Selenium status in patients with liver cirrhosis. Source: Akesson, B. Johansson, U. Selenium in biology and medicine : proceedings of the Third International Symposium on Selenium in Biology and Medicine, held May 27June 1, 1984, Xiangshan (Fragrance Hills) Hotel Beijing, People's Republic of China. New York : Van Nostrand Reinhold, c1987. page 968-975. ISBN: 0442221088

•

Slow metabolism and long half life of methadone in a patient with lung cancer and cirrhosis. Author(s): Pharmacie, Hopital Paul-Guiraud, 54, avenue de la Republique, 94806 Villejuif Cedex. [email protected] Source: Beauverie, P Furlan, V Edel, Y A Ann-Med-Interne-(Paris). 2001 November; 152 Suppl 7: 50-2 0003-410X

•

Specific reactivity of recombinant human PDC-E1 alpha in primary biliary cirrhosis. Author(s): Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis 95616. Source: Iwayama, T Leung, P S Coppel, R L Roche, T E Patel, M S Mizushima, Y Nakagawa, T Dickson, R Gershwin, M E J-Autoimmun. 1991 October; 4(5): 769-78 08968411

Nutrition

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Ursodeoxycholic acid enhances fractional calcium absorption in primary biliary cirrhosis. Author(s): Department of Medicine, Calderdale Royal Hospital, Halifax, UK. Source: Verma, A Maxwell, J D Ang, L Davis, T Hodges, S Northfield, T C Zaidi, M Pazianas, M Osteoporos-Int. 2002 August; 13(8): 677-82 0937-941X

Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

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Google: http://directory.google.com/Top/Health/Nutrition/

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Healthnotes: http://www.healthnotes.com/

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Open Directory Project: http://dmoz.org/Health/Nutrition/

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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/

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WebMDHealth: http://my.webmd.com/nutrition

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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The following is a specific Web list relating to cirrhosis; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

Vitamins Folic Acid Source: Healthnotes, Inc.; www.healthnotes.com Vitamin E Source: Healthnotes, Inc.; www.healthnotes.com

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Minerals Calcium Source: Healthnotes, Inc.; www.healthnotes.com Calcium: Which Form Is Best? Source: Healthnotes, Inc.; www.healthnotes.com Chromium Source: Healthnotes, Inc.; www.healthnotes.com L-carnitine Source: Healthnotes, Inc.; www.healthnotes.com Lecithin and Choline Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10040,00.html Lecithin/phosphatidylcholine/choline Source: Healthnotes, Inc.; www.healthnotes.com Magnesium Source: Healthnotes, Inc.; www.healthnotes.com Manganese Source: Healthnotes, Inc.; www.healthnotes.com Selenium Source: Healthnotes, Inc.; www.healthnotes.com Selenium Source: Integrative Medicine Communications; www.drkoop.com Zinc Source: Healthnotes, Inc.; www.healthnotes.com

Nutrition

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Food and Diet Chocolate Source: Healthnotes, Inc.; www.healthnotes.com Clams Source: Healthnotes, Inc.; www.healthnotes.com Diabetes Source: Healthnotes, Inc.; www.healthnotes.com High Cholesterol Source: Healthnotes, Inc.; www.healthnotes.com Low Back Pain Source: Healthnotes, Inc.; www.healthnotes.com Mussels Source: Healthnotes, Inc.; www.healthnotes.com Oysters Source: Healthnotes, Inc.; www.healthnotes.com Scallops Source: Healthnotes, Inc.; www.healthnotes.com

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CHAPTER 3. ALTERNATIVE MEDICINE AND CIRRHOSIS Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to cirrhosis. At the conclusion of this chapter, we will provide additional sources.

The Combined Health Information Database The Combined Health Information Database (CHID) is a bibliographic database produced by health-related agencies of the U.S. federal government (mostly from the National Institutes of Health) that can offer concise information for a targeted search. The CHID database is updated four times a year at the end of January, April, July, and October. Check the titles, summaries, and availability of CAM-related information by using the “Simple Search” option at the following Web site: http://chid.nih.gov/simple/simple.html. In the drop box at the top, select “Complementary and Alternative Medicine.” Then type “cirrhosis” (or synonyms) in the second search box. We recommend that you select 100 “documents per page” and to check the “whole records” options. The following was extracted using this technique: •

Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effects Source: Gaithersburg, MD: National Center for Complementary and Alternative Medicine. 2000. 12 p. Contact: Available from National Center for Complementary and Alternative Medicine Clearinghouse. P.O. Box 7923, Gaithersburg, MD 20898. (888) 644-6226; INTERNATIONAL PHONE: (301) 519-3153; TTY: (866) 464-3615; FAX: (866) 464-3616; EMAIL: [email protected]. PRICE: Free. Publication Number: D029. Summary: This evidence report details a systematic review summarizing clinical studies of milk thistle in humans. The report addresses two areas: (1) the effects of milk thistle on liver disease of alcohol, viral, toxin, cholestatic, and primary malignancy etiologies, and (2) the clinical adverse effects associated with milk thistle ingestion or contact. It addresses ten questions regarding whether milk thistle supplements (when compared with no supplement, placebo, other oral supplements, or drugs): (1) alter the physiologic

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markers of liver function, or (2) reduce mortality or morbidity, or improve the quality of life in adults with alcohol-related, toxin-induced, or drug-induced liver disease, viral hepatitis, cholestasis, or primary hepatic malignancy. One question addresses the constituents of commonly available milk thistle preparations, and three questions address the common and uncommon symptomatic adverse effects of milk thistle. The report explains the methodology, followed by a summary of its findings, including mechanisms of action, preparations of milk thistle, benefit of milk thistle for liver disease, and adverse effects. It summarizes conclusions and discusses areas for future research. The addendum includes evidence-based practice centers, topics, available evidence reports, and contact information.

National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to cirrhosis and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “cirrhosis” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to cirrhosis: •

18F-fluorodeoxyglucose positron emission tomography study of brain metabolism in cirrhosis: effect of liver transplantation. Author(s): Burra P, Dam M, Chierichetti F, Tedeschi U, Senzolo M, Sale E, Cagnin A, Ori C, Naccarato R, Ferlin G, Pizzolato G. Source: Transplantation Proceedings. 1999 February-March; 31(1-2): 418-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10083169&dopt=Abstract

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A case of adult chronic copper self-intoxication resulting in cirrhosis. Author(s): O'Donohue J, Reid M, Varghese A, Portmann B, Williams R. Source: European Journal of Medical Research. 1999 June 28; 4(6): 252. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10383882&dopt=Abstract

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A case of erythropoietic protoporphyria with liver cirrhosis suggesting a therapeutic value of supplementation with alpha-tocopherol. Author(s): Komatsu H, Ishii K, Imamura K, Maruyama K, Yonei Y, Masuda H, Tsuchihashi T, Sajima Y. Source: Hepatology Research : the Official Journal of the Japan Society of Hepatology. 2000 November; 18(3): 298-309. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11058833&dopt=Abstract

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A combined high-fiber, low-glycemic index diet normalizes glucose tolerance and reduces hyperglycemia and hyperinsulinemia in adults with hepatic cirrhosis. Author(s): Barkoukis H, Fiedler KM, Lerner E.

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Source: Journal of the American Dietetic Association. 2002 October; 102(10): 1503-7; Discussion 1507-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12396175&dopt=Abstract •

Adjuvant cholylsarcosine during ursodeoxycholic acid treatment of primary biliary cirrhosis. Author(s): Ricci P, Hofmann AF, Hagey LR, Jorgensen RA, Rolland Dickson E, Lindor KD. Source: Digestive Diseases and Sciences. 1998 June; 43(6): 1292-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9635620&dopt=Abstract

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An animal model for copper-associated cirrhosis in infancy. Author(s): Aston NS, Morris PA, Tanner MS, Variend S. Source: The Journal of Pathology. 1998 October; 186(2): 215-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9924439&dopt=Abstract

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Branched-chain amino acids supplements in the late evening decrease the frequency of muscle cramps with advanced hepatic cirrhosis. Author(s): Sako K, Imamura Y, Nishimata H, Tahara K, Kubozono O, Tsubouchi H. Source: Hepatology Research : the Official Journal of the Japan Society of Hepatology. 2003 August; 26(4): 327-329. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12963433&dopt=Abstract

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Breast carcinoma metastases to the liver simulating cirrhosis. Author(s): Burkill GJ, King LJ, Scurr E, Healy JC. Source: Radiology. 2002 December; 225(3): 917; Author Reply 917-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12461279&dopt=Abstract

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Changes in liver cirrhosis death rates in different countries in relation to per capita alcohol consumption and Alcoholics Anonymous membership. Author(s): Smart RG, Mann RE, Suurvali H. Source: J Stud Alcohol. 1998 May; 59(3): 245-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9598704&dopt=Abstract

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Cirrhosis of liver with ascites treatment based on principles of ayurved. Author(s): Patel JC. Source: Indian Journal of Medical Sciences. 2001 September; 55(9): 481-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11887296&dopt=Abstract

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Cirrhosis of the liver: MR imaging with mangafodipir trisodium (Mn-DPDP). Author(s): Murakami T, Baron RL, Federle MP, Peterson MS, Oliver JH 3rd, Davis PL, Confer SR.

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Source: Radiology. 1996 February; 198(2): 567-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8596867&dopt=Abstract •

Dietary linoleic acid in alcohol-induced liver cirrhosis. Author(s): Bailey JM, Fiskum G, Makheja AN, Vanderhoek JY. Source: Biochemical Society Transactions. 1995 May; 23(2): 247S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7672270&dopt=Abstract

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Dietary long-chain polyunsaturated fatty acids influence the recovery of thioacetamide-induced liver cirrhosis in rats. Author(s): Moreira E, Fontana L, Torres MI, Fernandez I, Rios A, Sanchez de Medina F, Gil A. Source: Jpen. Journal of Parenteral and Enteral Nutrition. 1995 November-December; 19(6): 461-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8748360&dopt=Abstract

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EDTA-dependent pseudothrombocytopenia in a case of liver cirrhosis. Author(s): Matarazzo M, Conturso V, Di Martino M, Chiurazzi F, Guida G, Morante R. Source: Panminerva Medica. 2000 June; 42(2): 155-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10965778&dopt=Abstract

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Effect of dietary selenium, zinc and allopurinol supplements on plasma and tissue manganese levels in rats with thioacetamide [correction of thiocetamide]-induced liver cirrhosis. Author(s): Al-Bader AA, Mosawi MH, Hussain TA, Dashti HM. Source: Molecular and Cellular Biochemistry. 1997 August; 173(1-2): 121-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9278262&dopt=Abstract

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Effect of gegen-tang on painful gynecomastia in patients with liver cirrhosis: a brief report. Author(s): Motoo Y, Taga H, Su SB, Sawabu N. Source: The American Journal of Chinese Medicine. 1997; 25(3-4): 317-24. Erratum In: Am J Chin Med 1998; 26(1): 114. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9358905&dopt=Abstract

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Effect of Lactobacillus johnsonii La1 and antioxidants on intestinal flora and bacterial translocation in rats with experimental cirrhosis. Author(s): Chiva M, Soriano G, Rochat I, Peralta C, Rochat F, Llovet T, Mirelis B, Schiffrin EJ, Guarner C, Balanzo J. Source: Journal of Hepatology. 2002 October; 37(4): 456-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12217598&dopt=Abstract

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Effect of niuche-shen-qi-wan on painful muscle cramps in patients with liver cirrhosis: a preliminary report. Author(s): Motoo Y, Taga H, Yamaguchi Y, Watanabe H, Okai T, Sawabu N. Source: The American Journal of Chinese Medicine. 1997; 25(1): 97-102. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9167002&dopt=Abstract

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Effect of preoperative interventions on outcome following liver resection in a rat model of cirrhosis. Author(s): Moser M, Zhang M, Gong Y, Johnson J, Kneteman N, Minuk GY. Source: Journal of Hepatology. 2000 February; 32(2): 287-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10707869&dopt=Abstract

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Effects of bathing in hot water on portal hemodynamics in healthy subjects and in patients with compensated liver cirrhosis. Author(s): Koda M, Komori S, Nagami M, Minohara M, Murawaki Y, Horie Y, Suou T, Kawasaki H, Ikawa S. Source: Intern Med. 1995 July; 34(7): 628-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7496071&dopt=Abstract

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Effects of branched-chain amino acid-enriched nutrient mixture on natural killer cell activity in viral cirrhosis. Author(s): Takegoshi K, Nanasawa H, Itoh H, Yasuyama T, Ohmoto Y, Sugiyama K. Source: Arzneimittel-Forschung. 1998 June; 48(6): 701-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9689432&dopt=Abstract

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Effects of hepatic stimulator substance, herbal medicine, selenium/vitamin E, and ciprofloxacin on cirrhosis in the rat. Author(s): Zhang M, Song G, Minuk GY. Source: Gastroenterology. 1996 April; 110(4): 1150-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8613004&dopt=Abstract

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Effects of quercetin on liver damage in rats with carbon tetrachloride-induced cirrhosis. Author(s): Pavanato A, Tunon MJ, Sanchez-Campos S, Marroni CA, Llesuy S, GonzalezGallego J, Marroni N. Source: Digestive Diseases and Sciences. 2003 April; 48(4): 824-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12741479&dopt=Abstract

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Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. Author(s): Pares A, Planas R, Torres M, Caballeria J, Viver JM, Acero D, Panes J, Rigau J, Santos J, Rodes J.

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Source: Journal of Hepatology. 1998 April; 28(4): 615-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9566830&dopt=Abstract •

Effects of silymarin MZ-80 on oxidative stress in patients with alcoholic cirrhosis. Results of a randomized, double-blind, placebo-controlled clinical study. Author(s): Lucena MI, Andrade RJ, de la Cruz JP, Rodriguez-Mendizabal M, Blanco E, Sanchez de la Cuesta F. Source: Int J Clin Pharmacol Ther. 2002 January; 40(1): 2-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11841050&dopt=Abstract

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Effects of supplementation with unsaturated fatty acids on plasma and membrane lipid composition and platelet function in patients with cirrhosis and defective aggregation. Author(s): Marra F, Riccardi D, Melani L, Spadoni S, Galli C, Fabrizio P, Tosti-Guerra C, Carloni V, Gentilini P, Laffi G. Source: Journal of Hepatology. 1998 April; 28(4): 654-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9566835&dopt=Abstract

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Effects of the Japanese herbal medicine “Sho-saiko-to” (TJ-9) on interleukin-12 production in patients with HCV-positive liver cirrhosis. Author(s): Yamashiki M, Nishimura A, Huang XX, Nobori T, Sakaguchi S, Suzuki H. Source: Developmental Immunology. 1999; 7(1): 17-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10636475&dopt=Abstract

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Effects of zinc deficiency/zinc supplementation on ammonia metabolism in patients with decompensated liver cirrhosis. Author(s): Yoshida Y, Higashi T, Nouso K, Nakatsukasa H, Nakamura SI, Watanabe A, Tsuji T. Source: Acta Medica Okayama. 2001 December; 55(6): 349-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11779097&dopt=Abstract

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Erythrocyte membrane lipids and serum selenium in post-viral and alcoholic cirrhosis. Author(s): Guarini P, Stanzial AM, Olivieri O, Casaril M, Galvani S, Pantalena M, Corrocher R. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 1998 February 23; 270(2): 139-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9544451&dopt=Abstract

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Failure of Lactobacillus spp. to prevent bacterial translocation in a rat model of experimental cirrhosis. Author(s): Bauer TM, Fernandez J, Navasa M, Vila J, Rodes J.

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Source: Journal of Hepatology. 2002 April; 36(4): 501-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11943421&dopt=Abstract •

Hepatic paraoxonase activity alterations and free radical production in rats with experimental cirrhosis. Author(s): Ferre N, Camps J, Cabre M, Paul A, Joven J. Source: Metabolism: Clinical and Experimental. 2001 September; 50(9): 997-1000. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11555827&dopt=Abstract

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Hepatopulmonary syndrome in liver cirrhosis: report of a case. Author(s): Chan CC, Wu HC, Wu CH, Hsu CY. Source: J Formos Med Assoc. 1995 April; 94(4): 185-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7606181&dopt=Abstract

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Herbal medicine Inchin-ko-to (TJ-135) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. Author(s): Sakaida I, Tsuchiya M, Kawaguchi K, Kimura T, Terai S, Okita K. Source: Journal of Hepatology. 2003 June; 38(6): 762-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12763369&dopt=Abstract

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Herbal medicine Sho-saiko-to (TJ-9) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. Author(s): Sakaida I, Matsumura Y, Akiyama S, Hayashi K, Ishige A, Okita K. Source: Journal of Hepatology. 1998 February; 28(2): 298-306. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9514543&dopt=Abstract

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Impact of portacaval anastomosis on plasma fatty acid profile in cirrhosis: a randomized 24-month follow-up study. Author(s): Cabre E, Navarro E, de Ramon M, Klaassen J, Planas R, Mingorance MD, Pastor MC, Lachica M, Boix J, Gassull MA. Source: Jpen. Journal of Parenteral and Enteral Nutrition. 1996 May-June; 20(3): 198-205. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8776693&dopt=Abstract

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Improvement of regional cerebral blood flow after treatment with branched-chain amino acid solutions in patients with cirrhosis. Author(s): Iwasa M, Matsumura K, Watanabe Y, Yamamoto M, Kaito M, Ikoma J, Gabazza EC, Takeda K, Adachi Y. Source: European Journal of Gastroenterology & Hepatology. 2003 July; 15(7): 733-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12811303&dopt=Abstract

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Influence of administration of long-chain polyunsaturated fatty acids on process of histological recovery in liver cirrhosis produced by oral intake of thioacetamide. Author(s): Fernandez I, Torres I, Moreira E, Fontana L, Gil A, Rios A.

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Source: Digestive Diseases and Sciences. 1996 January; 41(1): 197-207. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8565757&dopt=Abstract •

Inhibition of experimental cirrhosis in rats by HD-03. Author(s): Mitra SK, Udupa UV, Sheshadri SJ, Venkataranganna MV, Gopumadhavan S, Anturlikar SD. Source: Acta Pharmacologica Sinica. 2000 September; 21(9): 777-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11501156&dopt=Abstract

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Lack of renal effects of fish oil administration in patients with advanced cirrhosis and impaired glomerular filtration. Author(s): Badalamenti S, Salerno F, Salmeron JM, Lorenzano E, Rimola A, Gines P, Jimenez W, Graziani G, Arroyo V, Rodes J, Ponticelli C. Source: Hepatology (Baltimore, Md.). 1997 February; 25(2): 313-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9021940&dopt=Abstract

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Lamivudine and rapid regeneration of the atrophic liver in decompensated cirrhosis due to hepatitis B. Author(s): Saito T, Shinzawa H, Watanabe H, Sugahara K, Okumoto K, Togashi H, Kawata S. Source: The American Journal of Gastroenterology. 2002 February; 97(2): 493-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11866301&dopt=Abstract

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Low plasma levels of docosahexaenoic acid in patients with liver cirrhosis and its correction with a polyunsaturated fatty acid-enriched soft oil capsule. Author(s): Watanabe A, Saito S, Tsuchida T, Higuchi K, Okita M. Source: Nutrition (Burbank, Los Angeles County, Calif.). 1999 April; 15(4): 284-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10319360&dopt=Abstract

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Low selenium status in alcoholic cirrhosis is correlated with aminopyrine breath test. Preliminary effects of selenium supplementation. Author(s): Van Gossum A, Neve J. Source: Biological Trace Element Research. 1995 January-March; 47(1-3): 201-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7779548&dopt=Abstract

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MnDPDP-enhanced MRI vs dual-phase spiral CT in the detection of hepatocellular carcinoma in cirrhosis. Author(s): Bartolozzi C, Donati F, Cioni D, Crocetti L, Lencioni R. Source: European Radiology. 2000; 10(11): 1697-702. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11097390&dopt=Abstract

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Multifactorial gut barrier failure in cirrhosis and bacterial translocation: working out the role of probiotics and antioxidants. Author(s): Albillos A, de la Hera A. Source: Journal of Hepatology. 2002 October; 37(4): 523-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12217607&dopt=Abstract

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Myocardial perfusion scintigraphy in patients with liver cirrhosis evaluated for orthotopic liver transplantation. Author(s): Burra P, Graziotto A, Senzolo M, Bassanello M, Cillo U, Zucchetta P, Maraglino G, Bellotto F, Fagiuoli S, Naccarato R. Source: Transplantation Proceedings. 2001 February-March; 33(1-2): 1447-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11267367&dopt=Abstract

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Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Author(s): Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, Rossi Fanelli F, Abbiati R; Italian BCAA Study Group. Source: Gastroenterology. 2003 June; 124(7): 1792-801. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12806613&dopt=Abstract

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Oral antioxidant supplementation for fatigue associated with primary biliary cirrhosis: results of a multicentre, randomized, placebo-controlled, cross-over trial. Author(s): Prince MI, Mitchison HC, Ashley D, Burke DA, Edwards N, Bramble MG, James OF, Jones DE. Source: Alimentary Pharmacology & Therapeutics. 2003 January; 17(1): 137-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12492743&dopt=Abstract

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Oral supplementation with branched-chain amino acids improves survival rate of rats with carbon tetrachloride-induced liver cirrhosis. Author(s): Kajiwara K, Okuno M, Kobayashi T, Honma N, Maki T, Kato M, Ohnishi H, Muto Y, Moriwaki H. Source: Digestive Diseases and Sciences. 1998 July; 43(7): 1572-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9690397&dopt=Abstract

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Oral supplementation with branched-chain amino acids improves transthyretin turnover in rats with carbon tetrachloride-induced liver cirrhosis. Author(s): Usui T, Moriwaki H, Hatakeyama H, Kasai T, Kato M, Seishima M, Okuno M, Ohnishi H, Yoshida T, Muto Y. Source: The Journal of Nutrition. 1996 May; 126(5): 1412-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8618138&dopt=Abstract

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Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis.

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Author(s): Riordan SM, Skinner N, Nagree A, McCallum H, McIver CJ, Kurtovic J, Hamilton JA, Bengmark S, Williams R, Visvanathan K. Source: Hepatology (Baltimore, Md.). 2003 May; 37(5): 1154-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12717397&dopt=Abstract •

Plasma thrombopoietin levels in liver cirrhosis and kidney failure. Author(s): Stockelberg D, Andersson P, Bjornsson E, Bjork S, Wadenvik H. Source: Journal of Internal Medicine. 1999 November; 246(5): 471-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10583716&dopt=Abstract

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Prescribing habits in primary biliary cirrhosis: a national survey. Author(s): Verma A, Jazrawi RP, Ahmed HA, Northfield TC. Source: European Journal of Gastroenterology & Hepatology. 1999 August; 11(8): 817-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10514110&dopt=Abstract

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Probiotics for the hemodynamic alterations of patients with liver cirrhosis. Author(s): De Santis A, Famularo G, De Simone C. Source: The American Journal of Gastroenterology. 2000 January; 95(1): 323-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10638621&dopt=Abstract

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Protein-energy malnutrition in liver cirrhosis. Author(s): Moriwaki H. Source: Journal of Gastroenterology. 2002; 37(7): 578-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12162420&dopt=Abstract

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Radiofrequency ablation for treatment of hepatocellular carcinoma with cirrhosis. Author(s): Lo HW, Tsai YJ, Chen PH, Chen HY, Ker CG, Juan CC. Source: Hepatogastroenterology. 2003 May-June; 50(51): 645-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828052&dopt=Abstract

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Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis. Author(s): Curley SA, Izzo F, Ellis LM, Nicolas Vauthey J, Vallone P. Source: Annals of Surgery. 2000 September; 232(3): 381-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10973388&dopt=Abstract

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Regional cerebral blood flow changes in patients with cirrhosis assessed with 99mTcHM-PAO single-photon emission computed tomography: effect of liver transplantation. Author(s): Dam M, Burra P, Tedeschi U, Cagnin A, Chierichetti F, Ermani M, Ferlin G, Naccarato R, Pizzolato G.

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Source: Journal of Hepatology. 1998 July; 29(1): 78-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9696495&dopt=Abstract •

Safety and efficacy of Mangafodipir trisodium in patients with liver lesions and cirrhosis. Author(s): Marti-Bonmati L, Fog AF, de Beeck BO, Kane P, Fagertun H. Source: European Radiology. 2003 July; 13(7): 1685-92. Epub 2002 December 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12835986&dopt=Abstract

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Salviae miltiorrhizae ameliorates cirrhosis and portal hypertension by inhibiting nitric oxide in cirrhotic rats. Author(s): Wang H, Chen XP, Qiu FZ. Source: Hepatobiliary Pancreat Dis Int. 2003 August; 2(3): 391-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14599946&dopt=Abstract

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Serum 27-hydroxycholesterol in patients with primary biliary cirrhosis suggests alteration of cholesterol catabolism to bile acids via the acidic pathway. Author(s): Del Puppo M, Kienle MG, Petroni ML, Crosignani A, Podda M. Source: Journal of Lipid Research. 1998 December; 39(12): 2477-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9831637&dopt=Abstract

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Serum cholestanol, cholesterol precursors, and plant sterols during placebocontrolled treatment of primary biliary cirrhosis with ursodeoxycholic acid or colchicine. Author(s): Miettinen TA, Farkkila M, Vuoristo M, Karvonen AL, Leino R, Lehtola J, Friman C, Seppala K, Tuominen J. Source: Hepatology (Baltimore, Md.). 1995 May; 21(5): 1261-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7737632&dopt=Abstract

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Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Author(s): Angulo P, Patel T, Jorgensen RA, Therneau TM, Lindor KD. Source: Hepatology (Baltimore, Md.). 2000 November; 32(5): 897-900. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11050036&dopt=Abstract

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Simultaneous determination of pulmonary and intestinal permeability in patients with alcoholic liver cirrhosis. Author(s): Huglo D, De Botton S, Canva-Delcambre V, Colombel JF, Wallaert B, Steinling M, Marchandise X. Source: European Journal of Nuclear Medicine. 2001 October; 28(10): 1505-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11685493&dopt=Abstract

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Single-dose pharmacokinetics of citalopram in patients with moderate renal insufficiency or hepatic cirrhosis compared with healthy subjects. Author(s): Joffe P, Larsen FS, Pedersen V, Ring-Larsen H, Aaes-Jorgensen T, Sidhu J. Source: European Journal of Clinical Pharmacology. 1998 May; 54(3): 237-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9681666&dopt=Abstract

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Steatosis and collagen content in experimental liver cirrhosis are affected by dietary monounsaturated and polyunsaturated fatty acids. Author(s): Fernandez MI, Torres MI, Gil A, Rios A. Source: Scandinavian Journal of Gastroenterology. 1997 April; 32(4): 350-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9140157&dopt=Abstract

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The direct and indirect relationships between alcohol prevention measures and alcoholic liver cirrhosis mortality. Author(s): Xie X, Mann RE, Smart RG. Source: J Stud Alcohol. 2000 July; 61(4): 499-506. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10928719&dopt=Abstract

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The metabolism of cholestanol in primary biliary cirrhosis. Author(s): Gylling H, Vuoristo M, Farkkila M, Miettinen TA. Source: Journal of Hepatology. 1996 April; 24(4): 444-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8738731&dopt=Abstract

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The role of antioxidant vitamins (C and E), selenium and Nigella sativa in the prevention of liver fibrosis and cirrhosis in rabbits: new hopes. Author(s): Turkdogan MK, Agaoglu Z, Yener Z, Sekeroglu R, Akkan HA, Avci ME. Source: Dtsch Tierarztl Wochenschr. 2001 February; 108(2): 71-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11367885&dopt=Abstract

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The use of technetium-99m sestamibi in a patient with liver cirrhosis. Author(s): Tallaj JA, Kovar D, Iskandrian AE. Source: Journal of Nuclear Cardiology : Official Publication of the American Society of Nuclear Cardiology. 2000 November-December; 7(6): 722-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11144488&dopt=Abstract

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Treatment with zincum metallicum CH5 in patients with liver cirrhosis. Preliminary study. Author(s): Badulici S, Chirulescu Z, Chirila P, Chirila M, Rosca A. Source: Rom J Intern Med. 1994 July-September; 32(3): 215-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7866338&dopt=Abstract

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Unexpected toxicity after low-dose docetaxel treatment of a cancer patient with clinically latent HCV-positive hepatic cirrhosis.

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Author(s): Koukourakis MI, Kapsoritakis A, Maltezos E, Potamiano S, Mouzas I, Kouroumalis H. Source: Anticancer Res. 2002 July-August; 22(4): 2491-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12174950&dopt=Abstract •

Vitamin K replacement in osteoporosis associated with cirrhosis: another reason to “eat your vegetables”? Author(s): Lipkin EW, Kowdley KV. Source: The American Journal of Gastroenterology. 2002 April; 97(4): 786-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12003410&dopt=Abstract

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Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis. Author(s): Marchesini G, Fabbri A, Bianchi G, Brizi M, Zoli M. Source: Hepatology (Baltimore, Md.). 1996 May; 23(5): 1084-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8621138&dopt=Abstract

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Zinc supplementation improves glucose disposal in patients with cirrhosis. Author(s): Samman S. Source: Metabolism: Clinical and Experimental. 1999 August; 48(8): 1069-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10459576&dopt=Abstract

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Zinc supplementation improves glucose disposal in patients with cirrhosis. Author(s): Marchesini G, Bugianesi E, Ronchi M, Flamia R, Thomaseth K, Pacini G. Source: Metabolism: Clinical and Experimental. 1998 July; 47(7): 792-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9667223&dopt=Abstract

Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

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Chinese Medicine: http://www.newcenturynutrition.com/

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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html

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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

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Google: http://directory.google.com/Top/Health/Alternative/

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Healthnotes: http://www.healthnotes.com/

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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

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Open Directory Project: http://dmoz.org/Health/Alternative/

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HealthGate: http://www.tnp.com/

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WebMDHealth: http://my.webmd.com/drugs_and_herbs

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

The following is a specific Web list relating to cirrhosis; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

General Overview Abdominal Wall Inflammation Source: Integrative Medicine Communications; www.drkoop.com Alcohol Withdrawal Source: Healthnotes, Inc.; www.healthnotes.com Cystic Fibrosis Source: Integrative Medicine Communications; www.drkoop.com Gastritis Source: Healthnotes, Inc.; www.healthnotes.com Heart Attack Source: Healthnotes, Inc.; www.healthnotes.com Hepatitis Source: Healthnotes, Inc.; www.healthnotes.com Liver Cirrhosis Source: Healthnotes, Inc.; www.healthnotes.com Liver Disease Source: Integrative Medicine Communications; www.drkoop.com Malabsorption Source: Healthnotes, Inc.; www.healthnotes.com Peritonitis Source: Integrative Medicine Communications; www.drkoop.com Viral Hepatitis Source: Prima Communications, Inc.www.personalhealthzone.com

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•

Chinese Medicine Ershiwuwei Songshi Wan Alternative names: Ershiwuwei Songshi Pills (Used by Tibetan Nationality); Ershiwuwei Songshi Wan (Er Shi Wu Wei Song Shi Wan) Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China Hyperlink: http://www.newcenturynutrition.com/cgilocal/patent_herbs_db/db.cgi?db=default&Chinese=Ershiwuwei%20Songshi%20W an&mh=10&sb=---&view_records=View+Records Hugan Pian Alternative names: Hugan Tablets Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China Hyperlink: http://www.newcenturynutrition.com/cgilocal/patent_herbs_db/db.cgi?db=default&Chinese=Hugan%20Pian&mh=10&sb=--&view_records=View+Records

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Herbs and Supplements Alpha-lipoic Acid Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10002,00.html Astragalus Mem Alternative names: Huang-Qi; Astragalus membranaceus Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Betaine (trimethylglycine) Source: Healthnotes, Inc.; www.healthnotes.com Branched-chain Amino Acids Source: Healthnotes, Inc.; www.healthnotes.com Bupleurum Alternative names: Bupleurum chinense, Bupleurum falcatum Source: Healthnotes, Inc.; www.healthnotes.com Caffeine Source: Healthnotes, Inc.; www.healthnotes.com Diuretics Source: Healthnotes, Inc.; www.healthnotes.com Glutamine Source: Healthnotes, Inc.; www.healthnotes.com Glutamine Source: Integrative Medicine Communications; www.drkoop.com

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Gotu Kola Source: Prima Communications, Inc.www.personalhealthzone.com Gotu Kola Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10031,00.html Lecithin Source: Prima Communications, Inc.www.personalhealthzone.com Lipoic Acid Source: Prima Communications, Inc.www.personalhealthzone.com Liquorice Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Medium Chain Triglycerides Source: Healthnotes, Inc.; www.healthnotes.com Milk Thistle Alternative names: Silybum marianum, Carduus marianus Source: Healthnotes, Inc.; www.healthnotes.com Milk Thistle Alternative names: Silybum marianum, St. Mary's Thistle Source: Integrative Medicine Communications; www.drkoop.com Milk Thistle Source: Prima Communications, Inc.www.personalhealthzone.com Milk Thistle Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Milk Thistle Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10044,00.html Opcs (oligomeric Proanthocyanidins) Source: Prima Communications, Inc.www.personalhealthzone.com Ornithine Source: Healthnotes, Inc.; www.healthnotes.com S-Adenosylmethionine (SAMe) Source: Integrative Medicine Communications; www.drkoop.com

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SAMe Source: Healthnotes, Inc.; www.healthnotes.com SAMe Source: Integrative Medicine Communications; www.drkoop.com SAMe (S-Adenosylmethionine) Source: Prima Communications, Inc.www.personalhealthzone.com SAMe (S-Adenosylmethionine) Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,818,00.html Silybum Alternative names: Milk Thistle; Silybum marianum (L.) Gaertn. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Silybum Marianum Source: Integrative Medicine Communications; www.drkoop.com St. Mary's Thistle Source: Integrative Medicine Communications; www.drkoop.com

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

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CHAPTER 4. DISSERTATIONS ON CIRRHOSIS Overview In this chapter, we will give you a bibliography on recent dissertations relating to cirrhosis. 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 “cirrhosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cirrhosis, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Cirrhosis 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 cirrhosis. 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: •

Development of Recombinant Adeno-associated Virus Vectors for Gene Transfer to the Muscle and Its Application to an Experimental Cirrhosis Model by Zaratiegui Biurrun, Miguel Angel; Dr from Universidad De Navarra (spain), 2002, 204 pages http://wwwlib.umi.com/dissertations/fullcit/f327889

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Igf-1-modulated Gene Expression in Experimental Hepatic Cirrhosis by Mirpuri Merino, Eduardo; Dr from Universidad De Navarra (spain), 2002, 228 pages http://wwwlib.umi.com/dissertations/fullcit/f351985

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Interactions, in Rats, between Ccl4-induced Liver Cirrhosis and Chronic Treatment with the Organochlorine Insecticide Chlordane by Mahon, Desmond C; Phd from Simon Fraser University (canada), 1977 http://wwwlib.umi.com/dissertations/fullcit/NK35942

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Osteoporosis in Patients with End-stage Liver Cirrhosis: Evolution after Liver Transplantation. Study of the Mechanisms of Osteopenia and Their Correlation with

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Igf-i Synthesis by Pego Reigosa, Jose Maria; Dr from Universidad De Navarra (spain), 2002, 174 pages http://wwwlib.umi.com/dissertations/fullcit/f722433 •

Physiopathological Study of Thrombocytopenia in Liver Cirrhosis Patients: the Role of Thrombopoietin by Rios Fernandez, Raquel; Dr from Universidad De Navarra (spain), 2002, 132 pages http://wwwlib.umi.com/dissertations/fullcit/f722417

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Studies on the Activity and Transcriptional Expression of Ae2 Anion Exchanger in Cholangiocytes Isolated from Patients with Primary Biliary Cirrhosis by Melero Ibanez, Saida; Dr from Universidad De Navarra (spain), 2002, 169 pages http://wwwlib.umi.com/dissertations/fullcit/f741025

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The Nature of Immunoglobulin a in Human Pathological Conditions Iga Nephropathy, Henoch Schonlein Purpura, Liver Cirrhosis and Multiple Myeloma by Newkirk, Marianna Muriel; Phd from University of Toronto (canada), 1984 http://wwwlib.umi.com/dissertations/fullcit/NK65082

Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

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CHAPTER 5. CLINICAL TRIALS AND CIRRHOSIS Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning cirrhosis.

Recent Trials on Cirrhosis The following is a list of recent trials dedicated to cirrhosis.8 Further information on a trial is available at the Web site indicated. •

Gabapentin to treat itch in patients with liver disease Condition(s): Liver Disease; Cholestasis; Cirrhosis; Pruritus; Itching Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: In this study, the effect of the medication gabapentin to treat itching secondary to liver disease is being studied. There are some funds to cover travel expenses for patients who are not from New York. Gabapentin is approved to treat seizures in human beings. In this study, patients with liver disease who meet inclusion criteria are admitted to the research hospital of the New York Presbyterian Hospital to record scratching behavior by the use of a machine designed for that purpose. Blood work will be obtained. After completion of recording, patients are assigned by chance to receive active medication or placebo (a capsule that does not contain active medication). The patients will come to the outpatient office of the research hospital 2 weeks into the study for an interview and blood work. After 4 weeks, patients are readmitted to the hospital to record scratching behavior. After data are collected, the code is broken, if patient had been on inactive drug, active drug will be supplied as per protocol for 4 weeks. Blood work will be obtained. If patient had been randomized to active medication, the study will provide one week supply of drug. After that, the referring physician, with whom the study was previously discussed, could prescribe the medication as it is available. Phase(s): Phase III

8

These are listed at www.ClinicalTrials.gov.

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Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00058890 •

Peg-Intron for Prevention of Disease Progression in Chronic Hepatitis C Patients with Cirrhosis who failed with a Interferon plus Ribavirin Therapy Condition(s): Chronic Hepatitis C; Cirrhosis Study Status: This study is currently recruiting patients. Sponsor(s): Schering-Plough Purpose - Excerpt: The objective of the study is to evaluate the safety and efficacy of PEG-Intron vs. no treatment for the prevention of disease progression in adult subjects with compensated cirrhosis secondary to chronic hepatitis C, who failed to respond to therapy with an a interferon plus ribavirin. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00048724

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PEG-Intron Plus Rebetol Treatment of Chronic Hepatitis C Patients with Liver Fibrosis Who Failed to Respond to alpha-Interferon Plus Ribavirin Condition(s): Chronic Hepatitis C; Liver Fibrosis; Cirrhosis Study Status: This study is currently recruiting patients. Sponsor(s): Schering-Plough Purpose - Excerpt: The objective of this study is to determine the effectiveness of PEGIntron 1.5 ug/kg/wk plus REBETOL 800-1400 mg/day in adults with chronic hepatitis C with moderate to severe liver fibrosis or cirrhosis who failed to respond to previous treatment with an a interferon in combination with ribavirin. Patients who do not respond to PEG-Intron plus Rebetol will be enrolled in a long-term maintenance study to evaluate the effectiveness of PEG-intron therapy monotherapy versus no treatment for the prevention of disease progression (Protocols P02569 and P02570). Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00039871

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Prevention of Recurrent Hepatitis B after Liver Transplantation Condition(s): Hepatitis B; Cirrhosis; Acute Liver Failure; Hepatocellular Carcinoma Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: Hepatitis B accounts for approximately 5000 deaths per year in the United States. Liver transplantation offers the only hope for patients who develop endstage liver disease. Early results of liver transplantation for hepatitis B were poor with recurrence rate of 80% and 1-year survival of only 50%. Recent studies found that

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preventive therapy using hepatitis B immune globulin (HBIG) or antiviral medications such as lamivudine can reduce the recurrence rate to roughly 30% with accompanying improvement in survival. However, HBIG when given as intravenous infusion in high doses is very expensive, while long-term use of lamivudine is associated with drug resistance. Some studies found that preventive therapy using both HBIG and lamivudine may decrease recurrence rate to less than 10% but the dose and duration of HBIG needed when used in combination with lamivudine is not clear. Adefovir, a new antiviral medication, is effective against lamivudine resistant hepatitis B but its role in liver transplantation is uncertain because of the risk of kidney damage. Many studies showed that the risk of recurrent hepatitis B is related to the viral load before transplant. Thus, it may be possible to tailor the preventive therapy according to the risk. The aim of this study is to establish the most cost-effective preventive therapy for recurrent hepatitis B after liver transplantation. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00059267 •

Role of nitric oxide in cirrhosis: relationship with systemic hemodynamics, renal function, vasoactive systems and endotoxemia Condition(s): Cirrhosis; Liver Cirrhosis Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR) Purpose - Excerpt: This study is to determine whether a compound, nitric oxide, made within the body, is the factor responsible for the changes in blood pressure and renal (kidney) functions that may occur during the course of cirrhosis. Patients with cirrhosis (liver scarring which causes poor liver function) will be eligible to participate. A group of healthy subjects will also be studied to compare the effects of the treatment to patients with cirrhosis and to confirm safety. A total number of 30 patients with cirrhosis and 10 healthy subjects will be enrolled in the study. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005107

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Thymosin Plus PEG-Interferon in Hepatitis C Patients with Cirrhosis Who Did Not Respond to Interferon or Interferon Plus Ribavirin Condition(s): Hepatitis C; Hepatitis C, Chronic Study Status: This study is currently recruiting patients. Sponsor(s): SciClone Pharmaceuticals Purpose - Excerpt: Chronic hepatitis C infection is one of the leading causes of chronic liver disease in the United States. Approximately one-third of patients with hepatitis C infection develop cirrhosis of the liver, which can lead to liver failure or liver cancer. The current treatment for hepatitis C infection in previously untreated patients is successful in only about half of patients. There is no established therapy for non-responders. This is a randomized, double-blinded, multicenter trial to determine the effectiveness of thymosin alpha 1 (thymalfasin) 1.6 mg twice weekly plus PEGinterferon alfa-2a 180

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ug/wk compared to placebo plus PEGinterferon alfa-2a in adults with chronic hepatitis C with early cirrhosis or progression to cirrhosis who are non-responders to previous treatment with interferon or interferon plus ribavirin. The definition of non-response requires a positive HCV RNA test at the end of a course of at least 12 weeks of therapy. Patients will receive treatment for 12 months, and will be followed-up for a further 6 months after the end of therapy Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00039962 •

Treatment of Cholestatic Pruritus With Sertraline Condition(s): Pruritus; Liver Cirrhosis, Biliary; Hepatitis C Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The goal of this study is to find an effective and well-tolerated medical therapy for itching due to liver disease. Persons with primary biliary cirrhosis or chronic hepatitis C are currently being enrolled in the study. Persons participating in the study are given sertraline, a medication which is also often used for depression,to treat their itching. The dose is gradually increased as the effect on itching and any other potential side effects are carefully monitored. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00058903

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A Study to Prevent Complications of High Blood Pressure Caused by Hepatitis in Patients with Cirrhosis Condition(s): Hypertension, Portal; Liver Cirrhosis; Esophageal and Gastric Varices Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Yale University Purpose - Excerpt: Objectives: I. Evaluate the efficacy of a certain drug in preventing intestinal complications in patients with cirrhosis and high blood pressure in the hepatic portal vein. II. Evaluate vein pressure measurements to predict the development of internal bleeding. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004641

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Decompression Intervention of Variceal Rebleeding Trial (DIVERT) Condition(s): Esophageal and Gastric Varices; Liver Cirrhosis

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Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The Decompression Intervention of Variceal Rebleeding Trial (DIVERT) is a multi-center prospective randomized clinical trial comparing the radiologic procedure of transjugular intrahepatic portal-systemic shunt (TIPS) with the surgical procedure of distal splenorenal shunt (DSRS) for variceal bleeding in patients with Child's Class A and B cirrhosis. This is recognized nationally and internationally as the study that will answer the question as to which of these is the best treatment for decompression of varices in patients who have failed endoscopic and pharmacologic therapy. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006161 •

Long Term Interferon for Patients Who Did Not Clear Hepatitis C Virus with Standard Treatment Condition(s): Chronic Hepatitis C; Cirrhosis, Liver; Fibrosis, Liver; Hepatic Cirrhosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Allergy and Infectious Diseases (NIAID); National Center on Minority Health and Health Disparities (NCMHD); National Cancer Institute (NCI); Hoffmann-La Roche Purpose - Excerpt: The HALT-C Trial is a National Institute of Diabetes and Digestive and Kidney Diseases sponsored, randomized clinical trial of long-term use of Peginterferon alfa-2a (pegylated interferon) in patients who failed to respond to prior interferon treatment. All patients who enter the trial will be treated for 6 months with Peginterferon alfa-2a and Ribavirin. Patients who respond to this 6 month treatment will continue to be treated for an additional 6 months. Patients who do not respond to this treatment will be eligible for the long-term maintenance phase of this study where patients will be randomly selected to be treated with Peginterferon alfa-2a or to discontinue treatment for 3.5 years. Patients in both arms of this study will be followed closely with quarterly study visits. The combination of peginterferon plus ribavirin has recently been approved by the FDA for treatment of chronic HCV. Patients who remain HCV-RNA positive after being treated for at least 6 months with peginterferon and ribavirin outside of this study may be eligible to directly enter the randomized portion of the HALT-C Trial. The HALT-C study is designed to determine if continuing interferon long-term over several years will suppress Hepatitis C virus, prevent progression to cirrhosis, prevent liver cancer and reduce the need for liver transplantation. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006164

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Phase I Study of Colchicine Therapy in Childhood Hepatic Cirrhosis Condition(s): Cirrhosis; Liver Cirrhosis Study Status: This study is no longer recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Children's Hospital Denver Purpose - Excerpt: Objectives: I. Investigate the efficacy and safety of colchicine therapy in improving hepatic function and reducing hepatic fibrosis (scarring) in children with hepatic cirrhosis. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004368

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Pilot Study of Budesonide for Patients with Primary Sclerosing Cholangitis Condition(s): Cholangitis, Sclerosing; Liver Cirrhosis, Biliary Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Mayo Clinic Purpose - Excerpt: Objectives: I. Assess the safety and effectiveness of budesonide in patients with primary sclerosing cholangitis or primary biliary cirrhosis experiencing a suboptimal response to ursodeoxycholic acid. II. Estimate the efficacy of this therapy in these patient groups as a means of evaluating the feasibility of a long-term randomized trial. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004842

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Ursodiol-Methotrexate for Primary Biliary Cirrhosis Condition(s): Liver Cirrhosis, Biliary Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The major thrust is to determine whether treatment of patients with Primary Biliary Cirrhosis (PBC) with Ursodiol (Ursodeoxycholic Acid-UDCA) plus methotrexate (MTX) is more effective than treatment with UDCA alone. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006168

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Low-Dose Oral Methotrexate versus Colchicine for Primary Biliary Cirrhosis Condition(s): Liver Cirrhosis, Biliary

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Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); New England Medical Center Purpose - Excerpt: Objectives: I. Compare the efficacy of low-dose oral pulse methotrexate (MTX) and ursodiol versus colchicine and ursodiol in patients with primary biliary cirrhosis (PBC). II. Determine the optimum dose and duration of MTX treatment. III. Investigate the role of fibrogenic cytokines (FC) in PBC pathogenesis and the effect of treatment on FC production. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004748 •

North American Study for the Treatment of Refractory Ascites (NASTRA) Condition(s): Ascites; Liver Cirrhosis Study Status: This study is completed. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The NASTRA Clinical Trial is a multi-center, randomized, controlled clinical trial designed to determine if treatment with transjugular intrahepatic portasystemic shunts (TIPS) is superior to high volume paracentesis (total paracentesis, TP) for the treatment of refractory ascites due to cirrhosis. Only patients with clinically tense symptomatic ascites (shortness of breath, umbilical hernia, abdominal pain and/or distension, and/or limitation of activity) who have either diuretic-resistant ascites or diuretic-intractable ascites are being studied. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006166

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Phase II Study of Lactulose and Circadian Rhythms in Patients with Cirrhosis Condition(s): Portal Hypertension; Hepatic Encephalopathy; Cirrhosis Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); Northwestern University Purpose - Excerpt: Objectives: I. Assess the effect of lactulose on the circadian rhythm of plasma melatonin in patients with subclinical hepatic encephalopathy. II. Assess the intrasubject variability of circadian melatonin levels and neuropsychological tests. III. Assess which elements of the neuropsychological test battery show the response to lactulose. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004796

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Phase III Randomized Study of Ursodiol with vs without Methotrexate for Primary Biliary Cirrhosis Condition(s): Liver Cirrhosis, Biliary Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Texas Purpose - Excerpt: Objectives: I. Compare the effects of ursodiol (ursodeoxycholic acid), with and without methotrexate, on pruritus, incapacitation index, and serum markers of activity and severity in patients with primary biliary cirrhosis. II. Compare the effects of these regimens on the development of ascites, encephalopathy, varices (or bleeding from pre-existing varices), histologic liver changes, transplantation, and survival. III. Compare the toxicity and safety of each regimen. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004784

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Prevention of Esophageal Varices by Beta-Adrenergic Blockers Condition(s): Esophageal and Gastric Varices; Liver Cirrhosis; Portal Hypertension Study Status: This study is completed. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The purpose of this study is to learn whether timolol is useful in preventing or delaying the appearance of gastroesophageal varices, a complication that may develop in the future as a consequence of liver disease. Cirrhosis causes an increased resistance of blood flowing through the liver. This leads to an increased pressure in the portal vein (the vein that takes blood to your liver). High portal pressure is responsible for the appearance of complications of chronic liver disease such as varices and variceal bleeding (bleeding from veins in your esophagus). Timolol belongs to a group of medications called beta-blockers. Beta-blockers decrease high portal pressure and previous studies have shown that beta-blocker pills are useful in preventing bleeding from varices in patients who already have varices. A more desirable effect would be if these pills could prevent not only bleeding from varices but the appearance of varices (and therefore of bleeding). Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006398

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Safety and efficacy study of Interferon gamma-1b in hepatitis C patients with liver fibrosis or cirrhosis Condition(s): Liver Fibrosis; Cirrhosis Study Status: This study is completed. Sponsor(s): InterMune Pharmaceuticals

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Purpose - Excerpt: The purpose of this research study is to test the safety and effectiveness of Interferon gamma-1b (IFN-g 1b) injected subcutaneously (under the skin) for the treatment of advanced liver fibrosis and cirrhosis in patients with chronic hepatitis C infections. IFN-g 1b is not currently approved for the treatment of liver fibrosis. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00043303

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 “cirrhosis” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

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For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

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CHAPTER 6. PATENTS ON CIRRHOSIS 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 “cirrhosis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cirrhosis, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Cirrhosis By performing a patent search focusing on cirrhosis, 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

9Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on cirrhosis: •

Cardiovascular uses of cannabinoid compounds Inventor(s): Ellis; Earl F. (Midlothian, VA), Kunos; George (Bethesda, MD), Sanyal; Aron (Mechanicsville, VA), Varga; Karoly (Richmond, VA), Wagner; Jens (Richmond, VA) Assignee(s): Virginia Commonwealth University (Richmond, VA) Patent Number: 5,939,429 Date filed: September 29, 1998 Abstract: Hemorrhagic shock and in other conditions associated with excessive vasoconstriction, such as hypertension, peripheral vascular disease, cirrhosis of the liver, or certain forms of angina pectoris can be treated by using agonists of CB1 receptors as well as other cannabinoid receptors. In addition, it has been determined that in septic shock and cirrhosis of the liver when hypotension is due to activation of macrophages by bacterial endotoxin, the use of a drug that selectively blocks CB1 receptors or other cannabinoid receptors may be of therapeutic value by preventing or attenuating the endotoxin-induced hypotension. Excerpt(s): The invention relates to the cardiovascular effects of cannabinoid compounds, i.e. naturally occurring as well as synthetic substances that bind with high affinity to cannabinoid receptors in the brain and in peripheral tissues of mammals, including man. Naturally occurring cannabinoids may be divided into two categories, plant-derived and endogenous. Plant-derived cannabinoids are known to elicit dramatic psychobehavioral effects, exemplified by the well-known.DELTA.sup.9 tetrahydrocannabinol (THC), the psychotropic principle in marijuana. They are also known to have complex cardiovascular effects, a prominent component of which is hypotension (Vollmer et al. J. Pharm. Pharmacol. 1974, 26:186-198) Endogenous cannabinoids (endocannabinoids) are a class of lipid-like molecules that share receptor binding sites with plant-derived cannabinoids and mimic many of their neurobehavioral effects (Mechoulam et al. Adv. Exp. Bio. Med. 1996, 402:95-101.) Two endocannabinoids have been characterized in some detail: arachidonyl ethanolamide (anandamide) (Devane et al. Science 1992, 258:1946-1949; Felder et al. Proc. Natl. Acad. Sci. USA. 1993, 90:7656-7660) and 2-arachidonyl glyceride (2-AG) (Mechoulam et al. Biochem. Pharmacol 1995, 50:83-90). Like plant-derived cannabinoids, both anandamine and 2-AG are capable of eliciting hypotension (Varga et al. FASEB J. 1998, 12:1035-1044; Varga et al. Eur. J. Pharmacol. 1995, 278:279-283; Stein et al. Br. J. Pharmacol. 1996, 119:107-114; Varga et al. Hypertension 1996, 28:682-688; Lake et al. Hypertension 1997, 29:1204-1210; Calignano et al. Eur. J. Pharmacol. 1997, 337: R1-R2). In addition, various cannabinoid compounds have been produced synthetically. Cannabanoids exert their effects by binding to specific receptors located in the cell membrane. To date, two types of highaffinity cannabinoid receptors have been identified by molecular cloning: 1) CB1 receptors, present mostly in brain (Devane et al. Mol. Pharmacol. 1988, 34:605-613; Matsuda et al. Nature 1990, 346:561-564) but also in some peripheral tissues (Shire et al. J. Biol. Chem. 1995, 270:3726-3731; Ishac et al. Br. J. Pharmacol. 1996, 118:2023-2028), and 2) CB2 receptors, present on macrophages in the spleen (Munro et al. Nature 1993, 365:61-65). Web site: http://www.delphion.com/details?pn=US05939429__

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Composition for the control of wound scar production Inventor(s): Lee; Raphael C. (Chicago, IL) Assignee(s): Massachusetts Institute of Technology (Cambridge, MA) Patent Number: 5,902,609 Date filed: October 25, 1996 Abstract: This invention pertains to a composition for controlling wound scar production containing a calcium antagonist and a protein synthesis inhibitor. The method can be used to minimize wound scars, such as hypertrophic wound healing disorders keloids and burn scar contractures in humans or other mammals, particularly those individually prone to excesssive scarring Calcium antagonist treatment can also be used to control diseases associated with excessive scarring. such as cirrhosis of the liver, constructive pericarditis Dupuytren's disease of the hand, plantar fibrosis of the foot, and various other fibromatoses. Excerpt(s): The ability to heal by forming scars is essential for mammalian systems to survive wounding after injury. Normally, wound healing is a continuous process extending over a one-to-two-year period The process can be conceptually divided into three fundamentally distinct stages. The first stage is an intensely degradative phase called the inflammatory stage It occurs immediately after injury and provides a leans to remove the damaged tissues and foreign matter from the wound. Two-to-three days later, as fibroblasts from the surrounding tissue move into the wound, the repairing process enters its second stage, the proliferation and matrix synthesis stage. The fibroblasts in the wound proliferate and actively produce macromolecular such as collagen and proteoglycans, which are secreted into the extracellular matrix. The newlysynthesized collagen fibrils are cross-linked by lysyl oxidase and provide structural integrity to the wound. During this stage, fibroblasts also contract the intact collagen in order to reduce the surface area of the wound. This second stage lasts about three weeks. In the final, remodeling stage, the previous randomly-organized collagen fibril is aligned in the direction of mechanical tension and becomes more organized so that the mechanical strength of the wound area can be increased. The repair process is accomplished when the chemical and physical barrier functions of the skin are restored. Normal wound healing follows a well-regulated course. However, imbalances may cause abnormal scars to form. For example if the biosynthetic phase continues longer than necessary or degradation of collagen decreases, hypertrophic scars may form. These scars cause problems ranging from aesthetic deformity to severe limitation of motion. Hypertrophic scars more frequently occur among children and adolescents, suggesting that growth factors may influence the development of this type of scar. Hypertrophic scars are especially common in patients who have burns or wounds that heal by secondary intention. Another type of excess scar is the keloid. In this disorder, the cells appear to lace sensitivity to normal feedback signals. They are larger than hypertrophic scars and grow in an unregulated way, tending to invade normal tissue surrounding the wound. They rarely disappear spontaneously and often recur after surgical excision. The management of these scars remains a major unsolved clinical problem. Web site: http://www.delphion.com/details?pn=US05902609__

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Diagnostic kit Inventor(s): Hirose; Masao (Aichi, JP), Komai; Koichiro (Hyogo, JP), Mori; Masaki (Aichi, JP), Saito; Koichi (Hyogo, JP) Assignee(s): Sumitomo Chemical Company, Limited (Osaka, JP) Patent Number: 5,985,542 Date filed: May 20, 1997 Abstract: The present invention provides:a diagnostic kit for liver diseases such as hepatitis C and alcoholic cirrhosis to be applied to a human serum sample, which contains an antibody capable of recognizing a human cytochrome P450; anda process for determining the concentration of a cytochrome P450 in a human serum for diagnosis of hepatitis C and alcoholic cirrhosis. Excerpt(s): The present invention relates to a diagnostic kit for hepatitis C and alcoholic cirrhosis. Activities of enzymes such as GOT (glutamic-oxaloacetic transaminase), GPT (glutamic-pyruvic transaminase),.gamma.-GTP (.gamma.-glutamyl transpeptidase) and the like have been measured as biological markers of human liver complaints with certain kits for diagnosis. These enzyme activities, however, were not always satisfactory to specify a disease, since they did not distinguish liver diseases, such as viral hepatitides hepatitis A, hepatitis B, non-A non-B hepatitise, alcohol-induced hepatic injury and drug-induced hepatic injury. Web site: http://www.delphion.com/details?pn=US05985542__

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Furanone endothelin antagonists Inventor(s): Cheng; Xue-Min (Ann Arbor, MI), Doherty; Annette Marian (Ann Arbor, MI), Patt; William Chester (Chelsea, MI), Repine; Joseph Thomas (Ann Arbor, MI) Assignee(s): Warner-Lambert Company (Morris Plains, NJ) Patent Number: 5,998,468 Date filed: December 15, 1997 Abstract: Novel nonpeptide antagonists of endothelin (I) are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction, myocardial ischemia, cerebral vasospasm, cerebral ischemia, cerebral infarction, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, stroke, benign prostatic hyperplasia (BPH), and diabetes. Excerpt(s): The present invention relates to novel antagonists of endothelin useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the compounds of the present invention are antagonists of endothelin useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction and myocardial ischemia, cerebral vasospasm, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, pulmonary

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hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, and diabetes. Also, the compounds will be useful in cerebral ischemia or cerebral infarction resulting from a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, head injury, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma. Endothelin is involved in many human disease states. Web site: http://www.delphion.com/details?pn=US05998468__ •

Galenic preparation for prevention and treatment of hepatocarcinoma Inventor(s): Lee; Jung Sik (Seoul, KR) Assignee(s): Sam Chun Dang Pharm Co., Ltd. (Seoul, KR) Patent Number: 6,074,648 Date filed: August 7, 1998 Excerpt(s): The present invention relates to a galenic preparation for prevention and treatment of hepatocarcinoma. More specifically, the present invention relates to a galenic preparation which comprises an injectable composition having a good preventive and therapeutic effect particularly against viral hepatitis B and containing 4 kinds of main natural drugs, i.e., Hedyotidis herba, Curcumae longae rhizoma, Polygoni cuspidati radix and Sophorae tonlkinesis radix; and an oral composition having a preventive and therapeutic effect against fatty liver and hepatic cirrhosis and containing 10 kinds of natural drugs, i.e., Hedyotidis herba, Paridis rhizoma, Polygoni cuspidati radix, Sophorae tonkinesis radix, Gentianae scabrae radix, Rhei rhizoma, Forsythiae fructus, Paeoniae radix rubra, Curcumae longae rhizoma and Acori graminei rhizoma, and which can effectively prevent the development of hepatic diseases including hepatitis, fatty liver and hepatic cirrhosis into hepatocarcinoma and treat hepatocarcinoma by combined administration of two kinds of the compositions. The etiology of hepatocarcinoma have not yet been clearly established. However, hepatocarcinoma is statistically characterized by the fact that the incidence rate is higher in men, rather than in women, who are in their forties to sixties, and it may be accompanied by hepatic cirrhosis in approximately 80% and by hepatitis C in 10%. Such characteristics are consistent with the fact that the areas in which hepatocarcinoma is predominant, such as Far east and East South Asia including Korea, Southern Europe, Africa, etc. also has a high frequency of hepatitis B virus carrier. In these areas, it may be found that hepatocarcinoma attacks in the group of one family. Further, chronic hepatic disorders including hepatic cirrhosis, chronic hepatitis, etc. have a relatively high tendency to develop hepatocarcinoma, regardless of hepatitis B and C. In addition, it has been known that the frequency to develop hepatocarcinoma from chronic hepatitis and hepatic cirrhosis may be increased 6-8 times by alcohol intake or smoking. In many cases, hepatocarcinoma shows its unique symptoms only after it is considerably aggravated. Hepatocarcinoma shows various symptoms which include, generalized ones, such as systemic malais, anorexia, etc., hypertrophy of liver at right epigastrium and formation of mass in liver, and further a general deteriorated symptoms of hepatic cirrhosis such as ascites, jaundice, spleen hypertrophy, etc. Web site: http://www.delphion.com/details?pn=US06074648__

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Human cardiac/brain tolloid-like protein Inventor(s): Arleth; Anthony J (Hatfield, PA), Elshourbagy; Nabil A. (West Chester, PA), Li; Xiaotong (Devon, PA), Willette; Robert N (Pottstown, PA) Assignee(s): SmithKline Beecham Corporation (Philadelphia, PA) Patent Number: 6,008,017 Date filed: December 16, 1997 Abstract: HC/BTLP polypeptides and polynucleotides and methods for producing such polypeptides by recombinant techniques are disclosed. Also disclosed are methods for utilizing hC/BTLP polypeptides and polynucleotides in the design of protocols for the treatment of restenosis, atherosclerosis, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), benign prostatic hypertrophy (BPH), nephritis, fibrosis, glomerulonephritis, gliosis, cirrhosis and anomalies of wound healing, such as keloids among others, and diagnostic assays for such conditions. Excerpt(s): This invention relates to newly identified polynucleotides, polypeptides encoded by them and to the use of such polynucleotides and polypeptides, and to their production. More particularly, the polynucleotides and polypeptides of the present invention relate to the astacin protein family, hereinafter referred to as human cardiac/brain tolloid-like protein (hC/BTLP). The invention also relates to inhibiting or activating the action of such polynucleotides and polypeptides. The hC/BTLP gene appears to possess all of the important protein domains present in the bone morphogenetic protein (BMP)-1/procollagen C-proteinase (PCP) protein. Members of the astacin family of metalloproteinases, such as BMP-1, have previously been linked to cell differentiation and pattern formation during development through a proposed role in the activation of latent growth factors of the TGF-.beta. superfamily. In addition, recent findings indicate that BMP-1 is identical to PCP, which is a metalloproteinase involved in the synthesis of matrix collagen. This observation suggests that a functional link may exist between astacin metalloproteinases, growth factors and cell differentiation and pattern formation during development, as well as fibrotic processes characterized by the accumulation of matrix collagen. Nucleotide and amino acid sequence homologues suggest that hC/BTLP, like BMP-1, possesses PCP activity. PCP activity is one of the essential enzymatic steps required for the extracellular production of insoluble collagen fibrils from soluble procollagen. However, mouse mammalian tolloid-like protein is the most closely related homologue of hC/BTIP. Mouse mammalian tolloid-like protein and BMP-1 are distinct gene products with differential tissue distribution. Based on cross-species comparisons, the regulation and distribution of hC/BTIP would be expected to be distinct from BMP-1. Indeed, mouse mammalian tolloid-like protein exhibits a unique tissue distribution when compared to BMP-1. Thus, the selective inhibition of matrix collagen accumulation is important in highly localized fibrotic disorders, e.g., gliosis associated with neurotrauma and ventricular fibrosis associated with congestive heart failure. This indicates that the astacin protein family has an established, proven history as therapeutic targets. Web site: http://www.delphion.com/details?pn=US06008017__

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Identification of a novel retrovirus associated with primary biliary cirrhosis and autoimmune disorders Inventor(s): Mason; Andrew L. (New Orleans, LA), Neuberger; James (Worcester, GB), Xu; Lizhe (Metairie, LA) Assignee(s): Alton Ochsner Medical Foundation (New Orleans, LA) Patent Number: 6,468,737 Date filed: June 1, 2000 Abstract: The present invention relates, first, to the discovery, identification, and characterization of novel nucleic acid molecules, that are associated with PBC, Sjogren's syndrome, scleroderma, SLE, autoimmune thyroiditis and various other connective tissue disorders. The novel nucleotide sequences of the present invention are retroviral in origin and are indicative of a PBC retrovirus which bears a strong correlation with PBC. The present invention is based, in part, on the Applicant's data which is the first evidence to suggest that PBC patient's tissue may harbor a transmissible agent. The association of a retroviral infectious agent with PBC was first demonstrated by Applicants in vitro by co-culture of periportal lymph nodes derived from patients at time of transplantation and healthy biliary epithelium cells. The Applicant's discoveries as described herein, report the characterization of PBC-associated infectious agent as retroviral as demonstrated by electron microscopy and immunoblot reactivity. In addition, Applicants have characterized novel nucleotide sequences which are associated with the PBC-associated retrovirus. Excerpt(s): The present invention relates first, to the identification of a novel human retrovirus and the novel nucleotide sequences encoding a retroviral long terminal repeat and reverse transcriptase nucleotides associated with the existence of primary biliary cirrhosis (PBC), and other immune disorders such as Sjogren's syndrome, scleroderma, systemic lupus erythematosus (SLE), autoimmune thyroiditis and various other connective tissue disorders, in addition to lymphoma and breast cancer. The present invention further relates to methods for using the PBC retroviral nucleotides for the detection of PBC, Sjogren's syndrome, scleroderma, SLE, autoimmune thyroiditis and various other connective tissue disorders in patient samples. The present invention also relates to methods for using and targeting the PBC retroviral long terminal repeat and reverse transcriptase nucleotides in gene therapy protocols for the treatment of PBC, Sjogren's syndrome, scleroderma, SLE, autoimmune thyroiditis and various other connective tissue disorders in patients in need of such treatment. The present invention also relates to methods of treating or inhibiting PBC retroviral infection with antiviral agents, such as cytokines, inhibitors of reverse transcriptase, inhibitors of viral capping, and inhibitors of viral protease. The present invention further relates to diagnostic protocols and kits for the detection of PBC, Sjogren's syndrome, scleroderma, SLE, autoimmune thyroiditis and various other connective tissue disorders in tissue samples. Primary biliary cirrhosis (PBC) is a progressive pluriglandular disease affecting the liver, pancreas, salivary and lachrymal glands (Neuberger, 1997, Lancet 850:875-79; Epstein et al., 1980, Lancet 1:1166-68). The hepatic disease is characterized by a florid bile duct lesion with lymphocytic infiltration and granulomatous destruction of 30 to 80.mu.m sized interlobular bile ducts (Rubin et al., 1965, Am. J. Pathol. 46:387-407). There is no curative therapy, apart from liver transplantation, and patients usually develop cirrhosis (Neuberger et al., 1997, Lancet 250:875-879). It is estimated to account for approximately 2% of patients dying from cirrhosis in Europe and 10% of patients that requiring orthotopic liver transplantation in North America (Neuberger et al., 1997, Lancet 250:875-879). The autoimmune phenomena associated with PBC have been well

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characterized. Over 95% of PBC patients have antibodies that bind and inhibit the dihydrolipoamide acetyltransferase enzymatic function of the E2 subunit of the pyruvate dehydrogenase complex (PDC) (Gershwin et al., 1992, Molecular biology of the 2-oxo-acid dehydrogenase complexes and anti-microbial antibodies. Philadelphia W. B. Saunders) These AMA have a higher affinity to the dehydrogenase E2 enzymes of mammals as compared to invertebrates and react to the E2 sub-units of other highly conserved inner membrane mitochondrial proteins of the oxoglutarate dehydrogenase complex, and branched chain 2-oxoacid dehydrogenase complex, and also the E1.alpha. and E1.beta. sub-units of PDC. For patients with liver disease, reactivity to the E2 mitochondrial enzymes is specific to PBC but these AMA have been observed in individuals with Sjogren's syndrome and SLE as well (Van-de-Water et al., 1989, New Eng. J. Med. 320: 1377-80). The reason why PBC patients have an antigen driven immune response to human PDC-E2 may be partially explained by the findings of immunohistochemical studies. Using monoclonal and combinatorial AMA, PDC-E2 or antigens resembling PDC-E2 have been observed on the surface of cultured PBC biliary epithelium cells (Joplin et al., 1992, Lancet 339: 93-94), biliary epithelium and lymph node macrophages in PBC patient's tissues (Joplin et al., 1991, Hepatology 14: 442-447, Van-de-Water et al., 1993, J. Clin. Invest. 91: 2654-64), and salivary glands of patients with PBC and Sjogrens syndrome (Tsuneyama et al., 1994, Hepatology 20: 893-898). In essence, the tissues affected by the pluriglandular disease process are the same as those with the abnormal distribution of PDC-E2 antigens on epithelial cell surface. Web site: http://www.delphion.com/details?pn=US06468737__ •

Liver fat accumulation inhibitory composition, food additive for liver fat accumulation, inhibition, and method of inhibiting liver fat accumulation Inventor(s): Imada; Takuma (Saga, JP), Masaki; Kyosuke (Sendai, JP), Noda; Tsuneyuki (Kurume, JP), Shimizu; Seiichi (Otsu, JP), Toba; Masamichi (Tosu, JP) Assignee(s): Otsuka Pharmaceutical Co., Ltd. (Tokyo, JP) Patent Number: 6,468,556 Date filed: March 3, 2000 Abstract: A method of inhibiting liver fat accumulation which comprises administering a conjugated linoleic acid homolog to a mammal or making the mammal ingest it; and a liver fat accumulation inhibitory composition characterized by containing an effective amount of a conjugated linoleic acid homolog together with a support for medicinal preparations or foods. The administration or ingestion of CLA inhibits the total lipid content and the triglyceride content in the liver from increasing, and hence can effectively prevent diseases attributable to fatty liver, such as chronic hepatitis and hepatic cirrhosis. Excerpt(s): The present invention relates to a novel liver fat accumulation inhibitory composition, a food additive for liver fat accumulation inhibition, and a method of inhibiting liver fat accumulation. It has been considered that fatty liver, which is a disease wherein fat is excessively accumulated in the liver (hepatocytes), is caused by supernutrition, hyperingestion of alcohol, diabetes and side effects due to administration of pharmaceuticals, and can cause severe diseases such as chronic hepatitis and hepatic cirrhosis. It is an important subject to treat and prevent fatty liver; however, there have not been accomplished any other safe and effective method for treatment and prevention thereof than control of nutrition to be fed, and there have scarcely been made any development of drugs (pharmaceuticals) for treatment and

Patents 171

prevention. Fatty liver refers to a state where lipid, particularly neutral fat, is accumulated in hepatocytes to the degree exceeding a physiologically permissible range, but a morphological/biochemical clear definition for a quantitative standard of fat deposition has still to be made. In general, fatty liver refers to a case where a remarkable morphological change in accumulation of neutral fat is recognized in hepatocytes over a range of a third of all lobuli and any other remarkable morphological abnormality can not be recognized. From a biochemical point of view, a standard for judgment of fatty liver is that the weight of neutral fat is about 10% (100 mg/g wet weight) or more of the wet weight of hepatic tissue. Web site: http://www.delphion.com/details?pn=US06468556__ •

Method for measuring cholinesterase and method for distinguishing between liver cirrhosis and hepatitis Inventor(s): Hada; Toshikazu (Ikoma, JP), Kondo; Masahide (Zama, JP), Yasukawa; Kiyoshi (Sagamihara, JP) Assignee(s): Tosoh Corporation (Yamaguchi-Ken, JP) Patent Number: 6,333,162 Date filed: April 17, 1996 Abstract: The object of the present invention is to provide method for discriminating between liver cirrhosis and chronic hepatitis by serodiagnosis using a simple enzyme immunoassay method without performing histopathological examinations by biopsy and so forth.The present invention discloses an enzyme immunoassay method for cholinesterase using monoclonal antibody, a method for detecting Aleuria aurantia lectin-reactive cholinesterase using monoclonal antibody and Aleuria aurantia lectin, and a method for discriminating between liver cirrhosis and chronic hepatitis on the basis of those results. Excerpt(s): The present invention relates to a method for measuring total cholinesterase in, for example, serum; a method for measuring Aleuria aurantia lectin-reactive cholinesterase in, for example, serum; and an in vitro diagnostic method for distinguishing liver cirrhosis, liver carcinoma and hepatitis using those methods. Two types of cholinesterase exist in the body that differ in terms of enzymological properties, physiological function and distribution in the body. Namely, the first is acetylcholinesterase (E.C.3.1.1.7), which specifically breaks down acetylcholine, exists in a large amount in erythrocytes, neural tissue, muscle and so forth, and is distributed in relation to these physiological functions. The other is cholinesterase (also referred to as pseudocholinesterase or butylcholinesterase) (E.C.3.1.1.8), which acts on cholines, such as benzoylcholine and butylcholine, exists in a large amount in the serum and liver, is produced in the liver, and the physiological action of which is considered to most likely be involved with the neuromuscular system. At present, the cholinesterase that is frequently measured in clinical laboratory examinations is cholinesterase in serum (pseudocholinesterase or butylcholinesterase). This enzyme is a glycoprotein having a molecular weight of approximately 340,000 and is composed of four identical subunits. Each subunit is composed of 574 amino acids and has nine asparagine-coupled carbohydrate chains. Clinically, a decrease in its activity, as determined by measuring this enzyme, has significance in terms of determining the degree of functional impairment the liver parenchyma in liver disease, and particularly chronic liver parenchymal disorders such as liver cirrhosis and chronic hepatitis. Since serum cholinesterase is produced in liver parenchymal cells, its decrease indicates a chronic

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functional decrease of liver cells. In addition, acute decreases in cholinesterase activity are observed in cases of poisoning by organic phosphorous-based agricultural chemicals, measurement of the activity of this enzyme is indispensable in these cases. In addition, increases in the activity of this enzyme are observed prominently in nephrotic syndromes. Web site: http://www.delphion.com/details?pn=US06333162__ •

Method for preventing or arresting liver damage in humans Inventor(s): Oren; Ran (2600 Netherland Ave., Riverdale, NY 10463) Assignee(s): none reported Patent Number: 6,143,752 Date filed: July 31, 1998 Abstract: The invention provides methods for treating liver disease by inducing a hypothyroid state using (i) drugs, e.g., PTU, methimazole, lithium or carbimazole; (ii) surgery; or, (iii) radiation, e.g.,.sup.127 I or.sup.131 I. The liver diseases that can be treated using the methods of the invention include: infectious hepatitis, such as (i) viral hepatitis resulting from infection with hepatitis A, D, C, D, E, or G; or (ii) parasitic hepatitis resulting from infection with Schistosoma mansoni, Schistosoma hematobium or Schistosoma japonicum; or (iii) autoimmune disease, e.g., (a) autoimmune hepatitis or (b) primary biliary cirrhosis. Excerpt(s): This invention is directed to methods for preventing, attenuating, retarding or arresting liver damage caused by infection or autoimmune-mediated diseases. The liver is the target of attack for a wide range of diseases. These diseases include infectious, autoimmune, as well as non-infectious processes such as chemicals. Examples of infectious diseases include: (i) viral hepatitis, e.g., hepatitis A, B, C, D, E, and G and (ii) parasitic hepatitis, e.g., Schistosoma mansoni, Schistosoma hematobium, and Schistosoma japonicum. (Harrison's Principles of Internal Medicine, Fauci et al. eds., 1998, pgs 1660-1725). Examples of noninfectious diseases affecting the liver, include autoimmune diseases, such as, (i) autoimmune hepatitis and (ii) primary biliary cirrhosis. (Harrison's Principles of Internal Medicine, Fauci et al. eds., 1998, pgs 17011709). Regardless of whether the attack on the liver is infectious, autoimmune or noninfectious, the liver responds to injury by pouring inflammatory cells into the site of attack. The types of inflammatory cells entering the site of attack consist primarily of macrophages and neutrophils. After entry into the site of injury, the cells release various inflammatory cytokines, such as tumor necrosis factor (TNF). These cytokines mediate the local inflammatory response by inducing local changes, for example, proliferation of fibroblasts or vasodilation. If left untreated, repeated, chronic damage to the liver from infection, autoimmune disease or any other noninfectious processes causes scarring or fibrosis. This is a direct consequence of local proliferation of fibroblasts. (Kaplowitz, Biliary Diseases, pg. 139, Williams & Wilkins, 1992). In the case of the liver, the endstage of fibrosis is cirrhosis. Pathologically, cirrhosis is defined as extensive fibrosis in the liver in association with the formation of regenerative nodules. Cirrhosis is the final common pathway for many, if not all, types of chronic liver damage and is typically progressive. (Kaplowitz, Biliary Diseases, pg. 140, Williams & Wilkins, (1992). Web site: http://www.delphion.com/details?pn=US06143752__

Patents 173

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Method of treating liver disease and like indications with vasodilating agents Inventor(s): McLean; Allan Joseph (South Melbourne, AU) Assignee(s): Pharmacy and Therapeutic Advisory Consultancy Ltd. (London, GB) Patent Number: 6,174,917 Date filed: December 17, 1998 Abstract: Liver diseases, such as cirrhosis of the liver, toxic and medicamentary liver damage, a liver-parenchymic disorder or hepatitis, are treated by administering to a human or animal subject in need thereof a therapeutically active or prophylactically effective low dose amount of a vasodilating agent which selectively increases the supply of oxygenated blood to the liver by increasing hepatic arterial inflow; Suitable vasodilating agents include calcium blockers, such as a benzothiazepine derivative, nifedipine, felodipine or verapamil. Excerpt(s): The present invention relates to a method for the treatment of liver disease. The invention also relates to compositions suitable for the use in the treatment of liver disease. Diltiazem is the generic name given to the active component of a composition that is primarily used for the treatment of heart disease. Specifically it is known as 3acetoxy-5-(2-(dimethylaminoethyl)-2,3-dihydro-2-(4-methoxy phenyl)-1,5benzothiazepine4)5H-one. This compound is the active ingredient in the heart treatment drug Cardizem. Cardizem has particular efficacy in the treatment of ischaemic heart disease including angina pectoris and hypertension. Diltiazem is a member of a broad class of benzothiazepine derivatives that are the subject of Australian Patent 426146. The class of compounds are referred to in that specification as having particular utility as anti-depressants, tranquilizers and coronary vasodilators. Web site: http://www.delphion.com/details?pn=US06174917__

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Non-malignant disease treatment with Ras antagonists Inventor(s): Brownstein; Michael (Rockville, MD), Bruck; Rafael (Rishon Le-Zion, IL), Chapman; Joab (Kiryat Ono, IL), Karussis; Dimitrius (Jerusalem, IL), Kloog; Yoel (Herzliya, IL), Reif; Shimon (Karney Shomron, IL) Assignee(s): Ramot University Authority for Applied Research and Industrial Development (IL) Patent Number: 6,462,086 Date filed: June 19, 2000 Abstract: Disclosed is a method for inhibiting Ras-induced or mediated proliferation of cells associated with a non-malignant disease, disorder or pathological condition. The method entails administering to a patient a Ras antagonist in an amount effective to inhibit the proliferation. The invention is particularly applicable to diseases characterized by a proliferation of T-cells such as autoimmune disease, e.g., type 1 diabetes, lupus and multiple sclerosis, and pathological states such as graft rejection induced by the presentation of a foreign antigen such as a graft in response to a disease condition (e.g., kidney failure). Other non-malignant diseases characterized by proliferations of cells include cirrhosis of the liver and restenosis. Preferred Ras antagonists are S-trans-trans farnesylthiosalicylic acid (FTS) and structurally related compounds (or analogs) thereof.

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Excerpt(s): The present invention relates to the inhibition of the onset of or the treatment of non-malignant diseases, and particularly diseases having pathologies involving Rasinduced proliferation of cells. Autoimmune diseases include disorders involving dysfunction of the immune system, which mediates tissue damage. Any organ may be affected by such processes through precipitation of immune complexes, cellular immunity, or inappropriate generation or action of immuno-hormones such as cytokines. Epidemiologically, autoimmune diseases are significant because of the numbers of patients that they affect and the serious morbidity and mortality that they cause. Common chronic systemic diseases in this group include diabetes mellitus, thyroid disease, rheumatoid arthritis, systemic lupus erythematosus (SLE), primary antiphospholipid syndrome (APS), and a variety of diseases that affect the central nervous system. Neurological autoimmune diseases include disorders specific to the nervous system such as myasthenia gravis, Lambert Eaton myasthenic syndrome, Guillain-Barre syndrome, polymyositis, and multiple sclerosis. In addition, there are neurological complications of the systemic autoimmune diseases. Factors predisposing to autoimmune diseases include genetic predisposition and environmental agents such as certain infections and pharmaceutical products. Such factors result in pathological activation of the immune response in susceptible individuals, which is generally controlled by T lymphocytes (T cells). The activation T cells and B subtypes, involves a complex interaction of cell surface receptors resulting in equally complex signal transduction pathways which eventually affect gene regulation. Full activation of lymphocytes requires parallel stimulation of several signal transduction pathways. See Ohtsuka, et al., Biochim. Biophys. Acta. 1310:223-232 (1996). Although there is growing understanding about the function of T cells in the immune response, this knowledge has not explained the basis of most autoimmune diseases. There are still questions to be resolved such as how tolerance to self in normal individuals is maintained; how tolerance is broken in autoimmunity; and which autoantigens trigger the immune system to produce specific diseases. A recent review by V. Taneja and C. S. David (J. Clin. Invest. 101:921-926 (1998)) provides an overview of important issues in this field and emphasized how the generation of transgenic mice expressing functional HLA molecules is important for understanding the function of certain molecules in the induction of autoimmune disease, as well as circumvention of the xenogenic barrier. Regardless of the mechanisms involved in induction of autoimmune disease or the rejection of grafts, the common pathway for these events includes activation of a relatively small number of T lymphocytes. Web site: http://www.delphion.com/details?pn=US06462086__ •

Nucleic acids encoding proteins for early liver development Inventor(s): Mishra; Lopa (6910 Oakridge Ave., Bethesda, MD 20815) Assignee(s): none reported Patent Number: 5,955,594 Date filed: April 30, 1997 Abstract: Early developing stage-specific liver proteins and the genes coding for them that have been isolated and sequenced are provided, and these genes and proteins can be utilized to diagnose and/or treat a wide variety of liver disorders and other ailments. Included in the proteins identified and isolated in the present invention are the proteins known as elf 1-3, liyor-1 (145), pk, protein 106, and praja-1, along with the nucleic acid sequences coding for these and other proteins. Since the early developing liver proteins

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of the invention arise during embryogenesis when the liver and other organs are in transition from an undifferentiated state to a differentiated one, these proteins are involved in tissue differentiation and thus can be utilized in methods of diagnosing and treating a variety of liver diseases and other disorders including those relating to oncogenesis and tissue repair. Accordingly, the isolated early developing liver proteins in accordance with the present invention should have implications for diagnosis and treatment of a range of diseases from end stage cirrhosis to hepatocellular carcinoma and many other disease conditions. Excerpt(s): This invention relates to proteins isolated during early liver development and the genes coding for them, and to methods for their use in diagnosing and treating liver disease and other disorders. In the United States and other countries, end stage liver disease due to infection, genetic defects or alcoholic consumption is a major cause of widespread morbidity and mortality, causing great potential hardship and economic loss to millions of people throughout the world. In addition, numerous other diseases, including biliary problems and blood disorders, are associated with disruptions in the many functions carried out by the liver, including iron transport, hepatocyte formation and hematopoiesis. In general, severe problems associated with a breakdown of liver function are practically untreatable, and require a liver transplant as the only cure. However, in light of the great disparity between the number of patients needing liver transplants and the number of donors, thousands upon thousands of people are denied this operation, and transplantation is at the present time not a practical approach to the problem. At the same time, the precise nature of liver development and the role of early developing liver proteins has not been well understood. To date, no growth factors specific to the liver have been identified or isolated, and the precise molecular mechanisms behind hepatocyte (liver cell) formation remain to be elucidated. There thus has been a long felt need to identify and understand the changes in gene regulation and expression in the developing liver, including the determination as to which genes are switched on and off as a hepatocyte forms and a liver develops. Accordingly, isolating and identifying the genes and proteins which play critical roles in early liver development would be beneficial in understanding the effect of gene regulation and expression in the differentiating liver, and in diagnosing and treating many diseases states involving the liver and liver functions. Web site: http://www.delphion.com/details?pn=US05955594__ •

Pharmaceutical formulation for treating liver disorders Inventor(s): Henriksen; Bent (Morpeth, DK) Assignee(s): Pharma Nord ApS (Vojens, DK) Patent Number: 6,136,859 Date filed: October 23, 1998 Abstract: A pharmaceutical formulation comprising organic or inorganic selenium,.beta.-carotene or vitamin A, ascorbic acid or a salt or ester thereof;.alpha.tocopherol or a derivative thereof, methionine and coenzyme Q10 together with a pharmaceutically acceptable carrier therefor suitable for treating such diseases as primary biliary cirrhosis. Excerpt(s): The present invention relates to a pharmaceutical formulation suitable for use in the treatment of liver disorders such as primary biliary cirrhosis (PBC), viral hepatitis, steatohepatitis, alcoholic cirrhosis and related hepatic and biliary disorders.

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The invention also relates to the use of particular vitamins, amino acids, trace elements and ubiquinone for the preparation of a medicament suitable for the treatment of such liver disorders. Primary biliary cirrhosis is a chronic cholestatic liver disease with an autoimmune aetiology which results in the destruction of the bile ducts in the liver. The disease is progressive in nature, with a significant proportion of affected patients going on to develop cirrhosis with all its sequelae. Females are more commonly affected, with approximately 90% of all cases of PBC occurring in females. This disease has been diagnosed in patients as young a 23 years and as old as 72. The majority of cases are diagnosed in the 40-60 age group. Web site: http://www.delphion.com/details?pn=US06136859__ •

Polynucleotide encoding human serpin Inventor(s): Holloway; James L. (Seattle, WA) Assignee(s): ZymoGenetics, Inc. (Seattle, WA) Patent Number: 6,524,822 Date filed: November 20, 2000 Abstract: Members of the serine protease family play a role in carefully controlled processes, such as blood coagulation, fibrinolysis, complement activation, fertilization, and hormone production. The enzymatic activity of the serine proteases is regulated in part by serpins, serine protease inhibitors. Serpin dysfunction is associated with various disorders, including emphysema, blood clotting disorders, cirrhosis, Alzheimer disease, and Parkinson disease. Zserp11 is a new member of the serine protease inhibitor family. Excerpt(s): The present invention relates generally to a new gene that encodes an enzyme inhibitor. In particular, the present invention relates to a novel serpin, designated "Zserp11," and to nucleic acid molecules encoding Zserp11. Endogenous proteolytic enzymes provide a variety of useful functions, including the degradation of invading organisms, antigen-antibody complexes, and certain tissue proteins that are no longer necessary. The serine proteases comprise a large family of enzymes that use an activated serine residue in the substrate-binding site to catalytically hydrolyze peptide bonds. Typically, this serine residue can be identified by the irreversible reaction of its side chain hydroxyl group with diisopropylfluorophosphate. Serine proteases participate in carefully controlled processes, such as blood coagulation, fibrinolysis, complement activation, fertilization, and hormone production. Normally, serine proteases catalyze limited proteolysis, in that only one or two specific peptide bonds of the protein substrate are cleaved. Under denaturing conditions, serine proteases can hydrolyze multiple peptide bonds, resulting in the digestion of peptides, proteins, and even autolysis. Several diseases are thought to result from the lack of regulation of serine protease activity, including emphysema, arthritis, cancer metastasis, and thrombosis. Web site: http://www.delphion.com/details?pn=US06524822__

Patents 177

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Therapeutic agent for primary biliary cirrhosis Inventor(s): Nishiguchi; Shuhei (Osaka, JP), Sounaka; Ichirou (Kawasaki, JP) Assignee(s): Ajinomoto Co., Inc. (Tokyo, JP), The City of Osaka (Osaka, JP) Patent Number: 6,339,104 Date filed: October 16, 2000 Abstract: Disclosed is a therapeutic agent for primary biliary cirrhosis, which contains L-alanine or a pharmaceutically acceptable salt thereof as the active ingredient. The effect of this therapeutic agent is to reduce serum total bilirubin and transaminase value, thereby effectively curing primary biliary cirrhosis. This therapeutic agent can be chronically administrated for a long period of time and exhibits an effect superior to that obtained in ordinary medical therapy. Excerpt(s): The present invention relates to a therapeutic agent for primary biliary cirrhosis. Primary biliary cirrhosis is a liver disease of unknown etiology of middleaged women, which slowly advances and has, as a background, immunologic abnormality and chief complaints of fatigue, pruritus, jaundice, etc. Primary biliary cirrhosis is an intractable disease different from other diseases in both pathology and method of treatment. Concretely, alcohol-induced liver disease is caused by the intake of alcoholic drinks, and abstinence from alcoholic drinks is the primary selective treatment. The action of alanine contained in "antagonistic composition alcohol-induced hepatopathy" which will be described below is to accelerate the alcohol catabolism. Hepatitis, which is not induced by alcoholic drinks, is caused by virus of type A, B or C or by the intake of a large amount of a medicine or the intake of the medicine for a long period of time. For the treatment of hepatitis of such a type, interferon therapy is employed or strong Neo-Minophagen C is used for the treatment. The action of alanine contained in "therapeutic agents for hepatitis" which will be cited below is to inhibit the increase of transaminase by improving the mitochondria function. When these alcoholinduced hepatopathy and hepatitis become chronic, they develop into liver cirrhosis. As for the therapy for liver cirrhosis, only symptomatic therapy for hepatic encephalopathy, hypoalbuminemia and hemorrhage of digestive tracts is possible. However, no therapeutic method for curing liver cirrhosis itself or for inhibiting the advance thereof was developed and, as for alanine, its therapeutic effect on liver cirrhosis is unknown yet. On the other hand, primary biliary cirrhosis is a liver cirrhosis caused by cholestasis of unknown origin. After the outbreak of the disease, its progress is relatively slow. However, in many of the cases where the symptoms have already been shown, the disease reaches liver cirrhosis in 4 years and the patients die of hepatic insufficiency in about 5 years on average. Patients with primary biliary cirrhosis are thus not convalescing satisfactorily. Although ursodeoxycholic acid is used as the first selective medicine in the treatment of primary biliary cirrhosis, the therapeutic effect thereof is weakened as the conditions of the patients advance. In those advanced stages of diseases, cases in which the symptoms became more serious by the administration of ursodeoxycholic acid were reported. Further, because this disease surely progresses into hepatic insufficiency, patients having the terminal symptoms are obliged to rely on liver transplantation. However, the transplantation has problems such as insufficiency of the organs. Under these circumstances, the development of a medical drug therapy capable of controlling the symptoms and delaying the advance of the disease is demanded. Although it was known to use alanine alone or in combination with other amino acids for preparing a composition for treating patients suffering from alcohol-induced disorders [Japanese Patent Unexamined Published Application (hereinafter referred to as "J. P. KOKAI" No. Sho 63-54320), a composition for treating

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patients with alcohol-induced liver disorders (J. P.KOKAI No. Hei 5-213746), therapeutic agent for hepatitis (J. P. KOKAI No. Hei 5-221858), liver regeneration accelerator (J. P. KOKAI No. Hei 5-229940), etc., it has never been known that alanine is useful as a therapeutic agent for primary biliary cirrhosis. Web site: http://www.delphion.com/details?pn=US06339104__ •

Treatment of disease states Inventor(s): Gurney; Harry C. (Conifer, CO), McMichael; John (Delanson, NY) Assignee(s): Milkhaus Laboratory, Inc. (Delanson, NY) Patent Number: 6,303,127 Date filed: August 11, 1998 Abstract: The invention presents methods for the treatment of symptoms associated with diseases states including cardiomyopathy, Parkinson's Disease and degenerative liver disease including cirrhosis comprising treatment with an effective amount of a composition comprising beta-amyloid, streptolysin O, and growth hormone. Excerpt(s): This invention relates generally to methods and materials for the treatment and amelioration of the symptoms associated with cardiomyopathy in non-human animals, Parkinson's Disease, and degenerative liver disease including cirrhosis. Cardiomyopathy is a disease of the heart muscle. This form of heart disease is often distinctive, both in general symptoms and in patterns of blood flow, to allow a diagnosis to be made. Increasing recognition of this disease, along with improved diagnostic techniques, has shown that cardiomyopathy is a major cause of morbidity and mortality. In some areas of the world it may account for as many as 30 percent of all deaths due to heart disease. Cardiomyopathy can result from a variety of structural or functional abnormalities of the ventricular myocardium. A large number of cardiomyopathies are apparently not related to an infectious process and are not well understood. Some are congenital and may cause enlargement of the heart. Metabolic diseases associated with endocrine disorders may also cause cardiomyopathies. Infections, such as acute rheumatic fever and several viral infections, may cause a number of types of myocarditis. Myocarditis may also occur as a manifestation of a generalized hypersensitivity reaction, allergic or immunologic. The heart may also be affected by any of a considerable number of collagen diseases. Collagen is the principal connective tissue protein, and collagen diseases are diseases of the connective tissues. They include diseases primarily of the joints, skin, and systemic disease. Web site: http://www.delphion.com/details?pn=US06303127__

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Treatment of hepatic cirrhosis Inventor(s): Nagler; Arnon (Jerusalem, IL), Pines; Mark (Rehovot, IL) Assignee(s): Agricultural Research Organaization-Ministry of Agriculture (Bet Dagan, IL), Hadasit Medical Research Services & Development Co., Ltd. (Jerusalem, IL) Patent Number: 6,562,829 Date filed: October 13, 1999

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Abstract: A composition for treating hepatic fibrosis and a method of using and manufacturing the composition are provided. The composition includes a quinazolinone derivative, preferably Halofuginone. Excerpt(s): The present invention relates to the treatment of hepatic cirrhosis and, in particular, to the treatment of hepatic cirrhosis with quinazolinone derivatives such as Halofuginone. Hepatic cirrhosis has a number of causes, including hepatic fibrosis caused by chronic alcoholism, malnutrition, hemochromatosis, passive congestion, hypercholesterolemia, exposure to hepatotoxic chemical substances, exposure to drugs, immune reactions, genetically determined sensitivities to certain substances as seen with copper in Wilson's disease and infections such as viral hepatitis, syphilis and various parasitic infections including, but not limited to, Schistosomiasis mansoni and S. japonica. For reasons given in greater detail below, the disease is currently incurable and frequently fatal. The pathogenesis of hepatic cirrhosis progresses in a number of stages. First, an enlarged liver is seen with various fatty changes. Next, overt fibrosis is evident with a concomitant decrease in liver function. Finally, atrophy of the liver begins, with a corresponding reduction in the size and functionality of the liver. Necrosis of the liver can be seen at any stage, but is particularly pronounced by late stage cirrhosis. Microscopically, a complete disruption of the normal architecture of the liver is evident. Web site: http://www.delphion.com/details?pn=US06562829__

Patent Applications on Cirrhosis 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 cirrhosis: •

Acylated indanyl amines and their use as pharmaceuticals Inventor(s): Dharanipragada, Ramalinga M.; (Belle Meade, NJ), Safarova, Alena; (Tucson, AZ), Schonafinger, Karl; (Alzenau, DE), Strobel, Hartmut; (Liederbach, DE), Suzuki, Teri; (Tucson, AZ), Walser, Armin; (Tucson, AZ), Wohlfart, Paulus; (Bensheim, DE) Correspondence: Finnegan, Henderson, Farabow,; Garrett & Dunner, L.L.P.; 1300 I Street, N.W.; Washington; DC; 20005-3315; US Patent Application Number: 20030055093 Date filed: February 13, 2002 Abstract: The present invention relates to acylated indanyl amines according to the general formula (I) 1wherein R.sup.1-R.sup.4 have the meanings given in the description, A is CH.sub.2, CHOH or CH--(C.sub.1-C.sub.3-alkyl), B is CH.sub.2 or CH-(C.sub.1-C.sub.3-alkyl), and R.sup.5 is an aryl or heteroaryl group, possibly substituted by the substituents listed in the description. These compounds are useful in the upregulation of endothelial nitric oxide synthase (eNOS), and may therefore be useful for the manufacture of medicaments for the treatment of cardiovascular diseases, stable or unstable angina pectoris, coronary heart disease, Prinzmetal angina, acute coronary syndrome, heart failure, myocardial infarction, stroke, thrombosis, peripheral artery

10

This has been a common practice outside the United States prior to December 2000.

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occlusive disease, endothelial dysfunction, atherosclerosis, restenosis, endothelial damage after PTCA, hypertension, essential hypertension, pulmonary hypertension, secondary hypertension, renovascular hypertension, chronic glomerulonephritis, erectile dysfunction, ventricular arrhythmia, diabetes or diabetes complications, nephropathy or retinopathy, angiogenesis, asthma bronchiale, chronic renal failure, cirrhosis of the liver, osteoporosis, restricted memory performance, a restricted ability to learn, or for the lowering of cardiovascular risk of postmenopausal women or after intake of contraceptives. Excerpt(s): Endothelial NO synthase (eNOS, NOS-III) belongs to a group of three isoenzymes which produce nitric oxide (NO) by oxidation of arginine. Endothelially released NO is of central importance in a number of key cardiovascular mechanisms. It has a vasodilating effect and inhibits the aggregation of platelets, the adhesion of leukocytes to the endothelium and the proliferation of intimal smooth muscle cells. Endothelial NO synthase is subject to physiological and pathophysiological regulation both at the transcriptional and at the post-transcriptional level. Enzyme already present in the endothelium may undergo calcium-dependent and calcium-independent activation through phosphorylation of specific amino acids, but also by direct interactions with specific proteins. Stimulators of this, usually transient, NO release are, extracellular arginine, 17.beta.-estrogen and the mechanical stimulus exerted on the luminal surface of the endothelium by the blood flow (shear stress). The latter additionally leads to regulation of eNOS at the transcriptional level. Thus, for example, Sessa et al. (Circ. Research 74 (1994) 349-353) were able by means of exercise training and the increase in shear stress associated therewith to obtain a marked increase in ecNOS. Whether regulation at the post-transcriptional level is relevant in vivo, is not unambiguously proved. Thus, for example, administration of a high arginine dose is followed by only a transient improvement in the endothelium-dependent vasorelaxation in patients with coronary heart disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Adenosine A2A receptor antagonists for treating and preventing hepatic fibrosis, cirrhosis and fatty liver Inventor(s): Chan, Edwin; (New York, NY), Cronstein, Bruce N.; (New York, NY) Correspondence: Browdy And Neimark, P.L.L.C.; 624 Ninth Street, NW; Suite 300; Washington; DC; 20001-5303; US Patent Application Number: 20020002145 Date filed: February 12, 2001 Abstract: Hepatic cirrhosis and fibrosis and fatty liver can be prevented and treated by administering to a subject in need thereof an effective amount of at least one adenosine A.sub.2A receptor antagonist or at least one adenosine uptake promotor. Excerpt(s): The present application claims priority from provisional application Ser. No. 60/181,546, filed Feb. 10, 2000, the entire contents of which are hereby incorporated by reference. The present invention relates to methods and compositions for treating and preventing hepatic fibrosis and cirrhosis as well as fatty liver. Adenosine is a nucleoside with wide distribution in the body. Adenosine mediates a broad array of physiological responses, including central nervous system sedation, inhibition of platelet aggregation and vascular smooth muscle vasodilation. These effects occur largely through interaction of adenosine with one of four types of adenosine receptors.

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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Composition and method for treating nonalcoholic steatohepatitis Inventor(s): Fan, David; (Newport Beach, CA), Hsia, Houn Simon; (Irvine, CA) Correspondence: Lyon & Lyon Llp; Suite 4700; 633 West Fifth Street; Los Angeles; CA; 90071-2066; US Patent Application Number: 20010000028 Date filed: November 29, 2000 Abstract: Nonalcoholic steatohepatitis (NASH) is a disease of the liver characterized by inflammation and damage to the liver cells. Typically, steatohepatitis involves inflammation of the liver related to fat accumulation, and mimics alcoholic hepatitis but is observed in patients who seldom or never consume alcohol. Nonalcoholic steatohepatitis can lead to serious liver damage, and ultimately cirrhosis. The present invention provides methods and compositions useful for the treatment or alleviation of nonalcoholic steatohepatitis and the pharmaceutical formulations for their administration to a human. Specifically, compositions comprised of lecithin, antioxidants and vitamin B complex are administered parenterally, most preferably by oral administration. Specific therapeutic formulations include admixtures of these compounds and specific dosage formulations include daily oral administrations of these compounds in tablet or powder forms. Excerpt(s): 1. This is a divisional of co-pending application Ser. No. 09/205,082, filed on Dec. 4, 1998. The priority of the prior application is expressly claimed, and the disclosure of each of this prior application is hereby incorporated by reference in its entirety. 2. The present invention generally relates to dietary supplements containing lecithin, antioxidants and/or a vitamin B complex to treat liver disease. A preferred embodiment is a composition and the use thereof of a dietary supplement comprising lecithin, at least one antioxidant, and a vitamin B complex administered orally to treat or alleviate nonalcoholic steatohepatitis. 3. The liver is the largest organ in the human body, located in the superior portion of the right upper abdomen. This organ is highly complex and specialized and performs many crucial biochemical functions. The liver is critically involved in the removal of toxins from the body and in the manufacture of proteins including energy storage and blood clotting factors. The liver is also involved in storing minerals, vitamins and glucose in the form of glycogen, which is metabolized in large quantities to provide energy. The liver also plays a role in red blood cell metabolism and the break-down of certain metabolic byproducts in the blood stream. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Compounds for inhibition of ceramide-mediated signal transduction Inventor(s): Carson, Dennis A.; (Del Mar, CA), Cottam, Howard; (Fallbrook, CA) Correspondence: Schwegman, Lundberg, Woessner & Kluth, P.A.; P.O. Box 2938; Minneapolis; MN; 55402; US Patent Application Number: 20020165202 Date filed: September 13, 2001

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Abstract: Novel, heterocyclic compounds having at least one ring nitrogen, disclosed side chains and, in some embodiments, an oxygen ortho to the ring nitrogen inhibit inflammatory responses associated with TNF-.alpha. and fibroblast proliferation in vivo and in vitro. The compounds of the invention neither appreciably inhibit the activity of cAMP phosphodiesterase nor the hydrolysis of phosphatidic acid, and are neither cytotoxic nor cytostatic. Preferred compounds of the invention are esters. Methods for the use of the novel compounds to inhibit ceramide-mediated intracellular responses in stimuli in vivo (particularly TN-.alpha.) are also described. The methods are expected to be of use in reducing inflammatory responses (for example, after angioplasty), in limiting fibrosis (for example, of the liver in cirrhosis), in inhibiting cell senescence, cell apoptosis and UV induced cutaneous immune suppression. Compounds having enhanced water solubility are also described. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 08/367,102, filed Dec. 29, 1994 and a continuation-in-part of U.S. patent application Ser. No. 08/482,551, filed Jun. 7, 1995. The invention relates to compounds effective in modulating cellular responses stimulated by ceramide-mediated signal transduction, in particular in response to stimulus by the cytokine tumor necrosis factor.alpha. (TNF.alpha.). More specifically, it relates to compounds which inhibit the development of conditions associated with cell stimulus through the ceramide-mediated signal transduction pathway. The sphingomyelin pathway is a cellular signal transduction pathway that is believed to be involved in mediating cellular responses to several cytokines (including TNF-.alpha. and IL-I.beta.) and growth factors (e.g., platelet derived growth factor and fibroblast growth factor) (see, e.g., Dressier, et al., Science, 259:1715-1718, 1992; and, Jacobs and Kester, Amer.J.Physiol., 265: 740-747, 1993). It is believed that interaction of such molecules with cell surface receptors triggers activation of a plasma membrane sphingomyelinase. Sphingomyelinase in turn catalyzes the hydrolysis of sphingomyelin to deramide and phosphocholine. Ceramide is believed to act as a second messenger through activation of a proline-directed, serine/threonine kinase (ceramide-activated protein kinase or "CaPK"). Ceramide also interacts with MAP kinase and protein kinase C zeta (see, e.g., Rivas, et al., Blood, 83:2191-2197, 1993) and with a serine/threonine protein phosphatase (see, Hannun, et al., TIBS, 20:73-77, 1995). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compounds which interact with the thyroid hormone receptor for the treatment of fibrotic disease Inventor(s): Billingham, Michael Edward John; (Alresford, GB) Correspondence: Martin A. Hay; 13 Queen Victoria Street; Macclesfield Cheshire UK; Sk11 6lp; GB Patent Application Number: 20020049254 Date filed: November 13, 2001 Abstract: A method of alleviating a fibrotic disease selected from lung fibrosis and liver cirrhosis in a warm blooded animal, which comprises administering an effective amount of at least one compound having the formula (I) 1in which X stands for the oxygen or sulphur atom or for the imino (--NH--) or sulphonyl (--SO.sub.2--) radical, Y stands for a direct linkage, or for the oxygen or sulphur atom or for the sulphonyl (-SO.sub.2--) radical or for the radical of the formula --CR.sup.1R.sup.2--, wherein R.sup.1 and R.sup.2 which may be the same or different are hydrogen, alkyl or aryl radicals or

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R.sup.1 and R.sup.2 may be joined together to form a cycloalkyl ring, n is an integer having the value 0 or 1, provided that when n is 0, Y stands for the oxygen or sulphur atom or for the sulphonyl (--SO.sub.2--) radical, or an ester, amide or salt thereof. Excerpt(s): This invention relates to fibrotic diseases. There are many fibrotic diseases in the human. These are sometimes referred to as chronic connective tissue diseases, and include degradative and proliferative conditions. They include, for example, deterioration of the joints in arthritis, deformation of vessel walls in artherosclerosis, accelerated cardiovascular problems associated with diabetes, lung fibrosis and cirrhosis of the liver. These fibrotic diseases are generally considered and studied as separate and different problems However, it is possible that common pathways exist in all these fibrotic diseases Indeed, corticosteriods are used in the treatment of many of these diseases to relieve symptoms and prevent associated tissue destruction and scarring; however, the use of corticosteroids is associated with dose and treatment duration side-effects which limit the usefulness of this type of compound. Some fibrotic diseases are particularly distressing, such as, for example, those involving deterioration of cartilage and bone in the joint. Amelioration of such diseases is a particularly difficult target for the pharmaceutical industry. These conditions are often accompanied by distressing levels of pain and gradual impairment of structural body function and movement. An added difficulty in attempting to find a satisfactory cure or improvement is that joint disease appears to be largely species specific. Therefore, research into joint disease in man is made more difficult in that animal models may not be appropriate. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Epoxy-steroidal aldosterone antagonist and calcium channel blocker combination therapy for treatment of congestive heart failure Inventor(s): Schuh, Joseph R.; (St. Louis, MO) Correspondence: Pharmacia Corporation; Corporate Patent Law Department; Mail Zone O4e; 800 North Lindbergh BLVD.; ST. Louis; MO; 63167; US Patent Application Number: 20020042405 Date filed: July 27, 2001 Abstract: A combination therapy comprising a therapeutically-effective amount of an epoxy-steroidal aldosterone receptor antagonist and a therapeutically-effective amount of a calcium channel blocker is described for treatment of circulatory disorders, including cardiovascular disorders such as hypertension, congestive heart failure, cirrhosis and ascites. Preferred calcium channel blockers are those compounds having high potency and bioavailability. Preferred epoxy-steroidal aldosterone receptor antagonists are 20-spiroxane steroidal compounds characterized by the presence of a 9.alpha.,11.alpha.-substituted epoxy moiety. A preferred combination therapy includes the calcium channel blocker verapamil HCl (Benzenacetonitrile, (.+-.)-.alpha.[3[[2-(3,4dimethoxyphenyl) ethyl]methylamino]propyl]-3,4-dimethoxy-.alpha.-(1methylethyl)hydrochlor- ide) and the aldosterone receptor antagonist epoxymexrenone. Excerpt(s): Combinations of an epoxy-steroidal aldosterone receptor antagonist and a calcium channel blocker are described for use in treatment of circulatory disorders, including cardiovascular diseases such as hypertension, congestive heart failure, cardiac hypertrophy, cirrhosis and ascites. Of particular interest are therapies using an epoxycontaining steroidal aldosterone receptor antagonist compound such as epoxymexrenone in combination with a calcium channel blocker compound. Myocardial

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(or cardiac) failure, whether a consequence of a previous myocardial infarction, heart disease associated with hypertension, or primary cardiomyopathy, is a major health problem of worldwide proportions. The incidence of symptomatic heart failure has risen steadily over the past several decades. In clinical terms, decompensated cardiac failure consists of a constellation of signs and symptoms that arises from congested organs and hypoperfused tissues to form the congestive heart failure (CHF) syndrome. Congestion is caused largely by increased venous pressure and by inadequate sodium (Na.sup.+) excretion, relative to dietary Na.sup.+ intake, and is importantly related to circulating levels of aldosterone (ALDO). An abnormal retention of Na.sup.+ occurs via tubular epithelial cells throughout the nephron, including the later portion of the distal tubule and cortical collecting ducts, where ALDO receptor sites are present. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Heterocyclic carboxamide derivatives as inhibitors of nitric oxide production Inventor(s): Ohkawa, Takehiko; (Ibaraki, JP), Ohne, Kazuhiko; (Ibaraki, JP), Oku, Teruo; (Tokyo, JP), Setoi, Hiroyuki; (Ibaraki, JP), Shima, Ichiro; (Ibaraki, JP), Yoshihara, Kousei; (Ibaraki, JP), Zenko, Tatsuya; (Tokyo, JP) Correspondence: Oblon Spivak Mcclelland Maier & Neustadt PC; Fourth Floor; 1755 Jefferson Davis Highway; Arlington; VA; 22202; US Patent Application Number: 20020132809 Date filed: February 25, 2002 Abstract: 1wherein each symbol is as defined in the specification, and pharmaceutically acceptable salts thereof. The compound (I) of the present invention and pharmaceutically acceptable salts thereof possess a strong inhibitory activity on the production of nitric oxide (NO), and are useful for prevention and/or treatment of NOmediated diseases such as adult respiratory distress syndrome, cardiovascular ischemia, myocarditis, heart failure, synovitis, shock, diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, glomerulonephritis, peptic ulcer, inflammatory bowel disease, cerebral infarction, cerebral ischemia, cerebral hemorrhage, migraine, rheumatoid arthritis, gout, neuritis, postherpetic neuralgia, osteoarthritis, osteoporosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, metastasis, Alzheimer's disease, arthritis, CNS disorders, dermatitis, hepatitis, liver cirrhosis, multiple sclerosis, pancreatitis, atherosclerosis, and the like in human being and animals. Excerpt(s): This invention relates to new amide compounds and pharmaceutically acceptable salts thereof which are useful as medicament. Some peptide compounds have been known as described in, for example, EP 0 394 989 A2. This invention relates to new amide compounds. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Human FGF-21 gene and gene expression products Inventor(s): Itoh, Nobuyuki; (Kyoto, JP), Kavanaugh, W. Michael; (Mill Valley, CA) Correspondence: Seed Intellectual Property Law Group Pllc; 701 Fifth Ave; Suite 6300; Seattle; WA; 98104-7092; US Patent Application Number: 20020164713 Date filed: January 29, 2002 Abstract: This invention relates to human fibroblast growth factor (hFGF-21), and to variants thereof and to polynucleotides encoding FGF-21. The invention also relates to diagnostic and therapeutic agents related to the polynucleotides and proteins, including probes and antibodies, and to methods of treating liver disease such as cirrhosis and cancer, methods of treating conditions related to thymic function, and methods of treating conditions of the testis. The invention also relates to mouse fibroblast growth factor (mFGF-21), and to variants thereof and polynucleotides encoding mFGF-21. Excerpt(s): This application claims priority from U.S. Provisional Patent Application No. 60/166,540 filed Nov. 18, 1999 and U.S. Provisional Patent Application No. 60/203,633 filed May 11, 2000, which are incorporated by reference herein in their entirety. The present invention relates to nucleic acid sequences encoding a member of the fibroblast growth factor (FGF) family, and to polypeptides encoded by the nucleic acid sequence. The prototypic fibroblast growth factors (FGFs), FGF-1 and FGF-2, were originally isolated from brain and pituitary as mitogens for fibroblasts. However, FGF-1 and FGF-2 are widely expressed in developing and adult tissues, and are polypeptides with multiple biological activities including angiogenesis, mitogenesis, cellular differentiation and repair of tissue injury (Baird, A. et al., Cancer Cells 3:239-243 (1991); Burgess, W. H. et al., Annu. Rev. Biochem. 58:575-606 (1989). According to the published literature, the FGF family now consists of at least nineteen members, FGF-1 to FGF-19. FGF-3 was identified to be a common target for activation by the mouse mammary tumor virus (Dickson et al., Ann. N.Y. Acad. Sci. 638:18-26 (1991); FGF-4 to FGF-6 were identified as oncogene products (Yoshida et al., Ann. NY Acad. Sci. 638:27-37 (1991); Goldfarb et al., Ann. NY Acad. Sci 638:38-52 (1991); Coulier et al., Ann. NY Acad. Sci. 638:53-61 (1991)). FGF-10 was identified from rat lung by homology-based polymerase chain reaction (PCR) (Yamasaki et al., J. Biol. Chem. 271:15918-15921 (1996)). FGF-11 to FGF-14 (FGF homologous factors (FHFs) 1 to 4) were identified from human retina by a combination of random cDNA sequencing, data base searches and homology-based PCR (Smallwood et al., Proc. Natl. Acad. Sci. USA 93:9850-9857 (1996)). FGF-15 was identified as a downstream target of a chimeric homeodomain oncoprotein (McWhirter et al., Development 124:3221-3232 (1997)). FGF-16, FGF-17, and FGF-18 were identified from rat heart and embryos by homology-based PCR, respectively (Miyake et al., Biochem. Biophys. Res. Commun. 243:148-152 (1998); Hoshikawa et al., Biochem. Biophys. Res. Commun. 244:187-191 (1998); Ohbayashi et al., J. Biol. Chem. 273:18161-18164 (1998)). Recently, FGF-19 was identified from human fetal brain by data base search (Nishimura et al., Biochim. Biophys. Acta 1444:148-151 (1999)). They have a conserved.about.120amino acid residue core with.about.30 to 60% amino acid identity. These FGFs also appear to play important roles in both developing and adult tissues. Thus, there is a need in the art for additional FGF molecules having functions and activities that differ from the known FGFs and for FGF molecules specifically expressed in tissues implicated in human disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Immunomodulator Inventor(s): Hamuro, Junji; (Kawasaki-shi, JP), Murata, Yukie; (Kawasaki-shi, JP) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20030203006 Date filed: April 3, 2003 Abstract: An immunomodulator is provided which is capable of oral intake for improvement, treatment and prevention of human immunological diseases and which is used to treat, improve and prevent human immunological diseases, especially, autoimmune diseases and allergic diseases such as hepatic cirrhosis, hepatitis, diabetes, inflammatory bowel diseases, chronic rheumatoid arthritis, asthma and cutaneous atopy, allergic diseases and cancers by a new method that can control the redox state of macrophages or monocytes, and can be incorporated into a drug, a food, a nutrient, and an infusion. The contents of oxidative glutathione and reductive glutathione in macrophages are monitored, and the ratio of oxidative glutathione and reductive glutathione is examined, whereby macrophages are classified into oxidative macrophages and reductive macrophages having different functions. The degree of progression of various autoimmune diseases is analyzed from this standpoint. On the basis of the results, an immunomodulator capable of oral intake which contains a substance having an activity of changing a content of reductive glutathione in macrophages to solve the above-mentioned problem and which is intended to treat, improve and prevent human immune diseases is provided. Excerpt(s): The present invention relates to a novel immunomodulator. More specifically, the present invention relates to an immunomodulator capable of oral intake which has a novel suppressive function of macrophages (hereinafter sometimes abbreviated as "M.PHI.") or monocytes. The immunomodulator may be used for treatment, improvement and prevention of human autoimmune diseases such as hepatic cirrhosis, hepatitis, diabetes, inflammatory bowel diseases, chronic rheumatoid arthritis, asthma and cutaneous atopy, allergic diseases and cancers. The present invention also relates to a drug, a food, a nutrient and an infusion containing the immunomodulator. As used herein, the term "immune system" refers to one's bodily system for defending itself from exogenous infection by virus, bacteria or the like, or from invasion the body with transformed cells (tumor cells and the like) formed by transformation of autologous cells. However, the immune system occasionally behaves abnormally, i.e., it functions excessively and acts to reject autologous components. On the other hand, the immune system sometimes functions deficiently, resulting in an immunocompromised state. Diseases revealing these abnormal responses are generally called immunological diseases. Examples thereof include diverse diseases, such as, for example, acute or chronic inflammatory diseases such as atopic cutaneous inflammatory diseases, pollinosis, asthma and sarcoidosis; autoimmune diseases such as allergic diseases, chronic rheumatoid arthritis, diabetes, SLE and chronic fatigue syndrome; hepatitis, hepatic cirrhosis, inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease; and cancer cachexia. These immunological diseases originate from complex pathological causes. Systemic immunodeficiency and functional deficiency originate from pathological inflammation accompanied by cell proliferation, differentiation or cell necrosis through local production of cytokines or inflammatory mediators. As cells that participate in immunity, T lymphocytes and B lymphocytes are well known, exhibiting a wide variety of functions as cells playing roles in cellular immunity and humoral immunity respectively. Meanwhile, macrophages and

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monocytes are cells that intimately participate in both cellular immunity and humoral immunity, and they intimately participate in rejection of non-self foreign bodies, for example, immunological diseases such as allergy and rheumatism, cancers and bacterial infection. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

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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Novel long-term three-dimensional tissue culture system Inventor(s): Bowen, William C. JR.; (White Oak, PA), Michalopoulos, George; (Bethel, PA) Correspondence: Baker & Botts; 30 Rockefeller Plaza; New York; NY; 10112 Patent Application Number: 20030096411 Date filed: October 28, 2002 Excerpt(s): The present invention relates to a novel tissue culture system that provides for the long term culture of proliferating hepatocytes that retain hepatic function. Disclosed are methods and compositions for ex vivo culturing of hepatocytes and

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nonparenchymal cells on a matrix coated with a molecule that promotes cell adhesion, proliferation or survival, in the presence of growth factors, resulting in a long-term culture of proliferating hepatocytes that retain hepatic function. The co-culturing method results in the formation of matrix/hepatic cell clusters that may be mixed with a second structured or scaffold matrix that provides a three-dimensional structural support to form structures analogous to liver tissue counterparts. The hepatic cell culture system can be used to form bio-artificial livers through which a subjects blood is perfused. Alternatively, the novel hepatic cell culture system may be implanted into the body of a recipient host having a hepatic disorder. Such hepatic disorders, include, for example, cirrhosis of the liver, induced hepatitis, chronic hepatitis, primary sclerosing cholangitis and alpha.sub.1 antitrypsin deficiency. The present invention is based on the discovery that mixed cultures of proliferating hepatocytes and nonparenchymal cells, grown on a collagen-coated matrix in medium containing hepatocyte growth factor (HGF) and epidermal growth factor (EGF), maintain their capacity to proliferate while retaining hepatic functions. Further, it was discovered that addition of corticosteroids to the media resulted in phenotypic maturation of hepatocytes. One of the major functions of the liver is to break down harmful substances absorbed from the intestine or manufactured elsewhere in the body, followed by their excretion as harmless byproducts into the bile or blood. Abnormalities of liver function caused by insult to and/or death or malfunction of the cells in the liver can lead to a variety of different hepatic disorders including cirrhosis of the liver or hepatitis. Treatment of such disorders may include whole liver transplants, although this treatment is limited by organ availability, surgical complications, and immunologically-mediated graft rejection normally associated with liver transplantation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel substituted benzimidazol-2-ones as vasopressin receptor antagonists and neuropeptide Y modulators Inventor(s): Demarest, Keith T.; (Flemington, NJ), Gunnet, Joseph W. JR.; (Flemington, NJ), Urbanski, Maud J.; (Flemington, NJ) Correspondence: Audley A. Ciamporcero JR.; Johnson & Johnson; One Johnson & Johnson Plaza; New Brunswick; NJ; 08933-7003; US Patent Application Number: 20030073842 Date filed: October 23, 2001 Abstract: The invention is directed to substituted benzimidazol-2-ones of Formula I, 1wherein A, X, Y, m, n, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are as described in the specification, which are useful as vasopressin receptor antagonists or Neuropeptide Y Modulators for treating conditions such as aggression, obsessive-compulsive disorders, hypertension, dysmenorrhea, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, edema, ischemia, stroke, thrombosis, water retention, nephrotic syndrome, central nervous injuries, obesity, anorexia, hyperglycemia, diabetes, anxiety, depression, asthma, memory loss, sexual dysfunction, disorders of sleep and other circadian rhythms, and Cushing's disease. Excerpt(s): This application claims priority from U.S. Ser. No. 60/243,817, filed Oct. 27, 2000. This invention relates to novel substituted benzimidazol-2-ones. More particularly, the compounds of the present invention modulate the binding of the peptide hormone vasopressin and neuropeptide Y to their respective receptors and are therefore useful for

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treating conditions involving increased vascular resistance, cardiac insufficiency, and disorders of energy metabolism. Vasopressin is a nonapeptide hormone that is secreted primarily from the posterior pituitary gland. The hormone effects its actions through the vascular V-1 and renal V-2 receptor subtypes. The functions of vasopressin include contraction of uterine, bladder, and smooth muscle; stimulation of glycogen breakdown in the liver; induction of platelet aggregation; release of corticotropin from the anterior pituitary and stimulation of renal water reabsorption. As a neurotransmitter within the central nervous system (CNS), vasopressin can affect aggressive behavior, sexual behavior, the stress response, social behavior and memory. The V-1a receptor mediates central nervous system effects, contraction of smooth muscle and hepatic glycogenolytic effects of vasopressin, while the V-1b receptor mediates anterior pituitary effects of vasopressin. The V-2 receptor, presumably found only in the kidney, effects the antidiuretic actions of vasopressin via stimulation of adenylate cyclase. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Prevention of liver cancer by administration of simvastatin Inventor(s): Weinberg, Assa; (Los Angeles, CA) Correspondence: Dave B. Koo, ESQ.; Squire, Sanders & Dempsey L.L.P.; 801 S. Figueroa Street, 14th Floor; Los Angeles; CA; 90017-5554; US Patent Application Number: 20020151583 Date filed: April 11, 2001 Abstract: A method for preventing liver cancer is disclosed. In one embodiment, the method comprises administrating an effective amount of simvastatin to patients showing elevated alphafetoprotein levels. In another embodiment, the method comprises administrating simvastatin to patients upon detection of a liver condition, i.e viral Hepatitis B, Hepatitis C and liver cirrhosis. Excerpt(s): In spite of substantial advances in the understanding of the mechanism of oncogenesis (transformation of a normal cell into a malignant one), a method to prevent and reverse such oncogenic process has not been put into practice. Many environmental, dietary and genetic factors play a significant role in the formation of a malignant tumor, but no drug is known to prevent the formation of a malignant tumor. In many cases, patients affected with a malignant tumor are deemed to be terminal. Cancer of the liver or hepatocellular carcinoma is a particular case in point. It is an aggressive and rapidly spreading disease. Even with the combined use of the four classic treatment modalities, surgery, radiation, chemotherapy and immunotherapy--little has been changed to alter the grim prospect. The only methods capable of eradicating liver cancer at the present time are partial resection of the liver in the case where the malignancy is localized or complete extirpation of the malignant liver and a replacement by transplantation. In liver transplantation cases, the cost of the procedure is substantial, followed by a lifelong administration of anti-rejection drugs, and medical follow-up involving doctor visits, blood tests, and imaging studies. Patients with advanced liver diseases, and in particular, patients with viral hepatitis B and C are known to be at a high risk of developing liver cancer. In the United States, there are 70,000 new hepatitis B cases and more than 250,000 newly diagnosed hepatitis C cases each year. Around the world and especially in Southeast Asia and China, Hepatitis B and C are at epidemic proportion without a cure in sight. The case is particularly serious as the Hepatitis virus can be transmitted during delivery to the newborn baby. This was demonstrated in recent studies from Taiwan in which 40% of babies born to Hepatitis B or C carrier mothers

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were found to be positive for the same, a few days after delivery or a month later. In the same token hepatocellular carcinoma is at epidemic proportions in this region and represents a major public health issue for these countries. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Prophylactic and therapeutic use of oltipraz as an antifibrotic and anticirrhotic agent in the liver and pharmaceutical composition containing oltipraz Inventor(s): Kang, Keon-Wok; (Seoul, KR), Kim, Sang-Geon; (Seoul, KR) Correspondence: Cantor Colburn, Llp; 55 Griffin Road South; Bloomfield; CT; 06002 Patent Application Number: 20030191137 Date filed: October 2, 2002 Abstract: The present invention provides a prophylactic and therapeutic use of 5-(2pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) as an antifibrotic and anticirrhotic agent in the liver and a pharmaceutical composition containing oltipraz for treating and preventing hepatic fibrosis and cirrhosis.Oltipraz of the invention can be used as a medicine optionally with other drugs for treating and preventing hepatic fibrosis and cirrhosis and shows an inhibiting effect of hepatic fibrosis at a relatively low dosage. Formulations using an optimal dose of oltipraz, which is provided by the invention, have a surprisingly good effect on the treatment and prevention of hepatic fibrosis and cirrhosis and are safe drugs that have a low toxicity on the human body. Excerpt(s): The present invention relates to a prophylactic and therapeutic use of 5-(2pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) as an antifibrotic and anticirrhotic agent in the liver and to a pharmaceutical composition comprising oltipraz as an active ingredient. The liver plays a key role in the metabolism of xenobiotics and in the metabolism of endogenous substances and is an important organ with consistent enzymatic reactions and energy metabolism. Among the many chronic diseases in Korea, hepatitis, cirrhosis, and liver cancer are the most widespread and life threatening next to cardiovascular diseases. As Korea has a relatively large population of drinkers of alcoholic beverages when compared to developed countries, and as liver damage due to binge drinking is fairly high, a lot of attention has been given to the treatment of liver diseases. Often chronic liver damage resulting from viral infection or alcohol consumption causes cirrhosis or liver cancer. In consideration of the physiological characteristics and importance of the liver, and in view of the importance of treating and preventing liver disease, demand is high for the ultimate development of therapeutic and preventive drugs against liver damage. Various substances, including several synthetic compounds and galenical preparations, show hepatoprotective functions both in vitro and in vivo. Although it has been known that silymarin and betaine have liver protective effects as a result of the action mechanism of cytokine inhibition and an increase in the level of glutathione, a curative effect would be hard to expect because of its low effectiveness. Because no appropriate curative agents against liver disease are currently available, said agents are frequently used for clinical trials. Malotilate and its derivatives, the indication of which is the treatment of liver fibrosis, protect the liver from toxic chemicals and the possible action mechanism includes the induction of phase II conjugating enzymes and the inhibition of cytochrome P450s. However, the compounds non-selectively inhibit several cytochrome P450s and show only preventive effects. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 191

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Proton-transfer-reaction/ion-mobility-spectrometer and method of using the same Inventor(s): Beegle, Luther W.; (Pasadena, CA), Kanik, Isik; (Monrovia, CA) Correspondence: Daniel L. Dawes; Myers, Dawes & Andras Llp; Ste 1150; 19900 Macarthur Blvd; Irvine; CA; 92612; US Patent Application Number: 20030116705 Date filed: October 30, 2002 Abstract: A high-pressure hollow cathode ionizer is combined with an ion-mobilityspectrometer (IMS) for the detection of trace amounts of organic compounds in gas. The ionizer uses H.sub.30+, ions which do not react with air to ionize the organic compounds and the organic compounds are soft ionized. The ionized organic compounds are detected in the IMS at levels of parts per billion and identified using calibrated reference tables. Applications include but are not limited to the fields of: (1) medicine as a breath analyzer for detection of lung cancer, diabetes, liver cirrhosis, (2) law enforcement in drug interdiction and explosives detection, (3) food monitoring and control, (4) environmental monitoring and (5) space applications Excerpt(s): The present application is related to U.S. Provisional Patent Application serial No. 60/334,437, filed on Nov. 30, 2001, which is incorporated herein by reference and to which priority is claimed pursuant to 35 USC 119. The invention relates to the field of ionizers combined with ion-mobility spectrometers (IMS) for the detection of trace amounts of organic compounds in gas and methods of using the same. Miniature mass spectrometry is a powerful in-situ tool for identifying a wide variety of chemical compounds. For applications that cover many disciplines such as planetary exploration, residual gas analysis, and environmental applications, there is a need for an in-situ analytical separation device or chemical sensor which is rugged, light weight, low power, small, fast, and requires minute quantities of sample for analysis. These requirements are also applicable for the detection of certain organics in the medical sciences (analyzing human breath to detect compounds associated with certain deadly diseases such as lung cancer and cirrhosis of the liver), for a chemical sensor for use on the battlefield (chemical warfare agents), law enforcement (drug interdiction and explosives detection), and food monitoring and control. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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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

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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 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 imidazoles as selective modulators of bradykinin B2 receptors Inventor(s): DeSimone, Robert; (Durham, CT), He, Xiao-shu; (Branford, CT), Hodgetts, Kevin J.; (Killingworth, CT), Hutchison, Alan; (Madison, CT), Maynard, George D.; (Clinton, CT), Rachwal, Stanislaw; (Branford, CT), Shaw, Kenneth; (Weston, CT) Correspondence: Leslie-anne Horvath; Patent Department; Neurogen Corporation; 35 NE Industrial RD.; Branford; CT; 06405; US Patent Application Number: 20020115693 Date filed: January 17, 2001

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Abstract: Disclosed are compounds of the formula: 1or the pharmaceutically acceptable non-toxic salts thereof wherein Y, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 R.sub.7' are variables defined herein, which compounds are modulators of Bradykinin B.sub.2 receptors. These compounds are therefore useful in the diagnosis and treatment of renal diseases, heart failure, hypertension, Meniere's disease, vaginal inflammation and pain, peripheral circulatory disorders, climacteric disturbance, retinochoroidal circulatory disorders, myocardial ischemia, myocardial infarction, postmyocardial infarction syndrome, angina pectoris, restenosis after percutaneous transluminal coronary angioplasty, hepatitis, liver cirrhosis, pancreatitis, ileus, diabetes, diabetic complications, male infertility, glaucoma, pain, asthma, and rhinitis, and for the increase of permeability of the blood-brain barrier or the blood-brain-tumor barrier. Excerpt(s): This application claims priority from U.S. provisional patent application no. 60/176,869, filed Jan. 18, 2000. This invention relates to certain imidazoles which, when appropriately substituted, are selective modulators of Bradykinin B.sub.2 receptors (BK2 receptors). This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating a variety of central and peripheral disorders. Additionally, compounds of this invention are useful as positive controls in assays for BK-2 receptor activity and when appropriately labeled as probes for the localization of BK-2 receptors in tissue sections. Bradykinin (BK), a nonapeptide, and the closely related decapeptide kallidin (Lys-BK), are produced by proteolytic cleavage of high molecular weight kininogen by plasma kallikreins. The effects of bradykinin and kallidin are mediated by specific seven transmembrane Gprotein coupled receptors. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Treatment of acute and chronic liver disease Inventor(s): Grofte, Thorbjorn; (Viby J., DK), Vilstrup, Hendrik; (Risskov, DK) Correspondence: Browdy And Neimark, P.L.L.C.; 624 Ninth Street, N.W.; Washington; DC; 20001; US Patent Application Number: 20020028764 Date filed: August 14, 2001 Abstract: The present invention relates to IGF-1 treatment of an individual, such as e.g. a human being, suffering from an acute or chronic liver disease including hepatic cirrhosis. Acute and chronic liver disease according to the invention are characterized by low circulating IGF-1 and IGFBP3 levels. According to one preferred embodiment of the present invention, IGF-1 is administrered to a human being subcutaneously, preferably in the thigh or the abdominal skin, and preferably in two daily doses of about 50 microgram/kg twice a day. The present invention demonstrates that this dosis regime is able to restore normal IGF-1 levels in patients with liver cirrhosis, and the dose is well-tolerated by the patients. Excerpt(s): The invention relates to a method for treatment of acute and chronic liver disease in an individual. The treatment involves administration of insulin growth-like factor 1 (IGF-1) to an individual in need thereof. The liver disease may occur in combination with other diseases such as e.g. diabetes mellitus. Growth factors are growth promoting peptides that stimulate a wide variety of biological responses in a defined population of target cells. A variety of growth factors have been identified, including transforming growth factor beta (TGF-.beta.), epidermal growth factor (EGF),

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platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and insulin-like growth factor 1 (IGF-1). IGF-1 is a naturally occurring growth promoting peptide and shares considerable structural and functional homology with insulin and is synthesized in the liver. It consist of 70 amino acids in a single poly-peptide chain with homology to pro-insulin and has a molecular weight of approximately 7.5 kilodaltons (kD). 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

Patents 195

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Use of strains of parapoxvirus ovis against organ fibrosis Inventor(s): Hirth-Dietrich, Claudia; (Wuppertal, DE), Knorr, Andreas; (Erkrath, DE), Schlapp, Tobias; (Koln, DE), Siegling, Angela; (Paris, FR), Theiss, Gudrun; (Wuppertal, DE), Weber, Olaf; (Woodbridge, CT) Correspondence: Jeffrey M. Greenman; Vice President, Patents And Licensing; Bayer Corporation; 400 Morgan Lane; West Haven; CT; 06516; US Patent Application Number: 20020076418 Date filed: July 11, 2001 Abstract: The present invention relates to the use, in humans, of inactivated parapoxviruses for the prophylaxis and treatment of diseases which are accompanied by an increased deposition of collagen, with it being possible for both internal organs, such as the liver, and the skin and its appended structures, to be affected. The invention relates, in particular, to liver fibrosis and/or liver cirrhosis consequent upon virus hepatitis, or to ethanol-induced liver diseases and to cystic fibrosis. Excerpt(s): The present invention relates to the use in humans of inactivated parapoxviruses in the prophylaxis and treatment of diseases which are accompanied by increased deposition of collagen, in connection with which both internal organs, such as liver, and the skin and its appended structures can be affected. The invention relates, in particular, to liver fibrosis and liver cirrhosis following viral hepatitis, or ethanolinduced liver diseases, and also cystic fibrosis. The present invention relates, in particular, to the use in humans of isolates of Parapoxvirus ovis, for example the strains D1701, orf-11, Greek orf strain 176, Greek orf strain 155, New Zealand (NZ) isolates, e.g. NZ2, NZ7 and NZ10, and also Baypamun.RTM., which is derived from D1701. In addition to the starting strains, the invention also relates to the descendants which are obtained by passaging and/or adaptation to particular cells, for example WI 38. In addition to the complete viruses, the invention also relates to parts or fragments of these viruses. Parts are to be understood as being genomic or subgenomic fragments which are expressed using suitable vectors, for example vaccinia, in suitable systems such as fibroblast cell cultures. Fragments are understood as being the fractions which are obtained by biochemical purification, such as chromatography, or the particles which are obtained after using physical methods, such as disruption by means of sonication. 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 cirrhosis, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “cirrhosis” (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 cirrhosis. You can also use this procedure to view pending patent applications concerning cirrhosis. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 7. BOOKS ON CIRRHOSIS Overview This chapter provides bibliographic book references relating to cirrhosis. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on cirrhosis include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “cirrhosis” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on cirrhosis: •

Primary Biliary Cirrhosis: From Pathogenesis to Clinical Treatment Source: Boston, MA: Kluwer Academic Publishers. 1998. 176 p. Contact: Available from Kluwer Academic Publishers. Customer Service Deparment, P.O. Box 358, Accord Station, Hingham, MA 02018-0358. (781) 871-6600. Fax (781) 6819045. E-mail: [email protected]. Website: www.wkap.nl. Summary: This monograph reprints papers from a conference held in November 1997 in Chicago, Illinois, on the clinical features (symptoms), pathogenesis, and treatment of primary biliary cirrhosis (PBC). PBC is generally considered to be an autoimmune disease and one that occurs in patients who are genetically predisposed to the disease. The part played by mitochondrial antibodies (AMA) in pathogenesis of PBC remains controversial. Alternatively, the disease may have an infectious etiology (cause). Therapy can be directed against any of these injurious processes. Drug therapy, notably combinations of drugs, can be used. Fibrosis (scarring) of the bile ducts occurs in PBC

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and is responsible for the end picture of cirrhosis (liver scarring). Complications such as ascites (fluid accumulation) and portal hypertension (high blood pressure) need to be treated; other complications can include bone thinning and pruritus (itching). Liver (hepatic) transplantation performed before the terminal stages of PBC offers a five year survival exceeding 85 percent. There is evidence of recurrence in the graft. The monograph includes 20 chapters covering the natural history and demography of PBC, the immune basis for PBC, isolation and cloning of antimitochondrial antibodies, determining pathogenesis, molecular considerations of PBC, animal models of PBC, fibrogenesis in PBC, natural history models, portal hypertension in patients with PBC, osteoporosis, managing fatigue in the patients with PBC, pruritus associated with cholestasis (suppression of the flow of bile), immunosuppressant agents, methotrexate and colchicine in the treatment of PBC, corticosteroids in PBC, ursodeoxycholic acid treatment of PBC, ursodiol and combination therapy, transplantation, and new clinical trials in PBC. Each chapter concludes with references and a subject index concludes the monograph.

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 “cirrhosis” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “cirrhosis” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “cirrhosis” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

Advances in Cirrhosis, Hyperammonemia, and Hepatic Encephalopathy (Advances in Experimental Medicine and Biology, 420) by Vicente Felipo (Editor), et al (1997); ISBN: 0306455986; http://www.amazon.com/exec/obidos/ASIN/0306455986/icongroupinterna

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Cellular and Molecular Aspects of Cirrhosis by B. Clement (Editor), A. Guillouzo (Editor) (1996); ISBN: 2855984831; http://www.amazon.com/exec/obidos/ASIN/2855984831/icongroupinterna

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Chronic Liver Damage: Proceedings of the Annual Meeting of the Italian National Programme in Liver Cirrhosis, San Miniato, Italy, 11-13 January 1990 by Mario Umberto Dianzani, Paolo Gentilini; ISBN: 0444812113; http://www.amazon.com/exec/obidos/ASIN/0444812113/icongroupinterna

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Cirrhosis of the Liver and Alcoholism (World Health Statistics Report Series Volume 21, Number 11) by World Health Staff (1968); ISBN: 0686090071; http://www.amazon.com/exec/obidos/ASIN/0686090071/icongroupinterna

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Cirrhosis of the Liver: Methods and Fields of Research by N. Tygstrup, F. Orlandi (Editor); ISBN: 0444808922; http://www.amazon.com/exec/obidos/ASIN/0444808922/icongroupinterna

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Cirrhosis, Hepatic Encephalopathy, and Ammonium Toxicity (Advances in Experimental Medicine and Biology, 272) by Santiago Grisolia, et al; ISBN: 0306436663; http://www.amazon.com/exec/obidos/ASIN/0306436663/icongroupinterna

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Cirrhosis, Hyperammonemia, and Hepatic Encephalopathy (Advances in Experimental Medicine and Biology, 341) by Santiago Grisolia, Vicente Felipo (Editor) (1994); ISBN: 0306445956; http://www.amazon.com/exec/obidos/ASIN/0306445956/icongroupinterna

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Complications of Liver Cirrhosis: Internationaler Falk - Workshop, Bonn, February 1998 by T. Sauerbruch (Editor), et al (1998); ISBN: 3805567154; http://www.amazon.com/exec/obidos/ASIN/3805567154/icongroupinterna

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Liver Cirrhosis by K. Okita (Editor); ISBN: 4431702946; http://www.amazon.com/exec/obidos/ASIN/4431702946/icongroupinterna

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Liver Cirrhosis (Falk Symposium, Vol 44) by J.L. Boyer, L. Bianchi (Editor) (1987); ISBN: 0852009933; http://www.amazon.com/exec/obidos/ASIN/0852009933/icongroupinterna

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Liver Cirrhosis and its Development (Falk Symposium, Volume 115) by J. L. Boyer (Editor), et al (2001); ISBN: 0792387600; http://www.amazon.com/exec/obidos/ASIN/0792387600/icongroupinterna

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Liver Cirrhosis: Frontiers of Gastrointestinal Research Series by P. Gentilini (Editor), et al (1984); ISBN: 3805537247; http://www.amazon.com/exec/obidos/ASIN/3805537247/icongroupinterna

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Liver Disorders Sourcebook: Basic Consumer Health Information About the Liver, and How It Works; Liver Diseases, Including Cancer, Cirrhosis, Hepatitis and Toxic and Drug Relate by Joyce Brennfleck Shannon (Editor) (2000); ISBN: 0780803833; http://www.amazon.com/exec/obidos/ASIN/0780803833/icongroupinterna

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Molecular Aspects of Primary Biliary Cirrhosis by O. Epstein (Editor) (1986); ISBN: 0080342752; http://www.amazon.com/exec/obidos/ASIN/0080342752/icongroupinterna

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New Trends in Hepatology: The Proceedings of the Annual Meeting of the Italian National Programme on Liver Cirrhosis and Viral Hepatitis, San Miniato (Pisa), Italy, 7-9 january by Paolo Gentilini (Editor), M.U. Dianzani (Editor) (1996); ISBN: 0792387031; http://www.amazon.com/exec/obidos/ASIN/0792387031/icongroupinterna

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Pathogenesis of Sodium Retention & of Ascites Formation in Experimental Cirrhosis in Rates (Acta Biomedica Lovaniensia , No 137) by Guy Van Roey (1996); ISBN: 9061867673; http://www.amazon.com/exec/obidos/ASIN/9061867673/icongroupinterna

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Primary Biliary Cirrhosis - From Pathogenesis to Clinical Treatment by Keith D. Lindor (Editor), et al; ISBN: 0792387406; http://www.amazon.com/exec/obidos/ASIN/0792387406/icongroupinterna

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Progress in Hepatology 4 - Liver Cirrhosis Update by Masami Yamanaka; ISBN: 0444829407; http://www.amazon.com/exec/obidos/ASIN/0444829407/icongroupinterna

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The 2002 Official Patient's Sourcebook on Cirrhosis of the Liver: A Revised and Updated Directory for the Internet Age by Icon Health Publications (2002); ISBN: 0597832641; http://www.amazon.com/exec/obidos/ASIN/0597832641/icongroupinterna

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The Official Patient's Sourcebook on Primary Biliary Cirrhosis by James N., Md. Parker (Editor), et al; ISBN: 0597834024; http://www.amazon.com/exec/obidos/ASIN/0597834024/icongroupinterna

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The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “cirrhosis” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:11 •

Alcoholic cirrhosis and other toxic hepatopathias: symposium, September 29-October 1, 1969 Author: Engel, Arthur,; Year: 1965; Stockholm, Nordiska bokhandelns förlag, 1970

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An approach to the treatment of livercirrhosis [sic] and spontaneous gangrene. Author: Hieda, Kentar¯o.; Year: 1966; Tokyo, Igaku Shoin [1968]

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Biliary cirrhosis [by] Sir Roy Cameron and P. C. Hou (Hou Pao-Chang). Author: Cameron, Gordon Roy.; Year: 1966; Edinburgh, Oliver and Boyd [1962]

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Cirrhosis of the liver: methods and fields of research Author: Tygstrup, Niels.; Year: 1969; Amsterdam; New York: Elsevier; New York, NY, USA: Sole distributors for the USA and Canada, Elsevier Science Pub. Co., 1987; ISBN: 0444808920

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Cirrhosis of the liver mortality in Pennsylvania [by] George K. Tokuhata, Krishnam [sic] Ramaswamy [and] Edward Digon. Author: Tokuhata, George K.; Year: 1965; [Harrisburg] Pennsylvania Dept. of Health, Division of Research and Biostatistics, 1970

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Cirrhosis of the liver. Author: Kleckner, Martin Seler,; Year: 1966; Springfield, Ill., Thomas [c1960]

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Experimental and clinical hepatology: proceedings of the Annual Meeting of the Italian National Programme on Liver Cirrhosis and Viral Hepatitis, San Miniato (Pisa), Italy, 9-11 January 1992 Author: Italian National Programme on Liver Cirrhosis and Viral Hepatitis. Meeting; Year: 1969; Amsterdam; New York: Excerpta Medica; New York, NY, USA: Sole distributors for the USA and Canada, Elsevier Science Pub. Co., c1991; ISBN: 0444893598 http://www.amazon.com/exec/obidos/ASIN/0444893598/icongroupinterna

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Metabolic effects of branched-chain amino acids in patients with liver cirrhosis Author: Eriksson, Ljusk Siw.; Year: 1969; Stockholm: [s.n.], 1981

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Metabolism of 14C-5HT in experimental liver cirrhosis in the rat [by] P. Pentikäinen, M. Kekki & O. Mustala. Author: Pentikäinen, P.; Year: 1967; Helsinki, 1969

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Numerical taxonomy in the classification of cirrhosis: a computer assisted analysis of the material collected by the Copenhagen Study Group for Liver Diseases Author: Winkel, Per.; Year: 1972; [Copenhagen: s.n., 1975?]

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On the risk function for liver cirrhosis Author: Skog, Ole-Jørgen.; Year: 1971; Oslo: National Institute for Alcohol Research, 1982; ISBN: 8271710761

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In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a "Books" button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

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Pathophysiology of the liver: proceedings of the Annual Meeting of the Italian National Programme on Liver Cirrhosis, San Miniato, Italy, 7-9 January 1988 Author: Italian National Programme on Liver Cirrhosis. Meeting; Year: 1970; Amsterdam; New York: Excerpta Medica; New York, NY, USA: Sole distributors for the USA and Canada, Elsevier Science Pub. Co., 1988; ISBN: 0444809988 http://www.amazon.com/exec/obidos/ASIN/0444809988/icongroupinterna

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Plasma volume and renal function in cirrhosis; effects of changing serum albumin concentration and plasma osmolality. Author: McCloy, Randolph M.,; Year: 1965; [Minneapolis] 1966

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Primary biliary cirrhosis Author: Jones, E. Anthony.; Year: 1964; New York: ThiemeStratton, 1981

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Studies of the metabolism of 5HT in experimental cirrhosis in the rat Author: Pentikäinen, Pertti.; Year: 1969; Helsinki: [s.n.], 1970

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Unusual clinical features of cirrhosis and primary liver cell carcinoma, by Luis LeonSotomayor and Victor A. Moore. Author: Leon-Sotomayor, Luis,; Year: 1968; Springfield, Ill., Thomas [c1967]

Chapters on Cirrhosis In order to find chapters that specifically relate to cirrhosis, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and cirrhosis 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 “cirrhosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on cirrhosis: •

Cirrhosis Source: in Okuda, K., ed.,et al. Hepatobiliary Diseases: Pathophysiology and Imaging. Malden, MA: Blackwell Science, Inc. 2001. p. 119-151. Contact: Available from Blackwell Science, Inc. 350 Main Street, Commerce Place, Malden, MA 02148. (800) 215-1000 or (617) 388-8250. Fax (617) 388-8270. E-mail: [email protected]. Website: www.blackwell-science.com. PRICE: $275.00. ISBN: 0632055421. Summary: Cirrhosis (liver scarring) is an end stage of chronic diffuse liver disease. Cirrhosis is characterized by alteration of the normal liver architecture into structurally abnormal nodules of liver cells, surrounded by fibrosis (scar tissue). This chapter on cirrhosis is from a textbook that familiarizes the reader with various imaging modalities, the information they provide, and the merits of each, in order to facilitate the combined use of different imaging techniques in the diagnosis and management of hepatobiliary (liver and bile tract) diseases. Diseases that cause cirrhosis include alcoholic liver disease, chronic viral hepatitis, biliary obstruction, heart failure, metabolic disorders such as copper overload (Wilson's disease), and many others, but alcohol and hepatitis virus are by far the most common etiology. Clinical manifestations including wasting, ascites (fluid accumulation) and edema, splenomegaly (enlarged spleen), esophageal varices (enlarged veins or arteries in the esophagus), and encephalopathy (involvement of the brain tissue). The disease is progressive if it in not treated or if the offending agent

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is not removed, and for advanced cirrhosis, transplantation is the only cure. Most patients with uncomplicated cirrhosis die of variceal bleeding or hepatic (liver) failure. The author discusses epidemiology, pathophysiology, viral cirrhosis, clinical features, ascites and hepatic lymph, hepatic hydrothorax, portal-systemic encephalopathy, imaging features in cirrhosis, prognosis, and less common types of cirrhosis. 51 figures. 64 references. •

Clinical Disorders of Renal Function in Cirrhosis with Ascites Source: in Arroyo, V., et al, eds. Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment. Malden, MA: Blackwell Science, Inc. 1999. p.3662. Contact: Available from Blackwell Science, Inc. 350 Main Street, Malden, MA 02148. (800) 215-1000 or (781)-388-8250. Fax (781) 388-8270. E-mail: [email protected]. Website: www.blackwellscience.com. PRICE: $125.00 plus shipping and handling. ISBN: 0632043423. Summary: During the natural course of cirrhosis (scarring of the liver), a progressive impairment in kidney function occurs and the kidneys are no longer able to maintain the extracellular fluid volume within normal limits. As the disease progresses, a vasoconstriction of the renal circulation usually develops, which causes renal hypoperfusion and reduced glomerular filtration rate (GFR) and, eventually, renal failure (the so-called hepatorenal syndrome). This chapter on clinical disorders of renal (kidney) function in cirrhosis with ascites is from a textbook on ascites and renal dysfunction in liver disease. The authors describe the functional kidney abnormalities of cirrhosis. The authors emphasize the description of clinical aspects of these abnormalities. A general description of the pathogenetic factors contributing to kidney dysfunction is also included. Topics include sodium (salt) retention, water retention, and renal vasoconstriction and hepatorenal syndrome. The last section of the chapter describes other less common abnormalities of kidney function that may also be found in cirrhosis, including acute tubular necrosis (ATN), glomerular abnormalities, renal tubular acidosis (RTA), and drug-induced kidney failure. 8 figures. 4 tables. 187 references.

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Primary Biliary Cirrhosis: Diagnosis and Treatment Source: in McDonald, J.W.D.; Burroughs, A.K.; Feagan, B.G., eds. Evidence Based Gastroenterology and Hepatology. London, UK: BMJ Publishing Group. 1999. p. 345359. Contact: Available from BMJ Publishing Group. BMA Books, BMA House, Tavistock Square, London WCIH 9JR. Fax 44 (0)20 7383 6402. E-mail: [email protected]. Website: www.bmjbooks.com. PRICE: Contact publisher for price. Summary: Primary biliary cirrhosis (PBC) is an inflammatory disease of the interlobular and septal bile ducts of the liver; the disease is thought to be immune-mediated. Granulomatous destruction of these bile ducts leads to duct deficiency and hence, persistent cholestasis (stoppage of the flow of bile). Progressive fibrosis and eventual cirrhosis develop and liver failure is a terminal event unless intervention with a liver transplant occurs. This chapter on the diagnosis and treatment of PBC is from a book that emphasizes the approaches of evidence based medicine in gastroenterology (the study of the gastrointestinal tract and gastrointestinal diseases) and hepatology (the study of the liver and liver diseases). The author of this chapter notes that PBC may be diagnosed in several situations. Most commonly (60 percent of the time), PBC is

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diagnosed in a patient without symptoms, but with anicteric cholestatic biochemical tests, with a positive serological test for AMA (antimitochondrial antibodies), and with a diagnostic or confirmatory biopsy. Symptoms typical of PBC, such as fatigue, do not correlate with the severity of disease. However, the degree of hyperbilirubinemia has been shown to correlate extremely well with survival. Treatment with ursodeoxycholic acid (UDCA) is not curative. It may delay the progression of disease in some patients, but the evidence for this benefit is not clear. Several small trials of UDCA in combination with methotrexate, colchicine, and prednisolone have been conducted, but no study has been large enough to adequately assess the effectiveness of these drugs. Prognostic research indicates that liver transplantation leads to a marked survival benefit in patients with PBC. Currently, transplantation remains the only curative therapy for this disease. 1 table. 91 references. •

Hepatic Cirrhosis Source: in Sherlock, S.; Dooley, J. Diseases of the Liver and Biliary System. Malden, MA: Blackwell Science, Inc. 2002. p.365-380. Contact: Available from Blackwell Science, Inc. 350 Main Street, Commerce Place, Malden, MA 02148. (800) 215-1000 or (617) 388-8250. Fax (617) 388-8270. E-mail: [email protected]. Website: www.blackwell-science.com. PRICE: $178.95. ISBN: 0632055820. Summary: This chapter on hepatic cirrhosis (scarring of the liver) is from a textbook that presents a comprehensive and up-to-date account of diseases of the liver and biliary system. Cirrhosis is defined anatomically as a diffuse process with fibrosis and nodule formation. The chapter covers classification of cirrhosis, clinical cirrhosis, compensated cirrhosis, decompensated cirrhosis, prognosis, and treatment strategies. In cirrhosis, directed biopsies, using ultrasound or CT and a Trucut needle, are particularly helpful in obtaining adequate samples and avoiding other viscera, especially the gallbladder. The prognosis is determined by the extent of hepatocellular failure. Jaundice, spontaneous bruising, and ascites resistant to treatment are grave signs. Treatment options include nutrition, anti-fibrotic drugs, and surgery, although the latter is high risk and carries a high mortality in patients with cirrhosis. 14 figures. 4 tables. 84 references.

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Diagnosis and Therapy of Cirrhosis and Its Complications Source: in Danzi, J.T.; Scopelliti, J.A., eds. Office Management of Digestive Diseases. Malvern, PA: Lea and Febiger. 1992. p. 152-167. Contact: Available from Lea and Febiger. Box 3024, Malvern, PA 19355-9725. (215) 2512230. PRICE: $39.50. ISBN: 0812114361. Summary: This chapter, from a medical textbook about the office management of common gastrointestinal diseases, discusses the diagnosis and therapy of cirrhosis and its complications. Topics include ascites, including mechanism of formation, a rational approach to treatment, and the use of diuretics; spontaneous bacterial peritonitis, including the source of bacteria, immunologic disturbances in cirrhotics, its clinical features, and recommended treatment; and hepatic encephalopathy, its manifestations and treatment. One appendix lists a sample 1000-mg sodium diet plan. 2 figures. 3 tables. 57 references.

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Directories In addition to the references and resources discussed earlier in this chapter, a number of directories relating to cirrhosis have been published that consolidate information across various sources. The Combined Health Information Database lists the following, which you may wish to consult in your local medical library:12 •

1998-1999 Complete Directory for People with Rare Disorders Source: Lakeville, CT: Grey House Publishing, Inc. 1998. 726 p. Contact: Available from Grey House Publishing, Inc. Pocket Knife Square, Lakeville, CT 06039. (860) 435-0868. Fax (860) 435-0867. PRICE: $190.00. ISBN: 0939300982. Summary: This directory, from the National Organization for Rare Disorders (NORD) provides a wealth of information on diseases and organizations. The directory offers four sections: disease descriptions, disease specific organizations, umbrella organizations, and government agencies. In the first section, the directory includes descriptions of 1,102 rare diseases in alphabetical order. Each entry defines the disorder, then refers readers to the organizations that might be of interest. Diseases related to digestive diseases include achalasia, Addison's disease, Alagille syndrome, Barrett's esophagus, Budd Chiari syndrome, Caroli disease, celiac sprue, cholangitis, cholecystitis, cirrhosis, colitis, Crohn's disease, Cushing syndrome, cystic fibrosis, diverticulitis, Dubin Johnson syndrome, fructose intolerance, galactosemia, gastritis, gastroesophageal reflux, hepatitis, Hirschprung's disease, Hurler syndrome, imperforate anus, irritable bowel syndrome, jejunal atresia, Korsakoff's syndrome, lipodystrophy, maple syrup urine disease, Morquio syndrome, polyposis, porphyria, proctitis, prune belly syndrome, sarcoidosis, Stevens Johnson syndrome, Tropical sprue, tyrosinemia, valinemia, vitamin E deficiency, Whipple's disease, Wilson's disease, and Zollinger Ellison syndrome. Each of the 445 organizations listed in the second section is associated with a specific disease or group of diseases. In addition to contact information, there is a descriptive paragraph about the organization and its primary goals and program activities. Entries include materials published by the organization as well as the diseases the organizations cover, which refer readers to Section I. The third section lists 444 organizations that are more general in nature, serving a wide range of diseases (for example, the American Liver Foundation). The final section describes 74 agencies that are important federal government contacts that serve the diverse needs of individuals with rare disorders. A name and key word index concludes the volume.

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You will need to limit your search to “Directory” and “cirrhosis” using the "Detailed Search" option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find directories, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Select your preferred language and the format option “Directory.” Type “cirrhosis” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months.

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CHAPTER 8. MULTIMEDIA ON CIRRHOSIS Overview In this chapter, we show you how to keep current on multimedia sources of information on cirrhosis. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.

Video Recordings An excellent source of multimedia information on cirrhosis is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “cirrhosis” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Videorecording (videotape, videocassette, etc.).” Type “cirrhosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on cirrhosis: •

Hepatitis A Source: Princeton, NJ: Films for the Humanities and Sciences. 1997. (videocassette). Contact: Available from Films for the Humanities and Sciences. P.O. Box 2053, Princeton, NJ 08543-2053. (800) 257-5126 or (609) 275-1400. Fax (609) 275-3767. E-mail: [email protected]. Website: www.films.com. PRICE: $99.00; plus shipping and handling. Order number BXA7388. Summary: Hepatitis A, a viral infection of the liver, was once thought to be a problem of developing countries, where water supplies are often contaminated and sewage facilities may be inadequate. But in the past 15 years, more than 30 outbreaks have occurred in the United States. This program, hosted by Nancy Duerr and featuring Dr. Harold Margolis of the Centers for Disease Control and Prevention, explains current knowledge about this strain of the hepatitis virus and its causes, treatment, and prevention. The program is designed like a news report and begins with an overview of the role and functions of the liver. The program then reviews the various forms of the

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hepatitis virus, noting that all forms cause liver inflammation and cirrhosis and can cause symptoms like the flu, dark urine, or jaundice (yellowing of the skin). The narrators review the way each type is transmitted, the symptoms, the treatment and side effects, the prognostic factors, the availability of immunization, and the risk factors. The program goes into more depth on hepatitis A, interviewing patients and health care providers. Topics discussed are risk groups, including children in day care and people living in institutions or in crowded housing units; transmission; the geography of recent U.S. outbreaks; the symptoms of the disease; and treatment options, which are available only for the symptoms, since there is no treatment against the virus itself. The program notes that about 1 percent of people with hepatitis A develop fulminant hepatitis, which may need to be treated with liver transplantation. Another section reminds viewers of the risks of international travel and the importance of pretravel immunization. The program concludes with information about the American Liver Foundation (888-4437222) and a brief interview with Thelma King Theil, the chair of the Hepatitis Foundation International. •

Hepatitis C: The Silent Scourge Source: Princeton, NJ: Films for the Humanities and Sciences. 1996. (videocassette). Contact: Available from Films for the Humanities and Sciences. P.O. Box 2053, Princeton, NJ 08543-2053. (800) 257-5126 or (609) 275-1400. Fax (609) 275-3767. E-mail: [email protected]. Website: www.films.com. PRICE: $99.00 plus shipping and handling. Order number CAF6419. Summary: Hepatitis C virus (HCV) is a disease that is transmitted primarily by contact with infected blood and that manifests few symptoms. As many as 3.5 million people in the United States are believed to carry the virus, and many are not even aware that they have been exposed; 10,000 die from it each year. This program, hosted by Drs. Miriam Alter and Harold Margolis of the Centers for Disease Control and Prevention (CDC), explains current knowledge about the newest strain of the hepatitis virus, and its causes, treatment, and prevention. The program is designed like a news report and begins with an overview of the role and functions of the liver. The program then reviews the various forms of the hepatitis virus, noting that all of them cause liver inflammation and cirrhosis and can lead to symptoms like the flu, dark urine, or jaundice (yellowing of the skin). The narrators review the ways each type is transmitted, the symptoms, the treatment and side effects, prognostic factors, the availability of immunization, and risk factors. The program goes into more depth on hepatitis C, interviewing patients and health care providers. A brief section describes the use of liver transplantation as the final option for end stage liver failure caused by hepatitis. Another section interviews Thelma King Theil, the chair of the Hepatitis Foundation International, who focuses on the activities of the organization, particularly those related to prevention.

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Gastroenterology for the Primary Care Physician Source: Mount Laurel, NJ: CME Conference Video, Inc. 1994. (instructional package). Contact: Available from CME Conference Video, Inc. 2000 Crawford Place, Suite 100, Mount Laurel, NJ 08054. (800) 284-8433. Fax (800) 284-5964. PRICE: $450 plus $12.25 shipping and handling (as of 1995); group practice package available. Program No. 153. Summary: This continuing education course is designed to update internists, family practitioners, and other primary care physicians on new developments in gastroenterology. The format of the course focuses on case presentations emphasizing important and evolving concepts in gastroenterology. The emphasis is on practical

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diagnostic and therapeutic choices and the development of cost effective management algorithms. Topics include hepatitis C, non-cardiac chest pain, psychopharmacologic approaches to acid reduction, peptic ulcer disease, Helicobacter pylori, risk factors for NSAID injury, Clostridium difficile, travelers' diarrhea, constipation in the elderly, pancreatitis, endoscopic ultrasound, gastroesophageal reflux disease, Barrett's esophagus, liver disease, GI manifestations in AIDS, esophagitis, fecal incontinence, diagnostic testing, irritable bowel syndrome, inflammatory bowel disease, drug therapy, chronic diarrhea, gallstone disease, colon cancer, cirrhosis, and ascites. The program offers 11 hours of AMA-PRA Category 1 credit. (AA-M). •

Hepatitis B: The Enemy Within Source: Princeton, NJ: Films for the Humanities and Sciences. 1996. (videocassette). Contact: Available from Films for the Humanities and Sciences. P.O. Box 2053, Princeton, NJ 08543-2053. (800) 257-5126 or (609) 275-1400. Fax (609) 275-3767. E-mail: [email protected]. Website: www.films.com. PRICE: $99.00 plus shipping and handling. Order number CAF6423. Summary: This program, featuring Dr. Harold Margolis and Dr. Frank Mahoney of the Centers for Disease Control and Prevention, explains current knowledge about hepatitis B, and its causes, treatment, and prevention. The program is designed like a news report and begins with an overview of the role and functions of the liver. The program then reviews the various forms of the hepatitis virus, noting that all forms cause liver inflammation and cirrhosis and can cause symptoms like the flu, dark urine, or jaundice (yellowing of the skin). The narrators then review how each type of hepatitis is transmitted, the symptoms, the treatment and side effects, prognostic factors, the availability of immunization, and risk factors for hepatitis A and C. The program then goes into more depth on hepatitis B, interviewing patients and health care providers. One young woman (age 26) who contracted hepatitis B at birth, describes her experiences with the disease and the psychosocial impact it has had on her life. The program discusses occupational risk factors, transmission, the geographic incidence and prevalence of hepatitis B, its typical course, and the problems associated with the development of chronic active hepatitis. A brief section describes the use of liver transplantation as the final option for end stage liver failure caused by hepatitis. The program then focuses on immunization programs, including those designed to vaccinate babies at birth, infants (during routine immunization), and adolescents. There is also some discussion about the difficulties of instituting successful vaccination programs for some high risk groups, including intravenous (IV) drug users and people with multiple sexual partners.

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Hepatitis 101: Basic Tools for Teaching Liver Wellness and Hepatitis Prevention Source: Silver Spring, MD: Hepatitis Foundation International. 2002. (videorecording). Contact: Available from Hepatitis Foundation International. 504 Blick Drive, Silver Spring, MD 20904. (800) 891-0707. Fax: (301) 622-4702. E-mail: [email protected]. Website: www.hepfi.org. PRICE: $37.00; plus shipping and handling. Summary: This tutorial videotape was developed to help teachers, counselors, outreach workers, and health professionals offer effective and easy to communicate messages about liver wellness, and the prevention of viral hepatitis and substance abuse. Viral hepatitis is a disease caused by viruses that damage the liver. Serious cases can lead to life-threatening liver cirrhosis (or scarring), liver failure and eventually liver cancer. The most common forms of viral hepatitis include hepatitis A, hepatitis B and hepatitis C.

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This program focuses on hepatitis C and the risk factors that increase one's likelihood of contracting the disease, notably substance abuse. The program uses memorable analogies that everyone can relate to in their daily lives to motivate individuals to avoid liver damaging activities and to adopt healthier lifestyle behaviors. •

Basics of Alpha 1-Antitrypsin Liver Disease Source: Washington, DC: Alpha-1 Association. 200x. (videorecording). Contact: Available from Alpha-1 Association. 1225 Eye Street NW, Suite 1225, Washington, DC 20005-5918. (800) 521-3025 or (202) 887-1900. Fax: (202) 887-1964. Website: www.alpha1.org. E-mail: [email protected]. PRICE: Contact organization for copies. Summary: This videocassette depicts a slide lecture program given by Dr. Jeffrey Teckman at an Alpha-1 Association conference. Dr. Teckman describes the physiology and chemistry of the alpha-antitrypsin system, then the pathophysiology of alpha1antitrypsin deficiency. Dr. Teckman uses highly technical language, but then defines his terms and uses graphics to explain how the pathophysiology works (not all slides to which he refers are included in this videotape). Dr. Teckman also discusses the complications that are seen with this common, but underdiagnosed, genetic liver disease, including chronic hepatitis (liver inflammation), cirrhosis (scarring of the liver), liver cancer, and emphysema. Other topics include the Swedish research study that provided a great deal of basic information about this disease, the genetics, screening, diagnosis, the role of liver biopsy in diagnosis, and treatment options. The program concludes with a section of questions from the lecture audience, along with Dr. Teckman's answers.

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Hepatitis C: Unknown Epidemic Source: Princeton, NJ: Films for the Humanities and Sciences. 1998. (videocassette). Contact: Available from Films for the Humanities and Sciences. P.O. Box 2053, Princeton, NJ 08543-2053. (800) 257-5126 or (609) 275-1400. Fax (609) 275-3767. E-mail: [email protected]. Website: www.films.com. PRICE: $99.00 to purchase; $75.00 for rental; plus shipping and handling. Order number BVL9342. Summary: This videotape offers a segment of ABC's Nightline program that explores the epidemic of hepatitis C virus (HCV) infection in the United States. In this program, ABC News anchor Forrest Sawyer investigates the virus with Dr. Miriam Alter, epidemiologist at the Centers for Disease Control and Prevention; Dr. Jerome Groopman, professor at Harvard Medical School; and Andi Thomas, founder of the advocacy group Hep-C ALERT. Together they examine topics including risk factors associated with the disease, improvements in blood screening, the results of targeted looks back at past blood recipients, and the need for additional funding to increase research. Hepatitis C is characterized as a definite health epidemic: 15 percent of the people who get infected successfully fight it off; in 80 percent of those infected, the disease becomes chronic; and in 5 percent of those infected, HCV results in liver cirrhosis (scar tissue), which can then lead to cancer and death. It is virtually impossible to predict who will be in which category. The disease is spread predominantly through needle sharing, sexual contact, and blood transfusions occurring prior to the 1990's. The disease has been called the silent epidemic because it was only identified 10 years ago and the infection remains symptomless for decades. The three panelists interviewed share their information and differences of opinions on the wisdom of getting tested for HCV, the magnitude of the public health problem of the disease, the need for targeted

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look back for people who received blood transfusions, and the emotions of dealing with the disease. •

Hidden Epidemic: Unraveling the Mysteries of Hepatitis C Source: Silver Spring, MD: Hepatitis Foundation International. 2002. (videorecording). Contact: Available from Hepatitis Foundation International. 504 Blick Drive, Silver Spring, MD 20904. (800) 891-0707. Fax: (301) 622-4702. E-mail: [email protected]. Website: www.hepfi.org. PRICE: $45.00; plus shipping and handling. Summary: This videotape program provides an overview of hepatitis A, hepatitis B, and hepatitis C, with an emphasis on the latter. The program includes interviews with liver specialists, hepatitis patients, and patient advocated. The program includes basic information on the physiology of the liver, cirrhosis (scarring of the liver), treatment options, transplantation, and coping skills (managing a chronic disease). The video is designed to education patients, family members, and the general public about viral hepatitis.

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Your Liver Source: Bronx, NY: Latin Organization for Liver Awareness. 199x. (videocassette). Contact: Available from Latino Organization for Liver Awareness (LOLA). 1560 Mayflower Avenue, Bronx, New York, NY 10465. (718) 892-8697. Fax (718) 918-0527. (888) 367-LOLA. PRICE: $10.00; plus shipping and handling. Summary: This videotape program reviews the physiology of the liver, and describes different types of liver disease, focusing on hepatitis. Narrated by Debbie Delgado-Vega, a liver transplant recipient and advocate and educator in the field, the program first summarizes the functions of the liver. The liver stores vitamins and minerals, makes bsoleilwelile to help digestion, detoxifies chemicals, stores energy, removes poisons and pollutants that may be ingested from the air, makes clotting factors, and defends against germs that cause disease. The program then lists the types of liver disease, including liver disorders in children, alcohol related liver disease, liver cancer, cirrhosis (scarring), and viral hepatitis (inflammation of the liver due to viral infection). The program discusses hepatitis in depth, explaining the differences between acute disease (less than 6 months in duration) and chronic disease; the numbers of people in the United States with hepatitis B (1.2 million) and hepatitis C (4.8 million); the complications of chronic hepatitis that can lead to cirrhosis (inflammation, scarring and nodules); symptoms, notably fatigue; how hepatitis B and C are transmitted in blood and other body fluids; other risk factors, including the use of intranasal cocaine, intravenous drugs, tattoos or body piercing, pre 1992 blood transfusion, unprotected sex, and having served time in jail; treatment options, including interferons and ribavirin; and why it is important to get tested and treated, even if there are no apparent symptoms. The narrator stresses that more Latinos die from liver disease than any other minority group and chronic liver disease is the third leading cause of death among Latinos. The conclusion of the program shows clips and materials from educational programs and public health and advocacy activities conducted by LOLA (Latino Organization for Liver Awareness). The program is narrated in English, with some clips at the end in Spanish.

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Diagnosing Alpha 1 Antitrypsin Deficiency Source: Minneapolis, MN: Alpha 1 Association. 199x. (videocassette).

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Contact: Available from Alpha 1 Association. 8120 Penn Avenue, South, Suite 549, Minneapolis, MN 55431-1326. (800) 521-3025 or (612) 703-9979. Fax (612) 703-9977. Email: [email protected]. Website: www.alpha1.org. PRICE: $3.00 plus shipping and handling. Summary: This videotape program, narrated by Sandra Brandley, the Executive Director of the Alpha 1 National Association, reminds physicians of the symptoms and differential diagnosis of alpha 1 antitrypsin deficiency (A1AD or Alpha 1). The program features Dr. James Stoller, who describes the typical underdiagnosis of A1AD which is typical: the mean time until diagnosis is 7 years (from onset of symptoms) and the mean number of doctors consulted before diagnosis is 3.5. Alpha 1 is a relatively common genetic disorder that affects infants, children, and adults. It is the most common metabolic disorder that causes liver disease in infants and children; the disorder also causes cirrhosis and cancer of the liver in adults. Symptoms of A1AD deficiency in children include prolonged obstructive jaundice, low birth weight, mildly elevated liver enzymes, cholestasis, enlarged liver, abnormal bleeding, feeding difficulties, poor growth (or failure to thrive), and ascites (abnormal accumulation of fluids). In adults, the spectrum of liver disease associated with A1AD deficiency varies from mild to severe. Symptoms include chronic active hepatitis, cryptogenic cirrhosis (liver scarring of unknown cause), portal hypertension (high blood pressure in the portal vein of the liver), and hepatocellular carcinoma (liver cancer). A rare but telling symptom is panniculitis, a chronic inflammation of subcutaneous fat featuring ulcerated skin lesions on the torso. Dr. Stoller reminds viewers of the indications for A1AD screening: premature onset of moderate to severe chronic obstructive pulmonary disease (COPD) before age 50; predominant basilar emphysema; chronic bronchitis with airflow obstruction in a nonsmoker; bronchiectasis (irreversible dilation and destruction of the bronchial walls) without clear risk factors; development of unremitting asthma; family history of A1AD; cirrhosis without apparent risk factors; and family history of panniculitis. The program includes a chart of laboratory values and the risk of development of A1AD, and a series of interviews with patients about the interplay of early diagnosis and good quality of life. The program concludes with the contact information for the Alpha 1 National Association (800-521-3025). •

Healthy Liver-A Happier Life! Source: Cedar Grove, NJ: American Liver Foundation. 199x. Contact: Available from American Liver Foundation. 1425 Pompton Avenue, Cedar Grove, NJ 07009. (800) 223-0179 or (201) 256-2550. PRICE: $45 for video; $10 for resource packet; $50 if both are ordered. Summary: This videotape, produced by the American Liver Foundation, highlights lifegiving functions of the liver and ways to take care of it. The focus of the videotape is on prevention, describing how the liver can be seriously damaged, without warning, by viruses, drugs, alcohol, and other chemicals. Topics include liver cirrhosis and how it affects liver function; hepatitis viruses, notably hepatitis A, B, and C; the impact of vitamins and food supplements on the liver; and diagnostic tests. The video and accompanying printed materials are designed as supplements to existing substance and alcohol abuse prevention programs in schools, clinics, and businesses encouraging the adoption of healthier lifestyles. (AA-M).

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Viral Hepatitis and Blood Borne Pathogens: The Invisible Threat Source: Silver Spring, MD: Hepatitis Foundation International. 2002. (videorecording).

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Contact: Available from Hepatitis Foundation International. 504 Blick Drive, Silver Spring, MD 20904. (800) 891-0707. Fax: (301) 622-4702. E-mail: [email protected]. Website: www.hepfi.org. PRICE: $45.00; plus shipping and handling. Summary: Viral hepatitis is a disease caused by viruses that damage the liver. Serious cases can lead to life-threatening liver cirrhosis (or scarring), liver failure and eventually liver cancer. The most common forms of viral hepatitis include hepatitis A, hepatitis B and hepatitis C. This program focuses on hepatitis B and C and the risk factors that increase one's likelihood of contracting the disease, notably substance abuse. The video is designed for an adult audience. Topics include prevention of hepatitis B and C, AIDS, substance abuse, cirrhosis, and transmission of hepatitis. •

Update on Management of Hepatitis C Source: Kansas City, MO: American Academy of Family Physicians. 2000. (videocassette). Contact: Available from American Academy of Family Physicians. 8880 Ward Parkway, Kansas City, MO 64114-2797. (800) 274-2237. PRICE: $17.95 for members; $25.00 for nonmembers, plus shipping and handling. Summary: Viral hepatitis remains the most common cause of liver disease worldwide and infection with the hepatitis C virus (HCV) has become a serious health problem in the United States. This continuing education program assists family physicians in this new challenge of the identification and diagnosis of patients at greatest risk of HCV infection. While there is, as yet, no known cure for HCV, early medical intervention and lifestyle changes can significantly improve the prognosis. Infection with HCV can lead to chronic hepatitis, cirrhosis (liver scarring), and hepatocellular carcinoma (HCC, liver cancer). Unlike hepatitis A and B, there is no vaccination available to prevent hepatitis C, nor are there any preexposure or postexposure prophylaxis (prevention) options. This program reviews the epidemiology of HCV, identification of patients at risk, diagnosis, HCV related liver disease, and management approaches, including interferon monotherapy, combination therapy, side effects, contraindications, and ongoing medical monitoring. The program includes a video tape and a study guide; the latter includes references and a patient education handout, as well as a posttest with which viewers can qualify for continuing education credit. 6 figures. 13 tables. 31 references.

Audio Recordings The Combined Health Information Database contains abstracts on audio productions. To search CHID, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find audio productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Sound Recordings.” Type “cirrhosis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for sound recordings on cirrhosis: •

Fear of the Unknown: Anxiety & Stress in Caring for Patients With AIDS & Hepatitis B: 3rd National Forum on AIDS and Hepatitis B, Washington, D.C., November 21 - 23, 1988 Contact: Sound Solution, PO Box 566074, Dallas, TX, 75356, (214) 258-6144.

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Summary: This sound recording covers a workshop on fear of the unknown, especially as it relates to Acquired immunodeficiency syndrome (AIDS). The moderator opens the session with a discussion of Hepatitis B. He says that 25,000 cases are reported to the Centers for Disease Control and Prevention (CDC) each year, primarily among young adults, but it is estimated that 300,000 persons become infected each year. Approximately 4,000 deaths each year result from cirrhosis of the liver following Hepatitis B infection, and 800 deaths each year from liver cancer. He says that Hepatitis B among health-care workers is decreasing since recombinant vaccines were developed, but the infection among Intravenous drug users (IVDU's) continues to rise. Next, Dr. Hassib Aoun, a former holder of a fellowship in cardiology at Johns Hopkins Hospital, describes his experiences following his infection with Human immunodeficiency virus (HIV) after a laboratory accident in 1983. A capillary tube of blood that he was planning to test shattered and cut his finger. Three years later, he developed AIDS. Although the original accident was documented, and the patient's blood was later tested for AIDS, (there were no antibody tests in 1983) the hospital accepted no responsibility for his illness and provided no compensation or insurance coverage. He says he still believes that health-care workers should never deny care to AIDS patients, but if they are expected to risk their lives providing this care, they should be protected economically with appropriate insurance. Dr. Jeff Hackman, Assistant Professor of Psychiatry and Behavioral Medicine at George Washington University Medical Center, then discusses a project to train health-care workers in the medical and mental health aspects of AIDS. A battery of attitude questionnaires given to second-year medical students revealed that 75 per cent were worried about contracting AIDS, and 80 per cent felt that in the future, AIDS would prove to be more infectious than it is considered today. Fifty percent of the medical students believed that they could contract AIDS from the routine care of an AIDS patient. They also said that their families were more frightened and less supportive of AIDS patients than the medical students themselves.

Bibliography: Multimedia on Cirrhosis The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in cirrhosis (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on cirrhosis: •

Alcoholic cirrhosis [slide] Source: Association of Pathology Chairmen and National Medical Audiovisual Center; Year: 1975; Format: Slide; Atlanta: The Center, 1975

•

Anterior segmentectomy to the hepatocellular carcinoma with cirrhosis [videorecording] Source: produced by Studio Black and MTC; Year: 1990; Format: Videorecording; [United States?: s.n., 1990]

•

Biliary cirrhosis [videorecording] Source: Emory University School of Medicine; Year: 1974; Format: Videorecording; Atlanta: Georgia Regional Medical Television Network, [1974]

•

Care of the patient with cirrhosis [filmstrip] Source: Trainex Corporation; Year: 1970; Format: Filmstrip; Garden Grove, Calif.: Trainex, c1970

•

Cirrhosis [electronic resource] Source: Helene S. Charron, Roxanne L. Saxton; Year: 1984; Format: Electronic resource; Edwardsville, KS: Medi-Sim, c1984

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•

Cirrhosis [videorecording] Source: developed by Michael S. Shaw, David M. Taylor; [produced by] National Medical Audiovisual Center; Year: 1979; Format: Videorecording; [Bethesda, Md.]: Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, National Library of Medicine, 1979

•

Cirrhosis of the liver [videorecording] Source: NHV, National Health Video Inc; Year: 1998; Format: Videorecording; Los Angeles, CA: National Health Video; Medical Audio Visual Communications [distributor], c1998

•

Complications of cirrhosis [slide] Source: [authors, Emmet B. Keeffe. et al.]; Year: 1996; Format: Slide; [United States]: American Gastroenterological Association, c1996

•

Laparoscopic hepatic resection for hepatocellular carcinoma in a patient with advanced liver cirrhosis [videorecording]; Laparoscopic splenectomy with balloon occlusion of the splenic artery; Laparoscopic discectomy with anterior interbody fusion of L5-S1; A reproducible animal model for laparoscopic retroperitoneal aortobifemoral bypass in aortoiliac occlusive disease Year: 1996; Format: Videorecording; Woodbury, Conn.: Ciné-Med, [1996]

•

Mr. Hansie [electronic resource]: a gentleman with cirrhosis. Year: 1986; Format: Electronic resource; Philadelphia, PA: Lippincott, c1986

•

Systematic subsegmentectomy for small hepatocellular carcinoma associated with cirrhosis [videorecording]: total resection of the antero-superior area Source: produced by Institute of Medical A-V Education; Year: 1985; Format: Videorecording; Danbury, Conn.: Davis & Geck Surgical Film-Video Library, [1985]

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CHAPTER 9. PERIODICALS AND NEWS ON CIRRHOSIS Overview In this chapter, we suggest a number of news sources and present various periodicals that cover cirrhosis.

News Services and Press Releases One of the simplest ways of tracking press releases on cirrhosis 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 “cirrhosis” (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 cirrhosis. 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 “cirrhosis” (or synonyms). The following was recently listed in this archive for cirrhosis: •

Betaretrovirus infection linked to primary biliary cirrhosis Source: Reuters Medical News Date: June 23, 2003

•

Sclerotherapy should not be first-line treatment for variceal bleeding in cirrhosis Source: Reuters Industry Breifing Date: June 13, 2003

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•

Adjunctive spironolactone reduces portal hypertensive complications of cirrhosis Source: Reuters Industry Breifing Date: January 31, 2003

•

IGF-1 levels predict liver cancer in patients with HCV-related cirrhosis Source: Reuters Medical News Date: December 20, 2002

•

Wine consumption does not decrease cirrhosis risk Source: Reuters Medical News Date: November 06, 2002

•

No excess prevalence of hepatitis A seen in US patients with cirrhosis Source: Reuters Medical News Date: October 22, 2002

•

Vitamin K prevents bone loss in women with cirrhosis Source: Reuters Medical News Date: May 27, 2002

•

Excess alcohol use greatly increases cirrhosis risk in hemochromatosis patients Source: Reuters Medical News Date: March 12, 2002

•

Cause of scarring in cirrhosis identified Source: Reuters Health eLine Date: October 25, 2001

•

Cannabinoid receptor antagonist reverses cirrhosis-related systemic vasodilation Source: Reuters Industry Breifing Date: July 05, 2001

•

Study in rats gives clue to cirrhosis treatment Source: Reuters Health eLine Date: July 02, 2001

•

Cirrhosis patients should be screened for esophageal varices Source: Reuters Medical News Date: April 09, 2001

•

Heavy alcohol use greatly increases cirrhosis risk in hepatitis C-infected patients Source: Reuters Medical News Date: January 16, 2001

•

Prevalence of primary biliary cirrhosis in US exceeds rates in Europe Source: Reuters Medical News Date: December 20, 2000 The NIH

Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine.

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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 “cirrhosis” (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 “cirrhosis” (or synonyms). If you know the name of a company that is relevant to cirrhosis, 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/. 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 “cirrhosis” (or synonyms).

Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “cirrhosis” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on cirrhosis: •

More Iron Overload Screening Recommended Source: Tufts University Health and Nutrition Letter. 18(11):7. January 2001.

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Contact: 10 High Street, Suite 706, Boston, MA 02110. [email protected]. www.healthletter.tufts.edu. Summary: Iron overload, or hemochromatosis, is the most common genetic disorder in the United States, affecting about 5 people per 1,000. Hemochromatosis affects primarily Caucasians of northern European descent. Researchers at the University of Utah School of Medicine say that not enough men and women are screened for the disorder. Complications arise because the body absorbs too much iron from foods due to defective metabolism. The excess iron deposits itself in body tissues, causing everything from cirrhosis of the liver to arthritis to diabetes to congestive heart failure. Once the disorder is diagnosed, people have to go for bloodletting a few times a year in order to avoid the complications because much of the excess iron is stored in the red blood cells. The University of Utah research team believes that all Caucasians should undergo screening at least once in young adulthood. Screening involves a blood test that measures transferrin saturation, which is a marker for iron status. •

Sjogren's Syndrome and the Gastrointestinal Tract Source: Moisture Seekers Newsletter. 17(2): 1, 4-5. March 1999. Contact: Available from Sjogren's Syndrome Foundation, Inc. 8120 Woodmont Avenue, Suite 530, Bethesda, MD 20814-1437. (301) 718-0300 or (800) 475-6473. Fax (301) 718-0322. Website: www.sjogrens.org. Summary: This article on Sjogren's syndrome (SS) and the gastrointestinal tract is from a patient education newsletter for people with SS. The author outlines the areas where the gastroenterologist may play a role in caring for the person with SS, such as dealing with swallowing difficulties, dyspepsia (indigestion), diarrhea, and jaundice (usually due to primary biliary cirrhosis, or scarring). Difficulty in swallowing is usually due to the lack of saliva associated with SS, but occasionally it may be due to a blockage (postcricoid web) or a weakness of the muscle contractions involved in swallowing. In addition, those patients with SS are vulnerable to acid reflux, which causes heartburn symptoms. Children with SS are prone to achalasia, a type of muscle problem involving the lower esophageal sphincter. Dyspepsia (indigestion) is relatively common in patients with SS, as is inflammation of the stomach (gastritis). The author briefly discusses the role of the bacterium Helicobacter pylori in gastritis. There are at least two diseases associated with SS and diarrhea: chronic pancreatitis and celiac disease (gluten intolerance). The author notes that the link between SS and gastroenterological conditions is often via abnormal autoantibodies.

•

Alcohol and the Liver Source: Alcohol Alert. Number 19: 1-4. January 1993. Contact: Available from National Institute on Alcohol Abuse and Alcoholism. Scientific Communications Branch, Office of Scientific Affairs, 6000 Executive Boulevard, Suite 409, Bethesda, MD 20892-7003. (800) 729-6686. Summary: This issue of Alcohol Alert focuses on the impact of alcohol on the liver. The issue provides information about the normal liver; alcoholic liver disease, including fatty liver, alcoholic hepatitis and cirrhosis; incidence of alcohol-related cirrhosis; mechanisms by which alcohol injures the liver, including diet, genetics, free radicals and acetaldehyde, nonalcoholic hepatitis, the immune system, liver metabolism, gender, and environmental factors; and treatment for alcoholic hepatitis and for cirrhosis. The

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author stresses abstinence as the cornerstone of therapy for alcoholic liver disease. 45 references. •

Adverse Effects of Systemic Psoriasis Treatments: Methotrexate Source: National Psoriasis Foundation Forum. 3(4): 4-5. Winter 1997. Contact: Available from National Psoriasis Foundation. 6600 SW 92nd Avenue, Suite 300, Portland, OR 97223-7195. (503) 244-7404. Fax (503) 245-0626. Summary: This newsletter article provides health professionals with information on the adverse effects of methotrexate, which is one of the most effective drugs available for treating psoriasis. The main adverse effect is hepatoxicity, as confirmed by various studies. Patients who are alcoholic, obese, or diabetic are at greater risk of developing cirrhosis of the liver when treated with methotrexate. Other side effects include bone marrow suppression, gastrointestinal and pulmonary toxicity, phototoxicity, and malignancy. Methotrexate also poses risks for conception and pregnancy, with miscarriages and birth defects occurring if it is taken during pregnancy. In addition, it may temporarily affect male fertility. 10 tables.

•

Hepatitis C: Shedding Light on the Shadow Epidemic Source: Harvard Health Letter. 24(9): 1-3. July 1999. Contact: Available from Harvard Medical School Health Publications Group. Harvard Health Letter, P.O. Box 420300, Palm Coast, FL 32142-0300. (800) 829-9045. E-mail: [email protected]. Summary: When people learn they have hepatitis C, their initial reaction is often disbelief and confusion. Many of those carrying this silent and sometimes deadly bloodborne virus feel perfectly healthy and learn of their infection only after donating blood or having routine blood tests. This newsletter article reports on a recent effort by the Centers for Disease Control and Prevention (CDC) to improve people's awareness by launching a hepatitis C public information campaign. People who are not now infected with HCV are not likely to get it unless they use IV drugs. Improved blood screening has made the risk of contracting HCV from a transfusion exceedingly low. However, most people who have HCV don't realize they're carrying the virus, which can lurk in the liver for decades before symptoms appear. It is important for people to know they have HCV so they can avoid alcohol (which accelerates liver damage), undergo frequent blood tests to monitor their liver function, and consider treatments with antiviral drugs that can reduce or eliminate the virus in some people. The majority of carriers remain fairly healthy, but at least 20 to 30 percent eventually develop cirrhosis (scarring of the liver caused by prolonged inflammation). Several blood tests can determine if a person has been infected with HCV. The author describes these tests and then briefly outlines the treatment options for HCV. One sidebar offers the contact information (telephone numbers and websites) for three resource organizations. 2 references.

Academic Periodicals covering Cirrhosis Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to cirrhosis. In addition to these sources, you can search for articles covering cirrhosis that have been published by any of the

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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 10. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for cirrhosis. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI Advice for the Patient can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with cirrhosis. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The

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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to cirrhosis: Azathioprine •

Systemic - U.S. Brands: Imuran http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202077.html

Deferoxamine •

Systemic - U.S. Brands: Desferal http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203185.html

Hepatitis B Vaccine Recombinant •

Systemic - U.S. Brands: Engerix-B http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202281.html

Methyldopa •

Systemic - U.S. Brands: Aldomet http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202359.html

Sulfur •

Topical - U.S. Brands: Finac; Sulpho-Lac http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202543.html

Torsemide •

Systemic - U.S. Brands: Demadex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202740.html

Ursodiol •

Systemic - U.S. Brands: Actigall http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202587.html

Vitamin K •

Systemic - U.S. Brands: Note: http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202599.html

Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.

Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/.

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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 cirrhosis 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 “cirrhosis” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for cirrhosis: •

Ursodiol (trade name: URSO) http://www.rarediseases.org/nord/search/nodd_full?code=256

•

Ursodiol (trade name: Actigall) http://www.rarediseases.org/nord/search/nodd_full?code=262

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 Institute13: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

•

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

•

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

•

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

•

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

13

These publications are typically written by one or more of the various NIH Institutes.

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•

National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm

•

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

•

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

•

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

•

National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

•

National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/

•

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

•

National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

•

National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

•

National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm

•

National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

•

National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

•

National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

•

Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

•

National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

•

National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

•

Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

•

Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

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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.14 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:15 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

•

Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

•

Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

•

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

•

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

•

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

14

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 15 See http://www.nlm.nih.gov/databases/databases.html.

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•

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

•

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html The Combined Health Information Database

A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to one of the following: Brochure/Pamphlet, Fact Sheet, or Information Package, and “cirrhosis” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For the publication date, select “All Years.” Select your preferred language and the format option “Fact Sheet.” Type “cirrhosis” (or synonyms) into the “For these words:” box. The following is a sample result: •

Hepatitis C Update: Recommendations from the NIH and CDC Source: JAAPA. Journal of the American Academy of Physician Assistants. 11(12): 35-37. December 1998. Contact: Available from Medical Economics. 5 Paragon Drive, Montvale, NJ 07645. (800) 432-4570. Fax (201) 573-4956. Summary: In March 1997, the National Institutes of Health (NIH) conducted a consensus development conference on the management of hepatitis C virus (HCV) infection. In July 1998, the Centers for Disease Control and Prevention (CDC) held a consultants meeting on HCV, from which it developed recommendations for the prevention and control of HCV infection and related chronic disease. This article reviews these two sets of recommendations, summarizing and comparing the guidelines in the areas of screening, counseling, monitoring, and treatment. The CDC recommends screening persons at low risk of HCV infection with the enzyme immunoassay (EIA) HCV antibody test, which has a sensitivity of greater than 97 percent. If indicated, the recombinant immunoblot assay is used as a confirmation test. The NIH, on the other hand, recommends measurement of HCV RNA with the polymerase chain reaction, if indicated, as a confirmatory test of a positive EIA. The CDC recommends that people who test positive for HCV should be counseled about being evaluated for their disease and possibly being treated. They should be instructed about reducing the risk of transmitting the virus to another person and refraining from donating blood or other body tissues. The CDC recommends vaccination against hepatitis A in a person who has chronic HCV infection; the NIH recommends vaccination against hepatitis A and B. Liver biopsy remains the gold standard for assessing disease activity, including progression to fibrosis and cirrhosis. Treatment is recommended when findings on liver biopsy include periportal or bridging fibrosis and a moderate degree of inflammation and necrosis. Patients who have had one or more episodes of decompensated cirrhosis (ascites, variceal bleedings, or encephalopathy) should be referred to a center that performs liver transplantation. 1 figure. 3 references.

•

Terminology of Chronic Hepatitis: International Working Party Report Source: American Journal of Gastroenterology. 90(2): 181-189. February 1995.

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Summary: In this article, the authors present the proceedings of two panels on chronic hepatitis of the World Congresses of Gastroenterology (WCPG) working party. The authors hope that the suggested terms, definitions, and codes can: be used by clinicians and laboratory physicians as they jointly care for patients; keep the language in hepatology contemporary; and help to create data that lend themselves to improved computerized coding and retrieval in the interest of patient service and research. After a discussion of background and objectives, the authors present definitions, synonyms, and clinical, laboratory, and histological findings for the following conditions: autoimmune hepatitis; chronic hepatitis B; chronic hepatitis D; chronic hepatitis C; chronic drug hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis; Wilson's disease of the liver; and alpha-1-antitrypsin deficiency. One brief section discusses the grading and staging of chronic hepatitis. 2 tables. 28 references. •

Chronic Hepatitis B Virus Infection in Asian Countries Source: Journal of Gastroenterology and Hepatology. 15(12): 1356-1361. December 2000. Contact: Available from Blackwell Science. 54 University Street, Carlton South 3053, Victoria, Australia. +61393470300. Fax +61393475001. E-mail: [email protected]. Website: www.blackwell-science.com. Summary: Of the estimated 50 million new cases of hepatitis B virus (HBV) infection diagnosed annually, 5 to 10 percent of adults and up to 90 percent of infants will become chronically infected. Of those who become chronically infected, 75 percent are in Asia where hepatitis B is the leading cause of chronic hepatitis (liver infection), cirrhosis (liver scarring), and hepatocellular carcinoma (liver cancer). This article offers detailed statistics on chronic HBV infection in Asian countries, including Indonesia, the Phillipines, Thailand, China, Taiwan, and Malaysia. In the highly endemic countries in Asia (places where HBV is found on a routine basis in the population), the majority of infections are contracted postnatally or perinatally (during birth). Three phases of chronic HBV infection are recognized: phase 1 patients are HBeAg positive with high levels of virus in the serum (blood) and minimal hepatic (liver) inflammation; phase 2 patients have intermittent or continuous hepatitis of varying degrees of severity; phase 3 is the inactive phase during which viral concentrations are low and there is minimal inflammatory activity in the liver. In general, patients who clear HBeAg have a better prognosis than patients who remain HBeAg positive for prolonged periods of time. The outcome after anti HBe seroconversion depends on the degree of preexisting liver damage and any subsequent HBV reactivation. Without preexisting cirrhosis, there may be only slight fibrosis or mild chronic hepatitis, but with preexisting cirrhosis, further complications may happen. The annual incidence of hepatic decompensation (reduction in liver function) in HBV related cirrhosis varies from 2 to 10 percent and in these patients, the 5 year survival rate drops dramatically to 14 to 35 percent. The annual risk of developing HCC (liver cancer) in patients with cirrhosis varies between 1 and 6 percent. Chronic hepatitis B is not a static disease and the natural history of the disease is affected by both viral and host factors. The prognosis is poor with decompensated cirrhosis and effective treatment options are limited. The authors conclude that prevention of HBV infection through vaccination is still therefore the best strategy for decreasing the incidence of hepatitis B associated cirrhosis and HCC. 1 table. 32 references.

•

Hepatitis Report: A Critical Review of the Research and Treatment of Hepatitis C Virus (HCV) and Hepatitis and HIV Coinfection Source: New York, NY: Treatment Action Group. 2000. 134 p.

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Contact: Treatment Action Group. 350 Seventh Avenue, Suite 1603, New York, NY 10036. (212) 972-9022. Fax (212) 971-9019. Website: www.treatmentactiongroup.org. PRICE: Single copy free. Summary: This report is designed to bring clinicians, allied health care workers, and patients up to date on hepatitis C virus (HCV), including epidemiology, natural history, diagnosis, pathogenesis, and treatment. After an analysis of peer reviewed articles, over 40 researchers, clinicians, primary care physicians, government health administrators, industry representatives, and patients with viral hepatitis were interviewed for this report. Eleven chapters cover epidemiology, modes of transmission, and risk factors; pathogenesis, viral dynamics, and immunologic response; natural history, clinical manifestations, and prognostic indicators of disease progression and survival of HCV infection; diagnostic considerations; the use of interferon to treat HCV infection; the mechanism of HCV resistance to interferon; experimental treatments and new areas of research; hepatitis and HIV coinfection; current opinions and controversies in HCV infection; research and policy recommendations; and clinician's response. The natural history chapter reminds readers that not all patients with HCV inexorably deteriorate to end stage liver disease, liver transplantation, or death. The diagnosis of HCV is often complex with multiple tests and the confusion of liver biopsy evaluation. The role of HCV in response to HIV therapy is largely unknown. Approximately only half of HCV patients respond to current therapies, but the report considers whether perhaps only half may actually need therapy in the long term. Unfortunately, clinicians cannot determine which patients will progress to fibrosis and end stage liver disease and so most patients are treated, especially if they have some scarring without cirrhosis. Interferon remains the mainstay of therapy, with pegylated IFNs providing new advances. Each chapter includes illustrations and a list of references.

The NLM Gateway16 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.17 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “cirrhosis” (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

16 17

Items Found 68270 852 799 230 6 70157

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

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).

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HSTAT18 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.19 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.20 Simply search by “cirrhosis” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists21 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.22 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.23 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

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Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html.

19

The HSTAT URL is http://hstat.nlm.nih.gov/.

20

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations. 21 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html. 22

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 23 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.

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The Genome Project and Cirrhosis In the following section, we will discuss databases and references which relate to the Genome Project and cirrhosis. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).24 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “cirrhosis” (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 cirrhosis: •

Alpers Diffuse Degeneration of Cerebral Gray Matter with Hepatic Cirrhosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?203700

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Berry Aneurysm, Cirrhosis, Pulmonary Emphysema, and Cerebral Calcification Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?210050

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Biliary Cirrhosis, Primary Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?109720

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Cirrhosis, Familial Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?215600

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Cirrhosis, Familial Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?118900

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North American Indian Childhood Cirrhosis Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?604901 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: 24 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

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•

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

•

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 select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “cirrhosis” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database25 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html.

25

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html.

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The Genome Database26 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “cirrhosis” (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).

26

Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.

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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on cirrhosis can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to cirrhosis. 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 cirrhosis. 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 “cirrhosis”:

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Guides on cirrhosis Cirrhosis http://www.nlm.nih.gov/medlineplus/cirrhosis.html

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Other guides Cystic Fibrosis http://www.nlm.nih.gov/medlineplus/cysticfibrosis.html Hepatitis C http://www.nlm.nih.gov/medlineplus/hepatitisc.html Liver Diseases http://www.nlm.nih.gov/medlineplus/liverdiseases.html Pulmonary Fibrosis http://www.nlm.nih.gov/medlineplus/pulmonaryfibrosis.html

Within the health topic page dedicated to cirrhosis, the following was listed: •

General/Overviews Cirrhosis Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DS00373 Cirrhosis: Many Causes Source: American Liver Foundation http://www.liverfoundation.org/images/articles/1059/cirrhosis.pdf

•

Diagnosis/Symptoms Liver Biopsy Source: National Digestive Diseases Information Clearinghouse http://digestive.niddk.nih.gov/ddiseases/pubs/liverbiopsy/index.htm Ultrasound-Abdomen Source: American College of Radiology, Radiological Society of North America http://www.radiologyinfo.org/content/ultrasound-abdomen.htm

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Treatment Interventional Treatments for Liver Disease Source: Society of Interventional Radiology http://www.sirweb.org/patPub/liverDisease.shtml

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Nutrition Diet and Your Liver Source: American Liver Foundation http://www.liverfoundation.org/cgibin/dbs/articles.cgi?db=articles&uid=default&ID=1022&view_records=1

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Specific Conditions/Aspects Alcoholic Hepatitis Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=HQ00200 Cirrhosis and Portal Hypertension Source: American Academy of Family Physicians http://familydoctor.org/handouts/188.html Nonalcoholic Fatty Liver Disease: A Common but Preventable Condition Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=MC00012 Primary Biliary Cirrhosis Source: National Digestive Diseases Information Clearinghouse http://digestive.niddk.nih.gov/ddiseases/pubs/primarybiliarycirrhosis/index.ht m What Is Primary Biliary Cirrhosis (PBC)? Source: American Liver Foundation http://www.liverfoundation.org/cgibin/dbs/articles.cgi?db=articles&uid=default&ID=1014&view_records=1

•

Organizations American Gastroenterological Association http://www.gastro.org/ American Liver Foundation http://www.liverfoundation.org/ National Digestive Diseases Information Clearinghouse http://digestive.niddk.nih.gov/ National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov/

•

Prevention/Screening ALT (Alanine Aminotransferase) Test Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/alt/test.html Bilirubin Test Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/bilirubin/test.html Liver Panel Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/liver_panel/glance.html

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Statistics FASTATS: Chronic Liver Disease/Cirrhosis Source: National Center for Health Statistics http://www.cdc.gov/nchs/fastats/liverdis.htm

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Quick Facts: Alcohol Topics Source: National Institute on Alcohol Abuse and Alcoholism http://www.niaaa.nih.gov/databases/qf.htm 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 cirrhosis. 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: •

Primary Biliary Cirrhosis Source: Cedar Grove, NJ: American Liver Foundation. 1992. 2 p. Contact: Available from American Liver Foundation. 1425 Pompton Avenue, Cedar Grove, NJ 07009. (201) 256-2550 or (800) 223-0179. PRICE: Single copy free. Summary: Primary biliary cirrhosis (PBC) is a chronic liver disease that causes slow, progressive destruction of bile ducts in the liver. This fact sheet discusses PBC, covering its presentation, diagnosis, cause, prognosis, and treatment. Treatment includes diet therapy, drug therapy, and liver transplantation. A final section describes current research into the causes and development of the disease and drug therapy trials exploring the potential use of several medications to lessen the symptoms and control liver damage.

•

Cirrhosis of the Liver Source: Bethesda, MD: American Gastroenterological Association (AGA). 2001. [6 p.]. Contact: Available from American Gastroenterological Association (AGA). 4930 Del Ray Avenue, Bethesda, MD 20814-3015. (301) 654-2055. Fax (301) 654-3978. Website: www.gastro.org. PRICE: Single copy free to patient. Summary: The liver weighs about three pounds and is the largest organ in the body. When chronic diseases cause the liver to become permanently injured and scarred, the condition is called cirrhosis. This brochure outlines cirrhosis, noting that the scar tissue that forms in cirrhosis harms the structure of the liver, blocking the flow of blood through the organ. The loss of normal liver tissue slows the processing of nutrients, hormones, drugs, and toxins by the liver. Also slowed is production of proteins and other substances made by the liver. The brochure reviews the major causes of cirrhosis, the symptoms of the condition, diagnostic tests used to confirm and monitor cirrhosis, treatment options, and complications of cirrhosis and how they are treated. The

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brochure includes a simplified illustration of the digestive tract and a list of additional readings. 3 figures. 5 references. •

Cirrhosis: Many Causes Source: Cedar Grove, NJ: American Liver Foundation. 1995. 4 p. Contact: Available from American Liver Foundation. 1425 Pompton Avenue, Cedar Grove, NJ 07009. (800) 223-0179 or (201) 256-2550. PRICE: $0.50 each; $6 for 25 copies; $12 for 50 copies (as of 1995); discounts available for larger quantities. Summary: This brochure, written in question-and-answer format, presents basic facts about cirrhosis of the liver. Topics are causes, signs, symptoms, and treatments. Identification of conditions responsible for cirrhosis and its relationship to alcohol use and hepatitis are discussed. The treatments for complications, including ascites, coma, and hemorrhage from esophageal varices, are briefly described. Ways to avoid cirrhosis and the outlook for people with cirrhosis are discussed. 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 “cirrhosis” (or synonyms). The following was recently posted: •

Management of adult patients with ascites caused by cirrhosis Source: American Association for the Study of Liver Diseases - Private Nonprofit Research Organization; 1998 January; 9 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3450&nbr=2676&a mp;string=cirrhosis

•

Management of primary biliary cirrhosis Source: American Association for the Study of Liver Diseases - Private Nonprofit Research Organization; 2000 April; 9 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3445&nbr=2671&a mp;string=cirrhosis Healthfinder™

Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database:

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Cirrhosis of the Liver Summary: Cirrhosis is the seventh leading cause of death by disease. About 25,000 people die from cirrhosis each year. Source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=733

•

Hepatitis B Immunization Coverage Among Vietnamese-American Children 3 to 18 Years Old Summary: Persons with chronic hepatitis B virus (HBV) infection are at increased risk of chronic hepatitis, cirrhosis, and liver cancer. Source: American Academy of Pediatrics http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7366

•

Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effects (Summary) Summary: This evidence report details a systematic review summarizing clinical studies of milk thistle in humans. The scientific name for milk thistle is Silybum marianum. Source: Agency for Healthcare Research and Quality http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6477

•

Overview of Iron Overload and Hemochromatosis Summary: A consumer health education fact sheet about hemochromatosis, a disorder of iron metabolism that is known to exacerbate or cause cirrhosis of the liver, cardiac diseases and other chronic illnesses. Source: Office of Genomics and Disease Prevention, Centers for Disease Control and Prevention http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=2919 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 cirrhosis. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html.

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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

•

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMDHealth: http://my.webmd.com/health_topics

Associations and Cirrhosis The following is a list of associations that provide information on and resources relating to cirrhosis: •

Primary Biliary Cirrhosis Support Group Telephone: (281) 997-1516 Fax: (281) 412-9161 Email: [email protected] Web Site: http://pbcers.org Background: The PBCers Organization is a source of support and education for those who suffer from primary biliary cirrhosis and other autoimmune liver diseases. Family members and friends are also encouraged to join and learn more about PBC. The organization offers various types of support and education such as the e-mail PBC daily digest, quarterly newsletter and annual PBC conference. Members discuss medical information, pain management, medications, and research; ask questions; and vent anger and fears. The PBCers was formed in 1996. Current membership is more than 2,400 worldwide.

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to cirrhosis. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with cirrhosis. 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 cirrhosis. For more information, see the

246 Cirrhosis

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 “cirrhosis” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “cirrhosis”. 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 “cirrhosis” (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 “cirrhosis” (or a synonym) into the search box, and click “Submit Query.”

247

APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.27

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

27

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

248 Cirrhosis

libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)28: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

•

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

28

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

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•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

•

Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

•

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

•

Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

•

Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

•

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

•

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

•

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

•

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

•

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

•

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

•

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

•

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

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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

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

•

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

•

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

•

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

•

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

•

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

•

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

•

Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

•

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

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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

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

•

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

•

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

•

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

•

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

•

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

•

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

•

Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

•

Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

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•

South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

•

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

253

ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

•

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

•

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on cirrhosis: •

Basic Guidelines for Cirrhosis Alcoholic liver disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000281.htm CHF Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000158.htm Chronic active hepatitis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000271.htm Cirrhosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000255.htm Hepatitis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001154.htm Hepatitis B Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000279.htm

254 Cirrhosis

Hepatitis C Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000284.htm •

Signs & Symptoms for Cirrhosis Abdominal fullness, gaseous Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003124.htm Abdominal indigestion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003260.htm Abdominal pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003120.htm Anemia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000560.htm Bleeding disorders Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001304.htm Bleeding gums Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003062.htm Breast development in males Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003165.htm Choreoathetosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003197.htm Coagulopathy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001304.htm Coma Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003202.htm Confusion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003205.htm Confusion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003263.htm Distended abdomen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003122.htm Dysarthria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003204.htm Edema Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003103.htm Enlarged liver Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003275.htm

Online Glossaries 255

Erythema Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Gynecomastia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003165.htm Hepatomegaly Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003275.htm Icterus Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003243.htm Impotence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003164.htm Indigestion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003260.htm Jaundice Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003243.htm Nausea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm Stools, pale or clay colored Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003129.htm Stress Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Swelling, overall Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003103.htm Urine output, decreased Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003147.htm Vomiting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm Vomiting blood Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003118.htm Weakness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003174.htm Weight loss Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003107.htm Yellow eyes Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003243.htm

256 Cirrhosis

•

Diagnostics and Tests for Cirrhosis Abdominal X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003815.htm Albumin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003480.htm Alkaline phosphatase Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003470.htm ALP Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003470.htm Alpha fetoprotein Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003573.htm ALT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003473.htm Antimitochondrial antibody Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003529.htm AST Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003472.htm Bilirubin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003479.htm Biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003416.htm BUN Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003474.htm CBC Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm Ceruloplasmin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003662.htm Cholesterol test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003492.htm Complement Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003456.htm Creatinine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003475.htm CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm

Online Glossaries 257

ERCP Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003893.htm Ferritin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003490.htm HCT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003646.htm Hepatitis B surface antigen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003558.htm HGB Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003645.htm LDH Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003471.htm Liver biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003895.htm Liver function tests Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003436.htm Prothrombin time Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003652.htm PT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003652.htm Renin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003698.htm Sedimentation rate Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003638.htm Serum albumin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003480.htm Serum magnesium - test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003487.htm X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003337.htm •

Surgery and Procedures for Cirrhosis Liver transplant Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003006.htm

258 Cirrhosis

•

Background Topics for Cirrhosis Alcohol use Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001944.htm Chronic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002312.htm Hepatic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002378.htm Liver disease - support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002182.htm Physical examination Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002274.htm

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

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CIRRHOSIS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 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] Ablation: The removal of an organ by surgery. [NIH] Abscess: Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. [NIH] Absolute risk: The observed or calculated probability of an event in a population under study, as contrasted with the relative risk. [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] Accommodation: Adjustment, especially that of the eye for various distances. [EU] Acculturation: Process of cultural change in which one group or members of a group assimilates various cultural patterns from another. [NIH] Acetaldehyde: A colorless, flammable liquid used in the manufacture of acetic acid, perfumes, and flavors. It is also an intermediate in the metabolism of alcohol. It has a general narcotic action and also causes irritation of mucous membranes. Large doses may cause death from respiratory paralysis. [NIH] Acetaminophen: Analgesic antipyretic derivative of acetanilide. It has weak antiinflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylcholinesterase: An enzyme that catalyzes the hydrolysis of acetylcholine to choline and acetate. In the CNS, this enzyme plays a role in the function of peripheral neuromuscular junctions. EC 3.1.1.7. [NIH] Acetylglucosamine: The N-acetyl derivative of glucosamine. [NIH] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Actin: Essential component of the cell skeleton. [NIH] Acute Disease: Disease having a short and relatively severe course. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH]

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Acute tubular: A severe form of acute renal failure that develops in people with severe illnesses like infections or with low blood pressure. Patients may need dialysis. Kidney function often improves if the underlying disease is successfully treated. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenoma: A benign 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] Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of cyclic AMP and pyrophosphate from ATP. EC 4.6.1.1. [NIH] Adhesions: Pathological processes consisting of the union of the opposing surfaces of a wound. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [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] Aetiology: Study of the causes of disease. [EU] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH]

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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] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [NIH] Alanine Transaminase: An enzyme that catalyzes the conversion of L-alanine and 2oxoglutarate to pyruvate and L-glutamate. (From Enzyme Nomenclature, 1992) EC 2.6.1.2. [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] Alcohol-Induced Disorders: Disorders stemming from the misuse and abuse of alcohol. [NIH]

Aldosterone: (11 beta)-11,21-Dihydroxy-3,20-dioxopregn-4-en-18-al. A hormone secreted by 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] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU]

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Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] 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] Allogeneic: Taken from different individuals of the same species. [NIH] Allopurinol: A xanthine oxidase inhibitor that decreases uric acid production. [NIH] Alpha 1-Antichymotrypsin: Glycoprotein found in alpha(1)-globulin region in human serum. It inhibits chymotrypsin-like proteinases in vivo and has cytotoxic killer-cell activity in vitro. The protein also has a role as an acute-phase protein and is active in the control of immunologic and inflammatory processes, and as a tumor marker. It is a member of the serpin superfamily. [NIH] Alpha 1-Antitrypsin: Plasma glycoprotein member of the serpin superfamily which inhibits trypsin, neutrophil elastase, and other proteolytic enzymes. Commonly referred to as alpha 1-proteinase inhibitor (A1PI), it exists in over 30 different biochemical variant forms known collectively as the PI (protease inhibitor) system. Hereditary A1PI deficiency is associated with pulmonary emphysema. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alpha-fetoprotein: AFP. A protein normally produced by a developing fetus. AFP levels are usually undetectable in the blood of healthy nonpregnant adults. An elevated level of AFP suggests the presence of either a primary liver cancer or germ cell tumor. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. 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] Ambulatory Care: Health care services provided to patients on an ambulatory basis, rather than by admission to a hospital or other health care facility. The services may be a part of a hospital, augmenting its inpatient services, or may be provided at a free-standing facility. [NIH]

Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form

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proteins. [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] Amnestic: Nominal aphasia; a difficulty in finding the right name for an object. [NIH] Amphetamines: Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopression, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [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] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]

Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, 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] Anastomosis: A procedure to connect healthy sections of tubular structures in the body after the diseased portion has been surgically removed. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In

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addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] Anginal: Pertaining to or characteristic of angina. [EU] 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] Angiopathy: Disease of the blood vessels (arteries, veins, and capillaries) that occurs when someone has diabetes for a long time. There are two types of angiopathy: macroangiopathy and microangiopathy. In macroangiopathy, fat and blood clots build up in the large blood vessels, stick to the vessel walls, and block the flow of blood. In microangiopathy, the walls of the smaller blood vessels become so thick and weak that they bleed, leak protein, and slow the flow of blood through the body. Then the cells, for example, the ones in the center of the eye, do not get enough blood and may be damaged. [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] Angiosarcoma: A type of cancer that begins in the lining of blood vessels. [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]

Anomalies: Birth defects; abnormalities. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Anoxia: Clinical manifestation of respiratory distress consisting of a relatively complete

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absence of oxygen. [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] Anterior Cerebral Artery: Artery formed by the bifurcation of the internal carotid artery. Branches of the anterior cerebral artery supply the caudate nucleus, internal capsule, putamen, septal nuclei, gyrus cinguli, and surfaces of the frontal lobe and parietal lobe. [NIH] Antiallergic: Counteracting allergy or allergic conditions. [EU] 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]

Antibiotic Prophylaxis: Use of antibiotics before, during, or after a diagnostic, therapeutic, or surgical procedure to prevent infectious complications. [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] Antibodies, Anticardiolipin: Antiphospholipid antibodies found in association with systemic lupus erythematosus (lupus erythematosus, systemic), antiphospholipid syndrome, and in a variety of other diseases as well as in healthy individuals. The antibodies are detected by solid-phase immunoassay employing the purified phospholipid antigen cardiolipin. [NIH] Antibodies, Antiphospholipid: Autoantibodies directed against phospholipids. These antibodies are characteristically found in patients with systemic lupus erythematosus, antiphospholipid syndrome, related autoimmune diseases, some non-autoimmune diseases, and also in healthy individuals. [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] Antidepressant: A drug used to treat depression. [NIH] Antidiuretic: Suppressing the rate of urine formation. [EU] Antidote: A remedy for counteracting a poison. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody

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molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antihypertensive: An agent that reduces high blood pressure. [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] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]

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] Antiphospholipid Syndrome: The presence of antibodies directed against phospholipids (antibodies, antiphospholipid). The condition is associated with a variety of diseases, notably systemic lupus erythematosus and other connective tissue diseases, thrombopenia, and arterial or venous thromboses. In pregnancy it can cause abortion. Of the phospholipids, the cardiolipins show markedly elevated levels of anticardiolipin antibodies (antibodies, anticardiolipin). Present also are high levels of lupus anticoagulant (lupus coagulation inhibitor). [NIH] Antiplasmin: A member of the serpin superfamily found in human plasma that inhibits the lysis of fibrin clots which are induced by plasminogen activator. It is a glycoprotein, molecular weight approximately 70,000 that migrates in the alpha 2 region in immunoelectrophoresis. It is the principal plasmin inactivator in blood, rapidly forming a very stable complex with plasmin. [NIH] Antipruritic: Relieving or preventing itching. [EU] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Antiviral Agents: Agents used in the prophylaxis or therapy of virus diseases. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. [NIH] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Anxiolytic: An anxiolytic or antianxiety agent. [EU] Aorta: The main trunk of the systemic arteries. [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

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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] 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] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatic: Having a spicy odour. [EU] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriosus: Circle composed of anastomosing arteries derived from two long posterior ciliary and seven anterior ciliary arteries, located in the ciliary body about the root of the iris. [NIH]

Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Arteritis: Inflammation of an artery. [NIH] Arthroplasty: Surgical reconstruction of a joint to relieve pain or restore motion. [NIH] Articular: Of or pertaining to a joint. [EU] Ascites: Accumulation or retention of free fluid within the peritoneal cavity. [NIH] Ascitic Fluid: The serous fluid which accumulates in the peritoneal cavity in ascites. [NIH] Ascorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [NIH] Aspartate: A synthetic amino acid. [NIH] Asphyxia: A pathological condition caused by lack of oxygen, manifested in impending or actual cessation of life. [NIH] Aspiration: The act of inhaling. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asterixis: A motor disturbance marked by intermittency of sustained contraction of groups of muscles. [NIH] 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

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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] Atopic: Pertaining to an atopen or to atopy; allergic. [EU] Atresia: Lack of a normal opening from the esophagus, intestines, or anus. [NIH] Atrial: Pertaining to an atrium. [EU] Atrial Fibrillation: Disorder of cardiac rhythm characterized by rapid, irregular atrial impulses and ineffective atrial contractions. [NIH] 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] Attenuated: Strain with weakened or reduced virulence. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] 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] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autolysis: The spontaneous disintegration of tissues or cells by the action of their own autogenous enzymes. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autopsy: Postmortem examination of the body. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH]

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Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bacterial Translocation: The passage of viable bacteria from the gastrointestinal tract to extra-intestinal sites, such as the mesenteric lymph node complex, liver, spleen, kidney, and blood. Factors that promote bacterial translocation include overgrowth with gram-negative enteric bacilli, impaired host immune defenses, and injury to the intestinal mucosa resulting in increased intestinal permeability. These mechanisms can act in concert to promote synergistically the systemic spread of indigenous translocating bacteria to cause lethal sepsis. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacteriostatic: 1. Inhibiting the growth or multiplication of bacteria. 2. An agent that inhibits the growth or multiplication of bacteria. [EU] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Balloon Occlusion: Use of a balloon catheter to block the flow of blood through an artery or vein. [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] Bed Rest: Confinement of an individual to bed for therapeutic or experimental reasons. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benign prostatic hyperplasia: A benign (noncancerous) condition in which an overgrowth of prostate tissue pushes against the urethra and the bladder, blocking the flow of urine. Also called benign prostatic hypertrophy or BPH. [NIH]

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Benzodiazepines: A two-ring heterocyclic compound consisting of a benzene ring fused to a diazepine ring. Permitted is any degree of hydrogenation, any substituents and any Hisomer. [NIH] Benzoic Acid: A fungistatic compound that is widely used as a food preservative. It is conjugated to glycine in the liver and excreted as hippuric acid. [NIH] Benzoylcholine: The benzoic acid ester of choline. [NIH] Beta blocker: A drug used to slow the heart rate and reduce pressure inside blood vessels. It also can regulate heart rhythm. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [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] Bewilderment: Impairment or loss of will power. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile Ducts: Tubes that carry bile from the liver to the gallbladder for storage and to the small intestine for use in digestion. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biogenic Amine Neurotransmitters: Biogenic amines released by neurons as intercellular messengers. The biogenic amines norepinephrine, dopamine, histamine, and serotonin are neurotransmitters in both the central and peripheral nervous systems. [NIH] Biogenic Amines: A group of naturally occurring amines derived by enzymatic decarboxylation of the natural amino acids. Many have powerful physiological effects (e.g., histamine, serotonin, epinephrine, tyramine). Those derived from aromatic amino acids, and also their synthetic analogs (e.g., amphetamine), are of use in pharmacology. [NIH] Biological Markers: Measurable and quantifiable biological parameters (e.g., specific

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enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc. [NIH] 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] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [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] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] 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] Blast phase: The phase of chronic myelogenous leukemia in which the number of immature, abnormal white blood cells in the bone marrow and blood is extremely high. Also called blast crisis. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Cell Count: A count of the number of leukocytes and erythrocytes per unit volume in a sample of venous blood. A complete blood count (CBC) also includes measurement of the hemoglobin, hematocrit, and erythrocyte indices. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Coagulation Factors: Endogenous substances, usually proteins, that are involved in

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the blood coagulation process. [NIH] Blood Glucose: Glucose in blood. [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 heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood transfusion: The administration of blood or blood products into a blood vessel. [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] Blood Volume: Volume of circulating blood. It is the sum of the plasma volume and erythrocyte volume. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [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] 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] Breath Tests: Any tests done on exhaled air. [NIH] 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] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH]

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Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Budesonide: A glucocorticoid used in the management of asthma, the treatment of various skin disorders, and allergic rhinitis. [NIH] Burns: Injuries to tissues caused by contact with heat, steam, chemicals (burns, chemical), electricity (burns, electric), or the like. [NIH] Burns, Electric: Burns produced by contact with electric current or from a sudden discharge of electricity. [NIH] Buspirone: An anxiolytic agent and a serotonin receptor agonist belonging to the azaspirodecanedione class of compounds. Its structure is unrelated to those of the benzodiazepines, but it has an efficacy comparable to diazepam. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Cachexia: General ill health, malnutrition, and weight loss, usually associated with chronic disease. [NIH] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] Calcinosis: Pathologic deposition of calcium salts in tissues. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium blocker: A drug used to relax the blood vessel and heart muscle, causing pressure inside blood vessels to drop. It also can regulate heart rhythm. [NIH] Calcium channel blocker: A drug used to relax the blood vessel and heart muscle, causing pressure inside blood vessels to drop. It also can regulate heart rhythm. [NIH] Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cell membranes or on the release and binding of calcium in intracellular pools. Since they are inducers of vascular and other smooth muscle relaxation, they are used in the drug therapy of hypertension and cerebrovascular spasms, as myocardial protective agents, and in the relaxation of uterine spasms. [NIH] Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually composed of mineral salts. Also called stones. [NIH] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [NIH] Cannabidiol: Compound isolated from Cannabis sativa extract. [NIH] Cannabinoids: Compounds extracted from Cannabis sativa L. and metabolites having the cannabinoid structure. The most active constituents are tetrahydrocannabinol, cannabinol,

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and cannabidiol. [NIH] Cannabinol: A physiologically inactive constituent of Cannabis sativa L. [NIH] Cannula: A tube for insertion into a duct or cavity; during insertion its lumen is usually occupied by a trocar. [EU] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capillary Permeability: Property of blood capillary walls that allows for the selective exchange of substances. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas (tight junctions) which may limit large molecule movement. [NIH] Capsid: The outer protein protective shell of a virus, which protects the viral nucleic acid. [NIH]

Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbimazole: An imidazole antithyroid agent. Carbimazole is metabolized to methimazole, which is responsible for the antithyroid activity. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] Cardiac arrest: A sudden stop of heart function. [NIH] Cardiology: The study of the heart, its physiology, and its functions. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardioselective: Having greater activity on heart tissue than on other tissue. [EU] Cardiotonic: 1. Having a tonic effect on the heart. 2. An agent that has a tonic effect on the heart. [EU] 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

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can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [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] Case-Control Studies: Studies which start with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship of an attribute to the disease is examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catalyse: To speed up a chemical reaction. [EU] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] 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] Cathode: An electrode, usually an incandescent filament of tungsten, which emits electrons in an X-ray tube. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Celiac Artery: The arterial trunk that arises from the abdominal aorta and after a short course divides into the left gastric, common hepatic and splenic arteries. [NIH] Celiac Disease: A disease characterized by intestinal malabsorption and precipitated by gluten-containing foods. The intestinal mucosa shows loss of villous structure. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are

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made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell 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] Cellular Structures: Components of a cell. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [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 Hemorrhage: Bleeding into a cerebral hemisphere of the brain, including lobar, subcortical white matter, and basal ganglia hemorrhages. Commonly associated conditions include hypertension; intracranial arteriosclerosis; intracranial aneurysm; craniocerebral trauma; intracranial arteriovenous malformations; cerebral amyloid angiopathy; and cerebral infarction. [NIH] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [NIH]

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] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and

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vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemical Warfare: Tactical warfare using incendiary mixtures, smokes, or irritant, burning, or asphyxiating gases. [NIH] Chemical Warfare Agents: Chemicals that are used to cause the disturbance, disease, or death of humans during war. [NIH] Chemoembolization: A procedure in which the blood supply to the tumor is blocked surgically or mechanically, and anticancer drugs are administered directly into the tumor. This permits a higher concentration of drug to be in contact with the tumor for a longer period of time. [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] Chemotherapy: Treatment with anticancer drugs. [NIH] Chenodeoxycholic Acid: A bile acid, usually conjugated with either glycine or taurine. It acts as a detergent to solubilize fats for intestinal absorption and is reabsorbed by the small intestine. It is used as cholagogue, a choleretic laxative, and to prevent or dissolve gallstones. [NIH] Chest Pain: Pressure, burning, or numbness in the chest. [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] Cholangitis: Inflammation of a bile duct. [NIH] Cholecystitis: Inflammation of the gallbladder. [NIH] Cholelithiasis: Presence or formation of gallstones. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Choleretic: A choleretic agent. [EU] Cholestanol: A cholesterol derivative found in human feces, gallstones, eggs, and other biological matter. [NIH] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla. [NIH]

Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Cholestyramine: Strongly basic anion exchange resin whose main constituent is polystyrene trimethylbenzylammonium as Cl(-) anion. It exchanges chloride ions with bile salts, thus decreasing their concentration and that of cholesterol. It is used as a hypocholesteremic in diarrhea and biliary obstruction and as an antipruritic. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes,

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and in lipid metabolism. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic Fatigue Syndrome: Fatigue caused by the combined effects of different types of prolonged fatigue. [NIH] Chronic lymphocytic leukemia: A slowly progressing disease in which too many white blood cells (called lymphocytes) are found in the body. [NIH] Chronic myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. [NIH] Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [NIH] Chronic phase: Refers to the early stages of chronic myelogenous leukemia or chronic lymphocytic leukemia. The number of mature and immature abnormal white blood cells in the bone marrow and blood is higher than normal, but lower than in the accelerated or blast phase. [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] Cicatrix: The formation of new tissue in the process of wound healing. [NIH] Ciprofloxacin: A carboxyfluoroquinoline antimicrobial agent that is effective against a wide range of microorganisms. It has been successfully and safely used in the treatment of resistant respiratory, skin, bone, joint, gastrointestinal, urinary, and genital infections. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [NIH] Circadian Rhythm: The regular recurrence, in cycles of about 24 hours, of biological processes or activities, such as sensitivity to drugs and stimuli, hormone secretion, sleeping, feeding, etc. This rhythm seems to be set by a 'biological clock' which seems to be set by recurring daylight and darkness. [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] Citalopram: A selective neuronal serotonin reuptake inhibitor and a clinically effective antidepressant with tolerable side effects. The drug is also effective in reducing ethanol uptake in alcoholics and is used in depressed patients who also suffer from tardive dyskinesia (TD) in preference to tricyclic antidepressants, which aggravate this condition. [NIH]

Citrus: Any tree or shrub of the Rue family or the fruit of these plants. [NIH]

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Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clarithromycin: A semisynthetic macrolide antibiotic derived from erythromycin that is active against a variety of microorganisms. It can inhibit protein synthesis in bacteria by reversibly binding to the 50S ribosomal subunits. This inhibits the translocation of aminoacyl transfer-RNA and prevents peptide chain elongation. [NIH] Climacteric: Physiologic period, characterized by endocrine, somatic, and psychic changes with the termination of ovarian function in the female. It may also accompany the normal diminution of sexual activity in the male. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] 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] Coca: Any of several South American shrubs of the Erythroxylon genus (and family) that yield cocaine; the leaves are chewed with alum for CNS stimulation. [NIH] Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. [NIH]

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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] Collagen disease: A term previously used to describe chronic diseases of the connective tissue (e.g., rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis), but now is thought to be more appropriate for diseases associated with defects in collagen, which is a component of the connective tissue. [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] Colloidal: Of the nature of a colloid. [EU] Colorectal: Having to do with the colon or the rectum. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Common Bile Duct: The largest biliary duct. It is formed by the junction of the cystic duct and the hepatic duct. [NIH] Comorbidity: The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. [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, 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

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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] Complement 1: The first complement component to act in the cytolysis reaction. It is a trimolecular complex held together with Ca ions and, when activated, has esterase activity which initiates the next step in the sequence. [NIH] Complement 1 Inactivators: Compounds which inhibit, antagonize, or inactivate complement 1. A well-known inhibitor is a serum glycoprotein believed to be alpha-2neuroaminoglycoprotein. It inhibits the activated (esterase) form of complement 1 as well as kinin-forming, coagulation, and fibrinolytic systems. Deficiency of this inactivator has been found in patients with hereditary angioneurotic edema. These compounds are members of the serpin superfamily. [NIH] Complement Activation: The sequential activation of serum components C1 through C9, initiated by an erythrocyte-antibody complex or by microbial polysaccharides and properdin, and producing an inflammatory response. [NIH] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH] Compress: A plug used to occludate an orifice in the control of bleeding, or to mop up secretions; an absorbent pad. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the

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formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] 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] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of separate mating types exchange micronuclear material and then separate, each now being a fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [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] Connective Tissue Diseases: A heterogeneous group of disorders, some hereditary, others acquired, characterized by abnormal structure or function of one or more of the elements of connective tissue, i.e., collagen, elastin, or the mucopolysaccharides. [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] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU]

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Contraceptive: An agent that diminishes the likelihood of or prevents conception. [EU] 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] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Conus: A large, circular, white patch around the optic disk due to the exposing of the sclera as a result of degenerative change or congenital abnormality in the choroid and retina. [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] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [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 Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary Artery Bypass: Surgical therapy of ischemic coronary artery disease achieved by grafting a section of saphenous vein, internal mammary artery, or other substitute between the aorta and the obstructed coronary artery distal to the obstructive lesion. [NIH] Coronary Circulation: The circulation of blood through the coronary vessels of the heart. [NIH]

Coronary heart disease: A type of heart disease caused by narrowing of the coronary 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

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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] Coronary Vasospasm: Spasm of the large- or medium-sized coronary arteries. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [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] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cost Savings: Reductions in all or any portion of the costs of providing goods or services. Savings may be incurred by the provider or the consumer. [NIH] Coumarins: Synthetic or naturally occurring substances related to coumarin, the deltalactone of coumarinic acid. Coumarin itself occurs in the tonka bean. The various coumarins have a wide range of proposed actions and uses including as anticoagulants, pharmaceutical aids, indicators and reagents, photoreactive substances, and antineoplastic agents. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] 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] 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] Cystic Duct: The tube that carries bile from the gallbladder into the common bile duct and the small intestine. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein,

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cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] 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] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytostatic: An agent that suppresses cell growth and multiplication. [EU] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] Day Care: Institutional health care of patients during the day. The patients return home at night. [NIH] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] Death Certificates: Official records of individual deaths including the cause of death certified by a physician, and any other required identifying information. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Decompensation: Failure of compensation; cardiac decompensation is marked by dyspnea, venous engorgement, and edema. [EU] Decompression: Decompression external to the body, most often the slow lessening of external pressure on the whole body (especially in caisson workers, deep sea divers, and persons who ascend to great heights) to prevent decompression sickness. It includes also sudden accidental decompression, but not surgical (local) decompression or decompression applied through body openings. [NIH] Decompression Sickness: A condition occurring as a result of exposure to a rapid fall in ambient pressure. Gases, nitrogen in particular, come out of solution and form bubbles in body fluid and blood. These gas bubbles accumulate in joint spaces and the peripheral circulation impairing tissue oxygenation causing disorientation, severe pain, and potentially death. [NIH] Decongestant: An agent that reduces congestion or swelling. [EU] Decontamination: The removal of contaminating material, such as radioactive materials,

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biological materials, or chemical warfare agents, from a person or object. [NIH] Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Deoxyguanosine: A nucleoside consisting of the base guanine and the sugar deoxyribose. [NIH]

Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal 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] Depressive Disorder: An affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent. [NIH] Dermatitis: Any inflammation of the skin. [NIH] Dermatosis: Any skin disease, especially one not characterized by inflammation. [EU] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developed Countries: Countries that have reached a level of economic achievement through an increase of production, per capita income and consumption, and utilization of natural and human resources. [NIH] Developing Countries: Countries in the process of change directed toward economic growth, that is, an increase in production, per capita consumption, and income. The process of economic growth involves better utilization of natural and human resources, which results in a change in the social, political, and economic structures. [NIH] Diabetes Insipidus: A metabolic disorder due to disorders in the production or release of vasopressin. It is characterized by the chronic excretion of large amounts of low specific gravity urine and great thirst. [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 Imaging: Any visual display of structural or functional patterns of organs or tissues for diagnostic evaluation. It includes measuring physiologic and metabolic responses to physical and chemical stimuli, as well as ultramicroscopy. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH]

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Diaphragm: The musculofibrous partition that separates the thoracic cavity from the abdominal cavity. Contraction of the diaphragm increases the volume of the thoracic cavity aiding inspiration. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastole: Period of relaxation of the heart, especially the ventricles. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] 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] Dihydroxy: AMPA/Kainate antagonist. [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] Dilator: A device used to stretch or enlarge an opening. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] 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] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Disparity: Failure of the two retinal images of an object to fall on corresponding retinal points. [NIH] Disposition: A tendency either physical or mental toward certain diseases. [EU] 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

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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] Diuresis: Increased excretion of urine. [EU] Diuretic: A drug that increases the production of urine. [NIH] Diverticula: Plural form of diverticulum. [NIH] Diverticulitis: Inflammation of a diverticulum or diverticula. [NIH] Diverticulum: A pathological condition manifested as a pouch or sac opening from a tubular or sacular organ. [NIH] Docetaxel: An anticancer drug that belongs to the family of drugs called mitotic inhibitors. [NIH]

Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Double-blinded: A clinical trial in which neither the medical staff nor the person knows which of several possible therapies the person is receiving. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Design: The molecular designing of drugs for specific purposes (such as DNAbinding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH]

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Duodenum: The first part of the small intestine. [NIH] 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] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dysmenorrhea: Painful menstruation. [NIH] Dyspepsia: Impaired digestion, especially after eating. [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] Echocardiography: Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. [NIH] Eclampsia: Onset of convulsions or coma in a previously diagnosed pre-eclamptic patient. [NIH]

Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Effusion: The escape of fluid into a part or tissue, as an exudation or a transudation. [EU] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electroporation: A technique in which electric pulses of intensity in kilovolts per centimeter and of microsecond-to-millisecond duration cause a temporary loss of the semipermeability of cell membranes, thus leading to ion leakage, escape of metabolites, and increased uptake by cells of drugs, molecular probes, and DNA. Some applications of electroporation include introduction of plasmids or foreign DNA into living cells for transfection, fusion of cells to prepare hybridomas, and insertion of proteins into cell membranes. [NIH] Emboli: Bit of foreign matter which enters the blood stream at one point and is carried until

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it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embolism: Blocking of a blood vessel by a blood clot or foreign matter that has been transported from a distant site by the blood stream. [NIH] Embolization: The blocking of an artery by a clot or foreign material. Embolization can be done as treatment to block the flow of blood to a tumor. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] 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] Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Endarterectomy: Surgical excision, performed under general anesthesia, of the 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] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endogenous Retroviruses: Retroviruses that have integrated into the germline (Proviruses) that have lost infectious capability but retained the capability to transpose. [NIH] Endometrium: The layer of tissue that lines the uterus. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] 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

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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] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Enterohepatic: Of or involving the intestine and liver. [EU] Enterohepatic Circulation: Recycling through liver by excretion in bile, reabsorption from intestines into portal circulation, passage back into liver, and re-excretion in bile. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Environmental Monitoring: The monitoring of the level of toxins, chemical pollutants, microbial contaminants, or other harmful substances in the environment or workplace by measuring the amounts of these toxicants in the bodies of people and animals in that environment, among other methods. It also includes the measurement of environmental exposure. Levels in humans and animals are used as indicators of toxic levels of undesirable chemicals. [NIH] Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Activation: Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1) activation by ions (activators); 2) activation by cofactors (coenzymes); and 3) conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized

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causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epidural: The space between the wall of the spinal canal and the covering of the spinal cord. An epidural injection is given into this space. [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]

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] Erythrocyte Volume: Volume of circulating erythrocytes. It is usually measured by radioisotope dilution technique. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythromycin: A bacteriostatic antibiotic substance produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Esophageal Varices: Stretched veins in the esophagus that occur when the liver is not

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working properly. If the veins burst, the bleeding can cause death. [NIH] Esophagitis: Inflammation, acute or chronic, of the esophagus caused by bacteria, chemicals, or trauma. [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] Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethanolamine: A viscous, hygroscopic amino alcohol with an ammoniacal odor. It is widely distributed in biological tissue and is a component of lecithin. It is used as a surfactant, fluorimetric reagent, and to remove CO2 and H2S from natural gas and other gases. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evacuation: An emptying, as of the bowels. [EU] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excrete: To get rid of waste from the body. [NIH] Exfoliation: A falling off in scales or layers. [EU] 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] 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]

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Extrapyramidal: Outside of the pyramidal tracts. [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] Failure to Thrive: A condition in which an infant or child's weight gain and growth are far below usual levels for age. [NIH] Fallopian Tubes: Two long muscular tubes that transport ova from the ovaries to the uterus. They extend from the horn of the uterus to the ovaries and consist of an ampulla, an infundibulum, an isthmus, two ostia, and a pars uterina. The walls of the tubes are composed of three layers: mucosal, muscular, and serosal. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Fatty Liver: The buildup of fat in liver cells. The most common cause is alcoholism. Other causes include obesity, diabetes, and pregnancy. Also called steatosis. [NIH] Fatty Liver, Alcoholic: Fatty liver in alcoholics. It is potentially reversible and may be associated with alcoholic hepatitis or cirrhosis. [NIH] Febrile: Pertaining to or characterized by fever. [EU] Fecal Incontinence: Failure of voluntary control of the anal sphincters, with involuntary passage of feces and flatus. [NIH] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Felodipine: A dihydropyridine calcium antagonist with positive inotropic effects. It lowers blood pressure by reducing peripheral vascular resistance through a highly selective action on smooth muscle in arteriolar resistance vessels. [NIH] Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [NIH] Fetoprotein: Transabdominal aspiration of fluid from the amniotic sac with a view to detecting increases of alpha-fetoprotein in maternal blood during pregnancy, as this is an important indicator of open neural tube defects in the fetus. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibril: Most bacterial viruses have a hollow tail with specialized fibrils at its tip. The tail fibers attach to the cell wall of the host. [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]

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Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] 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] Fibronectin: An adhesive glycoprotein. One form circulates in plasma, acting as an opsonin; another is a cell-surface protein which mediates cellular adhesive interactions. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flatus: Gas passed through the rectum. [NIH] Flavivirus: A genus of Flaviviridae, also known as Group B arbovirus, containing several subgroups and species. Most are arboviruses transmitted by mosquitoes or ticks. The type species is yellow fever virus. [NIH] Flumazenil: A potent benzodiazepine receptor antagonist. Since it reverses the sedative and other actions of benzodiazepines, it has been suggested as an antidote to benzodiazepine overdoses. [NIH] Focus Groups: A method of data collection and a qualitative research tool in which a small group of individuals are brought together and allowed to interact in a discussion of their opinions about topics, issues, or questions. [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] Forearm: The part between the elbow and the wrist. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has

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calories. [NIH] Fructose Intolerance: An autosomal recessive fructose metabolism disorder due to deficient fructose-1-phosphate aldolase (EC 2.1.2.13) activity, resulting in accumulation of fructose-1phosphate. The accumulated fructose-1-phosphate inhibits glycogenolysis and gluconeogenesis, causing severe hypoglycemia following ingestion of fructose. Prolonged fructose ingestion in infants leads ultimately to hepatic failure and death. Patients develop a strong distaste for sweet food, and avoid a chronic course of the disease by remaining on a fructose- and sucrose-free diet. [NIH] 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] Galactosemia: Buildup of galactose in the blood. Caused by lack of one of the enzymes needed to break down galactose into glucose. [NIH] Galenical: 1. Usually cap: of or relating to Galen or his medical principles or method. 2. Constituting a galenical. [EU] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallstones: The solid masses or stones made of cholesterol or bilirubin that form in the gallbladder or bile ducts. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Gamma-Glutamyltransferase: An enzyme that catalyzes reversibly the transfer of a glutamyl group from a glutamyl-peptide and an amino acid to a peptide and a glutamylamino acid. EC 2.3.2.2. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gangrene: Death and putrefaction of tissue usually due to a loss of blood supply. [NIH] Gangrenous: A circumscribed, deep-seated, suppurative inflammation of the subcutaneous tissue of the eyelid discharging pus from several points. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Juices: Liquids produced in the stomach to help break down food and kill bacteria. [NIH]

Gastric Mucosa: Surface epithelium in the stomach that invaginates into the lamina propria, forming gastric pits. Tubular glands, characteristic of each region of the stomach (cardiac, gastric, and pyloric), empty into the gastric pits. The gastric mucosa is made up of several different kinds of cells. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastritis: Inflammation of the stomach. [EU] Gastroenterologist: A doctor who specializes in diagnosing and treating disorders of the

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digestive system. [NIH] Gastroenterology: A subspecialty of internal medicine concerned with the study of the physiology and diseases of the digestive system and related structures (esophagus, liver, gallbladder, and pancreas). [NIH] Gastroesophageal Reflux: Reflux of gastric juice and/or duodenal contents (bile acids, pancreatic juice) into the distal esophagus, commonly due to incompetence of the lower esophageal sphincter. Gastric regurgitation is an extension of this process with entry of fluid into the pharynx or mouth. [NIH] Gastroesophageal Reflux Disease: Flow of the stomach's contents back up into the esophagus. Happens when the muscle between the esophagus and the stomach (the lower esophageal sphincter) is weak or relaxes when it shouldn't. May cause esophagitis. Also called esophageal reflux or reflux esophagitis. [NIH] Gastrointestinal: Refers to the stomach and intestines. [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] Gelatinase A: A secreted endopeptidase homologous with interstitial collagenase, but which possesses an additional fibronectin-like domain. EC 3.4.24.24. [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]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic 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 testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetic transcription: The process by which the genetic information encoded in the gene, represented as a linear sequence of deoxyribonucleotides, is copied into an exactly complementary sequence of ribonucleotides known as messenger RNA. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Giant Cells: Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium

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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] Gliosis: The production of a dense fibrous network of neuroglia; includes astrocytosis, which is a proliferation of astrocytes in the area of a degenerative lesion. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. [NIH] 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] Gluconeogenesis: The process by which glucose is formed from a non-carbohydrate source. [NIH]

Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

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Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

Gluten: The protein of wheat and other grains which gives to the dough its tough elastic character. [EU] 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] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycans: Heteropolysaccharides which contain an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages consisting of either N-acetylglucosamine or Nacetylgalactosamine. [NIH] Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Goats: Any of numerous agile, hollow-horned ruminants of the genus Capra, closely related to the sheep. [NIH] 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] Government Agencies: Administrative units of government responsible for policy making and management of governmental activities in the U.S. and abroad. [NIH] Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Grading: A system for classifying cancer cells in terms of how abnormal they appear when examined under a microscope. The objective of a grading system is to provide information about the probable growth rate of the tumor and its tendency to spread. The systems used to grade tumors vary with each type of cancer. Grading plays a role in treatment decisions. [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] Grafting: The operation of transfer of tissue from one site to another. [NIH] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH]

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Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-Negative Bacteria: Bacteria which lose crystal violet stain but are stained pink when treated by Gram's method. [NIH] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Granuloma: A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. [NIH] Gravidity: Pregnancy; the condition of being pregnant, without regard to the outcome. [EU] Gravis: Eruption of watery blisters on the skin among those handling animals and animal products. [NIH] Group Practice: Any group of three or more full-time physicians organized in a legally recognized entity for the provision of health care services, sharing space, equipment, personnel and records for both patient care and business management, and who have a predetermined arrangement for the distribution of income. [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] Haematemesis: The vomiting of blood. [EU] 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] 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] Health Education: Education that increases the awareness and favorably influences the attitudes and knowledge relating to the improvement of health on a personal or community basis. [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [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] Hematoma: An extravasation of blood localized in an organ, space, or tissue. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH]

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Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] 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] Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemorrhagic stroke: A disorder involving bleeding within ischemic brain tissue. Hemorrhagic stroke occurs when blood vessels that are damaged or dead from lack of blood supply (infarcted), located within an area of infarcted brain tissue, rupture and transform an "ischemic" stroke into a hemorrhagic stroke. Ischemia is inadequate tissue oxygenation caused by reduced blood flow; infarction is tissue death resulting from ischemia. Bleeding irritates the brain tissues, causing swelling (cerebral edema). Blood collects into a mass (hematoma). Both swelling and hematoma will compress and displace brain tissue. [NIH] Hemorrhoids: Varicosities of the hemorrhoidal venous plexuses. [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]

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] Hepatic Artery: A branch of the celiac artery that distributes to the stomach, pancreas, duodenum, liver, gallbladder, and greater omentum. [NIH] Hepatic Encephalopathy: A condition that may cause loss of consciousness and coma. It is usually the result of advanced liver disease. Also called hepatic coma. [NIH] Hepatic Veins: Veins which drain 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

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contamination of food or water. [NIH] Hepatitis B: Hepatitis caused by hepatitis B virus. It may be transmitted by transfusion of contaminated blood or blood products. [NIH] Hepatitis D: Hepatitis caused by the hepatitis delta virus in association with hepatitis B. It is endemic in some European countries and is seen in drug users, hemophiliacs, and polytransfused persons. [NIH] Hepatitis Delta Virus: A defective virus, containing particles of RNA nucleoprotein in virion-like form, present in patients with acute hepatitis B and chronic hepatitis. Officially this is classified as a subviral satellite RNA. [NIH] Hepatitis Viruses: Any of the viruses that cause inflammation of the liver. They include both DNA and RNA viruses as well viruses from humans and animals. [NIH] 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] Hepatobiliary: Pertaining to the liver and the bile or the biliary ducts. [EU] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] 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] Hepatologist: A doctor who specializes in liver diseases. [NIH] Hepatology: The field of medicine concerned with the functions and disorders of the liver. [NIH]

Hepatoma: A liver tumor. [NIH] Hepatopulmonary Syndrome: A syndrome consisting of the triad of liver dysfunction, pulmonary vascular dilatation, and abnormal arterial oxygenation in the absence of detectable intrinsic disease of the lung and heart. [NIH] Hepatorenal Syndrome: Renal failure in those with liver disease, usually liver cirrhosis or obstructive jaundice. Historically called Heyd disease, urohepatic syndrome, or bile nephrosis. [NIH] Hepatotoxic: Toxic to liver cells. [EU] 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] Hernia: Protrusion of a loop or knuckle of an organ or tissue through an abnormal opening. [NIH]

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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]

Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [NIH]

Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hospital Mortality: A vital statistic measuring or recording the rate of death from any cause in hospitalized populations. [NIH] Hospitals, Public: Hospitals controlled by various types of government, i.e., city, county, district, state or federal. [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] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] 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] Hydrocephalus: Excessive accumulation of cerebrospinal fluid within the cranium which may be associated with dilation of cerebral ventricles, intracranial hypertension; headache; lethargy; urinary incontinence; and ataxia (and in infants macrocephaly). This condition may be caused by obstruction of cerebrospinal fluid pathways due to neurologic abnormalities, intracranial hemorrhages; central nervous system infections; brain neoplasms; craniocerebral trauma; and other conditions. Impaired resorption of

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cerebrospinal fluid from the arachnoid villi results in a communicating form of hydrocephalus. Hydrocephalus ex-vacuo refers to ventricular dilation that occurs as a result of brain substance loss from cerebral infarction and other conditions. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [NIH]

Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolases: Any member of the class of enzymes that catalyze the cleavage of the substrate and the addition of water to the resulting molecules, e.g., esterases, glycosidases (glycoside hydrolases), lipases, nucleotidases, peptidases (peptide hydrolases), and phosphatases (phosphoric monoester hydrolases). EC 3. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] 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] Hyperammonemia: Metabolic disorder characterized by elevated level of ammonia in blood. [NIH] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperlipidemia: An excess of lipids in the blood. [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] Hypersplenism: Condition characterized by splenomegaly, some reduction in the number of circulating blood cells in the presence of a normal or hyperactive bone marrow, and the potential for reversal by splenectomy. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertension, Pulmonary: Increased pressure within the pulmonary circulation, usually

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secondary to cardiac or pulmonary disease. [NIH] Hypertension, Renovascular: Hypertension due to compression or obstruction of the renal artery or its branches. [NIH] Hyperthyroidism: Excessive functional activity of the thyroid gland. [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] Hypesthesia: Absent or reduced sensitivity to cutaneous stimulation. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypoglycemia: Abnormally low blood sugar [NIH] Hypokinesia: Slow or diminished movement of body musculature. It may be associated with basal ganglia diseases; mental disorders; prolonged inactivity due to illness; experimental protocols used to evaluate the physiologic effects of immobility; and other conditions. [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypotensive: Characterized by or causing diminished tension or pressure, as abnormally low blood pressure. [EU] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [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] 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] Ileus: Obstruction of the intestines. [EU] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune Complex Diseases: Group of diseases mediated by the deposition of large soluble complexes of antigen and antibody with resultant damage to tissue. Besides serum sickness and the arthus reaction, evidence supports a pathogenic role for immune complexes in many other systemic immunologic diseases including glomerulonephritis, systemic lupus erythematosus and polyarteritis nodosa. [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 Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [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

effects

of

foreign

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microorganisms or to the toxic effect of antigenic substances. [NIH] 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] Immunization Programs: Organized services to administer immunization procedures in the prevention of various diseases. The programs are made available over a wide range of sites: schools, hospitals, public health agencies, voluntary health agencies, etc. They are administered to an equally wide range of population groups or on various administrative levels: community, municipal, state, national, international. [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [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] Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunodeficiency syndrome: The inability of the body to produce an immune response. [NIH]

Immunogenic: Producing immunity; evoking an immune response. [EU] 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] Immunomodulator: New type of drugs mainly using biotechnological methods. Treatment of cancer. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [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] Imperforate Anus: A birth defect in which the anal canal fails to develop. The condition is treated with an operation. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH]

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Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] 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] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Indigestion: Poor digestion. Symptoms include heartburn, nausea, bloating, and gas. Also called dyspepsia. [NIH] Indinavir: A potent and specific HIV protease inhibitor that appears to have good oral bioavailability. [NIH] 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] Infantile: Pertaining to an infant or to infancy. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] 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

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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] Inoperable: Not suitable to be operated upon. [EU] Inorganic: Pertaining to substances not of organic origin. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [NIH] 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] 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,

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immune and nonimmune defense mechanisms, and oncogenic transformation. [NIH] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]

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-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] 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-10: Factor that is a coregulator of mast cell growth. It is produced by T-cells and B-cells and shows extensive homology with the Epstein-Barr virus BCRFI gene. [NIH] Interleukin-11: Lymphohematopoietic cytokine that has the ability to modulate antigenspecific antibody responses, potentiate megakaryocytes, and regulate bone marrow adipogenesis. [NIH] Interleukin-12: A heterodimeric cytokine that stimulates the production of interferon gamma from T-cells and natural killer cells, and also induces differentiation of Th1 helper cells. It is an initiator of cell-mediated immunity. [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] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds,

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wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Interstitial Collagenase: A member of the metalloproteinase family of enzymes that is principally responsible for cleaving fibrillar collagen. It can degrade interstitial collagens, types I, II and III. EC 3.4.24.7. [NIH] Intestinal: Having to do with the intestines. [NIH] Intestinal Flora: The bacteria, yeasts, and fungi that grow normally in 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] Intracranial Aneurysm: A saclike dilatation of the walls of a blood vessel, usually an artery. [NIH]

Intracranial Arteriosclerosis: Vascular diseases characterized by thickening, hardening, and remodeling of the walls of intracranial arteries. There are three subtypes: (1) atherosclerosis, marked by fatty depositions in the innermost layer of the arterial walls, (2) Monckeberg's sclerosis, which features calcium deposition in the media and (3) arteriolosclerosis, which refers to sclerosis of small caliber arteries. Clinically, this process may be associated with transient ischemic attack, brain infarction, intracranial embolism and thrombosis, or intracranial aneurysm. [NIH] Intrahepatic: Within the liver. [NIH] Intrahepatic bile ducts: The bile ducts that pass through and drain bile from the liver. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs). [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Inulin: A starch found in the tubers and roots of many plants. Since it is hydrolyzable to fructose, it is classified as a fructosan. It has been used in physiologic investigation for determination of the rate of glomerular function. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Invertebrates: Animals that have no spinal column. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH] Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active or passive. Passive ion transport (facilitated diffusion) derives its energy from the concentration gradient of the ion itself and allows the transport of a single solute in one direction (uniport). Active ion transport is usually coupled to an energy-yielding chemical or photochemical reaction such as ATP hydrolysis. This form of primary active transport is

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called an ion pump. Secondary active transport utilizes the voltage and ion gradients produced by the primary transport to drive the cotransport of other ions or molecules. These may be transported in the same (symport) or opposite (antiport) direction. [NIH] 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] Irritable Bowel Syndrome: A disorder that comes and goes. Nerves that control the muscles in the GI tract are too active. The GI tract becomes sensitive to food, stool, gas, and stress. Causes abdominal pain, bloating, and constipation or diarrhea. Also called spastic colon or mucous colitis. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoenzyme: Different forms of an enzyme, usually occurring in different tissues. The isoenzymes of a particular enzyme catalyze the same reaction but they differ in some of their properties. [NIH] Isoprenoid: Molecule that might anchor G protein to the cell membrane as it is hydrophobic. [NIH]

Isosorbide: 1,4:3,6-Dianhydro D-glucitol. Chemically inert osmotic diuretic used mainly to treat hydrocephalus; also used in glaucoma. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kallidin: A decapeptide bradykinin homolog produced by the action of tissue and glandular kallikreins on low-molecular-weight kininogen. It is a smooth-muscle stimulant and hypotensive agent that functions through vasodilatation. [NIH] Kallikreins: Proteolytic enzymes from the serine endopeptidase family found in normal blood and urine. Specifically, Kallikreins are potent vasodilators and hypotensives and increases vascular permeability and affects smooth muscle. They act as infertility agents in men. Three forms are recognized, plasma kallikrein (EC 3.4.21.34), tissue kallikrein (EC 3.4.21.35), and prostate-specific antigen (EC 3.4.21.77). [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]

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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] Keratoconjunctivitis: Simultaneous inflammation of the cornea and conjunctiva. [NIH] Keratoconjunctivitis Sicca: Drying and inflammation of the conjunctiva as a result of insufficient lacrimal secretion. When found in association with xerostomia and polyarthritis, it is called Sjogren's syndrome. [NIH] Keto: It consists of 8 carbon atoms and within the endotoxins, it connects poysaccharide and lipid A. [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. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [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] Lactulose: A mild laxative. [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] Lamivudine: A reverse transcriptase inhibitor and zalcitabine analog in which a sulfur atom replaces the 3' carbon of the pentose ring. It is used to treat HIV disease. [NIH] Laparoscopy: Examination, therapy or surgery of the abdomen's interior by means of a laparoscope. [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] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH]

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Lavage: A cleaning of the stomach and colon. Uses a special drink and enemas. [NIH] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]

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] Leptin: A 16-kD peptide hormone secreted from white adipocytes and implicated in the regulation of food intake and energy balance. Leptin provides the key afferent signal from fat cells in the feedback system that controls body fat stores. [NIH] Lesion: An area of abnormal tissue change. [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] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukocytosis: A transient increase in the number of leukocytes in a body fluid. [NIH] Levo: It is an experimental treatment for heroin addiction that was developed by German scientists around 1948 as an analgesic. Like methadone, it binds with opioid receptors, but it is longer acting. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] 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] Lipid Peroxides: Peroxides produced in the presence of a free radical by the oxidation of unsaturated fatty acids in the cell in the presence of molecular oxygen. The formation of lipid peroxides results in the destruction of the original lipid leading to the loss of integrity of the membranes. They therefore cause a variety of toxic effects in vivo and their formation is considered a pathological process in biological systems. Their formation can be inhibited by antioxidants, such as vitamin E, structural separation or low oxygen tension. [NIH] Lipodystrophy: A collection of rare conditions resulting from defective fat metabolism and characterized by atrophy of the subcutaneous fat. They include total, congenital or acquired, partial, abdominal infantile, and localized lipodystrophy. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU]

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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] Lithium: An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH]

Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver cancer: A disease in which malignant (cancer) cells are found in the tissues of the liver. [NIH]

Liver Cirrhosis: Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules. [NIH] Liver Mitochondria: Yellow discoloration of the liver due to fatty degeneration of liver parenchymal cells; the cause may be chemical poisoning. [NIH] Liver Regeneration: Repair or renewal of hepatic tissue. [NIH] Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [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 study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Long-Term Care: Care over an extended period, usually for a chronic condition or disability, requiring periodic, intermittent, or continuous care. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Lovastatin: A fungal metabolite isolated from cultures of Aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. [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]

Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The

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color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lumen: The cavity or channel within a tube or tubular organ. [EU] 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] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [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] 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] Lymphokines: Soluble protein factors generated by activated lymphocytes that affect other cells, primarily those involved in cellular immunity. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lymphoscintigraphy: A method used to identify the sentinel node (the first draining lymph node near a tumor). A radioactive substance that can be taken up by lymph nodes is injected at the site of the tumor, and a doctor follows the movement of this substance on a computer screen. Once the lymph nodes that have taken up the substance are identified, they can be removed and examined to see if they contain tumor cells. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] 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] Macrophage Activation: The process of altering the morphology and functional activity of macrophages so that they become avidly phagocytic. It is initiated by lymphokines, such as the macrophage activation factor (MAF) and the macrophage migration-inhibitory factor (MMIF), immune complexes, C3b, and various peptides, polysaccharides, and immunologic adjuvants. [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] Maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. [NIH]

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Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] 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] Manic: Affected with mania. [EU] Maple Syrup Urine Disease: A genetic disorder involving deficiency of an enzyme necessary in the metabolism of branched-chain amino acids, and named for the characteristic odor of the urine. [NIH] Mastitis: Inflammatory disease of the breast, or mammary gland. [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] 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] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] Medical Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and

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store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Fluidity: The motion of phospholipid molecules within the lipid bilayer, dependent on the classes of phospholipids present, their fatty acid composition and degree of unsaturation of the acyl chains, the cholesterol concentration, and temperature. [NIH] Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They 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] Menarche: The establishment or beginning of the menstrual function. [EU] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesothelial: It lines the peritonealla and pleural cavities. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [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] 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

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the original (primary) tumor. The plural is metastases. [NIH] Methimazole: A thioureylene antithyroid agent that inhibits the formation of thyroid hormones by interfering with the incorporation of iodine into tyrosyl residues of thyroglobulin. This is done by interfering with the oxidation of iodide ion and iodotyrosyl groups through inhibition of the peroxidase enzyme. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [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] 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] Microgram: A unit of mass (weight) of the metric system, being one-millionth of a gram (106 gm.) or one one-thousandth of a milligram (10-3 mg.). [EU] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Midazolam: A short-acting compound, water-soluble at pH less than 4 and lipid-soluble at physiological pH. It is a hypnotic-sedative drug with anxiolytic and amnestic properties. It is used for sedation in dentistry, cardiac surgery, endoscopic procedures, as preanesthetic medication, and as an adjunct to local anesthesia. Because of its short duration and cardiorespiratory stability, it is particularly useful in poor-risk, elderly, and cardiac patients. [NIH]

Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Milk Thistle: The plant Silybum marianum in the family Asteraceae containing the bioflavonoid complex silymarin. For centuries this has been used traditionally to treat liver disease. [NIH] Milligram: A measure of weight. A milligram is approximately 450,000-times smaller than a pound and 28,000-times smaller than an ounce. [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] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it

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occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mitotic inhibitors: Drugs that kill cancer cells by interfering with cell division (mitostis). [NIH]

Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Probes: A group of atoms or molecules attached to other molecules or cellular structures and used in studying the properties of these molecules and structures. Radioactive DNA or RNA sequences are used in molecular genetics to detect the presence of a complementary sequence by molecular hybridization. [NIH] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monocyte: A type of white blood cell. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monotherapy: A therapy which uses only one drug. [EU] 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 forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Motor Cortex: Area of the frontal lobe concerned with primary motor control. It lies anterior

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to the central sulcus. [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Multivalent: Pertaining to a group of 5 or more homologous or partly homologous chromosomes during the zygotene stage of prophase to first metaphasis in meiosis. [NIH] Multivariate Analysis: A set of techniques used when variation in several variables has to be studied simultaneously. In statistics, multivariate analysis is interpreted as any analytic method that allows simultaneous study of two or more dependent variables. [NIH] Muscle Contraction: A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Musculature: The muscular apparatus of the body, or of any part of it. [EU] Mustard Gas: Severe irritant and vesicant of skin, eyes, and lungs. It may cause blindness and lethal lung edema and was formerly used as a war gas. The substance has been proposed as a cytostatic and for treatment of psoriasis. It has been listed as a known carcinogen in the Fourth Annual Report on Carcinogens (NTP-85-002, 1985) (Merck, 11th ed). [NIH] Mutagen: Any agent, such as X-rays, gamma rays, mustard gas, TCDD, that can cause abnormal mutation in living cells; having the power to cause mutations. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Myalgia: Pain in a muscle or muscles. [EU] Myasthenia: Muscular debility; any constitutional anomaly of muscle. [EU] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelitis: Inflammation of the spinal cord. Relatively common etiologies include infections; autoimmune diseases; spinal cord; and ischemia (see also spinal cord vascular diseases).

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Clinical features generally include weakness, sensory loss, localized pain, incontinence, and other signs of autonomic dysfunction. [NIH] Myelofibrosis: A disorder in which the bone marrow is replaced by fibrous tissue. [NIH] 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] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [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] Myofibrils: Highly organized bundles of actin, myosin, and other proteins in the cytoplasm of skeletal and cardiac muscle cells that contract by a sliding filament mechanism. [NIH] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Naloxone: A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors. [NIH] Naltrexone: Derivative of noroxymorphone that is the N-cyclopropylmethyl congener of naloxone. It is a narcotic antagonist that is effective orally, longer lasting and more potent than naloxone, and has been proposed for the treatment of heroin addiction. The FDA has approved naltrexone for the treatment of alcohol dependence. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Nasal 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] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [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] Necrolysis: Separation or exfoliation of tissue due to necrosis. [EU] Necrosis: A pathological process caused by the progressive degradative action of enzymes

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that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Needle Sharing: Usage of a single needle among two or more people for injecting drugs. Needle sharing is a high-risk behavior for contracting infectious disease. [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] Nephrogenic: Constant thirst and frequent urination because the kidney tubules cannot respond to antidiuretic hormone. The result is an increase in urine formation and excessive urine flow. [NIH] Nephron: A tiny part of the kidneys. Each kidney is made up of about 1 million nephrons, which are the working units of the kidneys, removing wastes and extra fluids from the blood. [NIH] Nephropathy: Disease of the kidneys. [EU] Nephrosis: Descriptive histopathologic term for renal disease without an inflammatory component. [NIH] Nephrotic: Pertaining to, resembling, or caused by nephrosis. [EU] Nephrotic Syndrome: Clinical association of heavy proteinuria, hypoalbuminemia, and generalized edema. [NIH] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neural tube defects: These defects include problems stemming from fetal development of the spinal cord, spine, brain, and skull, and include birth defects such as spina bifida, anencephaly, and encephalocele. Neural tube defects occur early in pregnancy at about 4 to 6 weeks, usually before a woman knows she is pregnant. Many babies with neural tube defects have difficulty walking and with bladder and bowel control. [NIH] Neuralgia: Intense or aching pain that occurs along the course or distribution of a peripheral or cranial nerve. [NIH] Neuritis: A general term indicating inflammation of a peripheral or cranial nerve. Clinical manifestation may include pain; paresthesias; paresis; or hypesthesia. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neuroglia: The non-neuronal cells of the nervous system. They are divided into macroglia (astrocytes, oligodendroglia, and schwann cells) and microglia. They not only provide physical support, but also respond to injury, regulate the ionic and chemical composition of

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the extracellular milieu, participate in the blood-brain and blood-retina barriers, form the myelin insulation of nervous pathways, guide neuronal migration during development, and exchange metabolites with neurons. Neuroglia have high-affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitters, but their role in signaling (as in many other functions) is unclear. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neuropsychological Tests: Tests designed to assess neurological function associated with certain behaviors. They are used in diagnosing brain dysfunction or damage and central nervous system disorders or injury. [NIH] Neuropsychology: A branch of psychology which investigates the correlation between experience or behavior and the basic neurophysiological processes. The term neuropsychology stresses the dominant role of the nervous system. It is a more narrowly defined field than physiological psychology or psychophysiology. [NIH] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]

Neurotransmitters: Endogenous signaling molecules that alter the behavior of neurons or effector cells. Neurotransmitter is used here in its most general sense, including not only messengers that act directly to regulate ion channels, but also those that act through second messenger systems, and those that act at a distance from their site of release. Included are neuromodulators, neuroregulators, neuromediators, and neurohumors, whether or not acting at synapses. [NIH] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Neutrophil Infiltration: The diffusion or accumulation of neutrophils in tissues or cells in response to a wide variety of substances released at the sites of inflammatory reactions. [NIH] Nifedipine: A potent vasodilator agent with calcium antagonistic action. It is a useful antianginal agent that also lowers blood pressure. The use of nifedipine as a tocolytic is being investigated. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It

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is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal 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] 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] Nucleocapsid: A protein-nucleic acid complex which forms part or all of a virion. It consists of a capsid plus enclosed nucleic acid. Depending on the virus, the nucleocapsid may correspond to a naked core or be surrounded by a membranous envelope. [NIH] Nucleotidases: A class of enzymes that catalyze the conversion of a nucleotide and water to a nucleoside and orthophosphate. EC 3.1.3.-. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Observational study: An epidemiologic study that does not involve any intervention, experimental or otherwise. Such a study may be one in which nature is allowed to take its course, with changes in one characteristic being studied in relation to changes in other characteristics. Analytical epidemiologic methods, such as case-control and cohort study designs, are properly called observational epidemiology because the investigator is observing without intervention other than to record, classify, count, and statistically analyze results. [NIH] Occupational Exposure: The exposure to potentially harmful chemical, physical, or biological agents that occurs as a result of one's occupation. [NIH] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of

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prevalent cases. [NIH] Office Management: Planning, organizing, and administering activities in an office. [NIH] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oltipraz: A drug used in cancer prevention. [NIH] Omentum: A fold of the peritoneum (the thin tissue that lines the abdomen) that surrounds the stomach and other organs in the abdomen. [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] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [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] 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 suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Orf: A specific disease of sheep and goats caused by a pox-virus that is transmissible to man and characterized by vesiculation and ulceration of the lips. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [NIH] Osmolality: The concentration of osmotically active particles in solution expressed in terms of osmoles of solute per kilogram of solvent. The osmolality is directly proportional to the colligative properties of solutions; osmotic pressure, boiling point elevation, freezing point depression, and vapour pressure lowering. [EU] Osmoles: The standard unit of osmotic pressure. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis,

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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] 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] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [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] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [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]

Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] 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] Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] 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 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

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associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] Panniculitis: General term for inflammation of adipose tissue, usually of the skin, characterized by reddened subcutaneous nodules. [NIH] Paracentesis: A procedure in which fluid is withdrawn from a body cavity via a trocar and cannula, needle, or other hollow instrument. [NIH] Paraffin: A mixture of solid hydrocarbons obtained from petroleum. It has a wide range of uses including as a stiffening agent in ointments, as a lubricant, and as a topical antiinflammatory. It is also commonly used as an embedding material in histology. [NIH] Parapoxvirus: A genus of the family Poxviridae, subfamily Chordopoxvirinae, which infect ungulates and may infect humans. Orf virus is the type species. [NIH] Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Parenchyma: The essential elements of an organ; used in anatomical nomenclature as a general term to designate the functional elements of an organ, as distinguished from its framework, or stroma. [EU] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Paresis: A general term referring to a mild to moderate degree of muscular weakness, occasionally used as a synonym for paralysis (severe or complete loss of motor function). In the older literature, paresis often referred specifically to paretic neurosyphilis. "General paresis" and "general paralysis" may still carry that connotation. Bilateral lower extremity paresis is referred to as paraparesis. [NIH] Paresthesias: Abnormal touch sensations, such as burning or prickling, that occur without an outside stimulus. [NIH] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] Parietal Lobe: Upper central part of the cerebral hemisphere. [NIH] Parity: The number of offspring a female has borne. It is contrasted with gravidity, which refers to the number of pregnancies, regardless of outcome. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] 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] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease.

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[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]

Peer Review: An organized procedure carried out by a select committee of professionals in evaluating the performance of other professionals in meeting the standards of their specialty. Review by peers is used by editors in the evaluation of articles and other papers submitted for publication. Peer review is used also in the evaluation of grant applications. It is applied also in evaluating the quality of health care provided to patients. [NIH] Pelvic: Pertaining to the pelvis. [EU] Penicillin: An antibiotic drug used to treat infection. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Pepsin A: Formed from pig pepsinogen by cleavage of one peptide bond. The enzyme is a single polypeptide chain and is inhibited by methyl 2-diaazoacetamidohexanoate. It cleaves peptides preferentially at the carbonyl linkages of phenylalanine or leucine and acts as the principal digestive enzyme of gastric juice. [NIH] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU] Peptic Ulcer: Ulcer that occurs in those portions of the alimentary tract which come into contact with gastric juice containing pepsin and acid. It occurs when the amount of acid and pepsin is sufficient to overcome the gastric mucosal barrier. [NIH] Peptic Ulcer Hemorrhage: Bleeding from a peptic ulcer. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide Chain Elongation: The process whereby an amino acid is joined through a substituted amide linkage to a chain of peptides. [NIH] Peptide Hydrolases: A subclass of enzymes from the hydrolase class that catalyze the hydrolysis of peptide bonds. Exopeptidases and endopeptidases make up the sub-subclasses for this group. EC 3.4. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericarditis: Inflammation of the pericardium. [EU] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU]

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Periodicity: The tendency of a phenomenon to recur at regular intervals; in biological systems, the recurrence of certain activities (including hormonal, cellular, neural) may be annual, seasonal, monthly, daily, or more frequently (ultradian). [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nerves: The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [NIH] Peripheral Vascular Disease: Disease in the large blood vessels of the arms, legs, and feet. People who have had diabetes for a long time may get this because major blood vessels in their arms, legs, and feet are blocked and these limbs do not receive enough blood. The signs of PVD are aching pains in the arms, legs, and feet (especially when walking) and foot sores that heal slowly. Although people with diabetes cannot always avoid PVD, doctors say they have a better chance of avoiding it if they take good care of their feet, do not smoke, and keep both their blood pressure and diabetes under good control. [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] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneovenous Shunt: An operation for the continuous emptying of ascitic fluid into the venous system. Fluid removal is based on intraperitoneal and intrathoracic superior vena cava pressure differentials and is performed via a pressure-sensitive one-way valve connected to a tube traversing the subcutaneous tissue of the chest wall to the neck where it enters the internal jugular vein and terminates in the superior vena cava. It is used in the treatment of intractable ascites. [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] Pernicious: Tending to a fatal issue. [EU] Pernicious anemia: A type of anemia (low red blood cell count) caused by the body's inability to absorb vitamin B12. [NIH] Peroxidase: A hemeprotein from leukocytes. Deficiency of this enzyme leads to a hereditary disorder coupled with disseminated moniliasis. It catalyzes the conversion of a donor and peroxide to an oxidized donor and water. EC 1.11.1.7. [NIH] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield

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combustible fuels, petrochemicals, and lubricants. [NIH] P-Glycoprotein: A 170 kD transmembrane glycoprotein from the superfamily of ABC transporters. It serves as an ATP-dependent efflux pump for a variety of chemicals, including many antineoplastic agents. Overexpression of this glycoprotein is associated with multidrug resistance. [NIH] Pgp: Protein that pumps chemotherapy drugs out of tumor cells before they can kill those cells. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [NIH] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] 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] Phenylephrine: An alpha-adrenergic agonist used as a mydriatic, nasal decongestant, and cardiotonic agent. [NIH] Phlebotomy: The letting of blood from a vein. Although it is one of the techniques used in drawing blood to be used in diagnostic procedures, in modern medicine, it is used commonly in the treatment of erythrocytosis, hemochromocytosis, polycythemia vera, and porphyria cutanea tarda. Its historical counterpart is bloodletting. (From Cecil Textbook of Medicine, 19th ed & Wintrobe's Clinical Hematology, 9th ed) Venipuncture is not only for the letting of blood from a vein but also for the injecting of a drug into the vein for diagnostic analysis. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [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]

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Phosphoric Monoester Hydrolases: A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate. EC 3.1.3. [NIH] Phosphorous: Having to do with or containing the element phosphorus. [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] 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] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Plant sterols: Plant-based compounds that can compete with dietary cholesterol to be absorbed by the intestines. This results in lower blood cholesterol levels. They may have some effect in cancer prevention. Also known as phytosterols. [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] Plasma Kallikrein: A peptidohydrolytic enzyme that is formed from prekallikrein by factor XIIA. It activates factor XII, factor VII, and plasminogen. It is selective for both arginine and to a lesser extent lysinebonds. EC 3.4.21.34. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU]

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Plasma Volume: Volume of plasma in the circulation. It is usually measured by indicator dilution techniques. [NIH] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [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 Inactivators: Important modulators of the activity of plasminogen activators. Four inhibitors, all belonging to the serpin family of proteins, have been implicated in plasminogen activation inhibition. They are PAI-1, PAI-2, protease-nexin, and protein C inhibitor (PAI-3). All inhibit both the tissue-type and urokinase-type plasminogen activators. [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 Count: A count of the number of platelets per unit volume in a sample of venous blood. [NIH] Platelet Factor 4: A high-molecular-weight proteoglycan-platelet factor complex which is released from blood platelets by thrombin. It acts as a mediator in the heparin-neutralizing capacity of the blood and plays a role in platelet aggregation. At high ionic strength (I=0.75), the complex dissociates into the active component (molecular weight 29,000) and the proteoglycan carrier (chondroitin 4-sulfate, molecular weight 350,000). The molecule exists in the form of a dimer consisting of 8 moles of platelet factor 4 and 2 moles of proteoglycan. [NIH]

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] 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]

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] Pleural cavity: A space enclosed by the pleura (thin tissue covering the lungs and lining the interior wall of the chest cavity). It is bound by thin membranes. [NIH] Pleural Effusion: Presence of fluid in the pleural cavity resulting from excessive transudation or exudation from the pleural surfaces. It is a sign of disease and not a diagnosis in itself. [NIH]

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Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Policy Making: The decision process by which individuals, groups or institutions establish policies pertaining to plans, programs or procedures. [NIH] Pollen: The male fertilizing element of flowering plants analogous to sperm in animals. It is released from the anthers as yellow dust, to be carried by insect or other vectors, including wind, to the ovary (stigma) of other flowers to produce the embryo enclosed by the seed. The pollens of many plants are allergenic. [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] Polycythemia Vera: A myeloproliferative disorder of unknown etiology, characterized by abnormal proliferation of all hematopoietic bone marrow elements and an absolute increase in red cell mass and total blood volume, associated frequently with splenomegaly, leukocytosis, and thrombocythemia. Hematopoiesis is also reactive in extramedullary sites (liver and spleen). In time myelofibrosis occurs. [NIH] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [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] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [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]

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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] 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] Portacaval: Surgical creation of an anastomosis between the portal and caval veins. [NIH] Portal Pressure: The venous pressure measured in the portal vein. [NIH] Portal Vein: A short thick vein formed by union of the superior mesenteric vein and the splenic vein. [NIH] Portosystemic Shunt: An operation to create an opening between the portal vein and other veins around the liver. [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] Postherpetic Neuralgia: Variety of neuralgia associated with migraine in which pain is felt in or behind the eye. [NIH] 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] Postprandial: Occurring after dinner, or after a meal; postcibal. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [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] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH] Potentiate: 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 convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precipitating Factors: Factors associated with the definitive onset of a disease, illness, accident, behavioral response, or course of action. Usually one factor is more important or more obviously recognizable than others, if several are involved, and one may often be regarded as "necessary". Examples include exposure to specific disease; amount or level of an infectious organism, drug, or noxious agent, etc. [NIH] Precipitation: The act or process of precipitating. [EU]

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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] Predictive factor: A situation or condition that may increase a person's risk of developing a certain disease or disorder. [NIH] 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] Preeclampsia: A toxaemia of late pregnancy characterized by hypertension, edema, and proteinuria, when convulsions and coma are associated, it is called eclampsia. [EU] Prekallikrein: A plasma protein which is the precursor of kallikrein. Plasma that is deficient in prekallikrein has been found to be abnormal in thromboplastin formation, kinin generation, evolution of a permeability globulin, and plasmin formation. The absence of prekallikrein in plasma leads to Fletcher factor deficiency, a congenital disease. [NIH] Preload: The tension in the heart muscle at the end of diastole (before the contraction). [EU] 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] 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] 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] Proenzyme: 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] Prognostic factor: A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease, or the chance of the disease recurring (coming back). [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] 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] Prophase: The first phase of cell division, in which the chromosomes become visible, the

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nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [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] Propranolol: A widely used non-cardioselective beta-adrenergic antagonist. Propranolol is used in the treatment or prevention of many disorders including acute myocardial infarction, arrhythmias, angina pectoris, hypertension, hypertensive emergencies, hyperthyroidism, migraine, pheochromocytoma, menopause, and anxiety. [NIH] Prospective Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] 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] Prostatic Hyperplasia: Enlargement or overgrowth of the prostate gland as a result of an increase in the number of its constituent cells. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of

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proteases (endopeptidases). [NIH] Protective Agents: Synthetic or natural substances which are given to prevent a disease or disorder or are used in the process of treating a disease or injury due to a poisonous agent. [NIH]

Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] 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] Proteoglycans: Glycoproteins which have a very high polysaccharide content. [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]

Prothrombin Time: Measurement of clotting time of plasma recalcified in the presence of excess tissue thromboplastin. Factors measured are fibrinogen, prothrombin, and factors V, VII, and X. It is used for monitoring anticoagulant therapy with coumarins. [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] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Prune Belly Syndrome: A syndrome characterized by abdominal wall musculature deficiency, cryptorchism, and urinary tract abnormalities. The syndrome derives its name from its characteristic distended abdomen with wrinkled skin. [NIH] Pruritus: An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. [NIH] Pseudocholinesterase: An aspect of cholinesterases. [NIH] Psoriasis: A common genetically determined, chronic, inflammatory skin disease

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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] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychophysiology: The study of the physiological basis of human and animal behavior. [NIH]

Psychotropic: Exerting an effect upon the mind; capable of modifying mental activity; usually applied to drugs that effect the mental state. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary 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 Embolism: Embolism in the pulmonary artery or one of its branches. [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 Gas Exchange: The exchange of oxygen and carbon dioxide between alveolar air and pulmonary capillary blood. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [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]

Pupil: The aperture in the iris through which light passes. [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

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pus. [EU] Putrefaction: The process of decomposition of animal and vegetable matter by living organisms. [NIH] Pyramidal Tracts: Fibers that arise from cells within the cerebral cortex, pass through the medullary pyramid, and descend in the spinal cord. Many authorities say the pyramidal tracts include both the corticospinal and corticobulbar tracts. [NIH] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH] Pyruvate Dehydrogenase Complex: An organized assembly of three kinds of enzymes; catalyzes the oxidative decarboxylation of pyruvate. [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] Quercetin: Aglucon of quercetrin, rutin, and other glycosides. It is widely distributed in the plant kingdom, especially in rinds and barks, clover blossoms, and ragweed pollen. [NIH] Quiescent: Marked by a state of inactivity or repose. [EU] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radioimmunoassay: Classic quantitative assay for detection of antigen-antibody reactions using a radioactively labeled substance (radioligand) either directly or indirectly to measure the binding of the unlabeled substance to a specific antibody or other receptor system. Nonimmunogenic substances (e.g., haptens) can be measured if coupled to larger carrier proteins (e.g., bovine gamma-globulin or human serum albumin) capable of inducing antibody formation. [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] 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

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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] Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. [NIH] Randomization: Also called random allocation. Is allocation of individuals to groups, e.g., for experimental and control regimens, by chance. Within the limits of chance variation, random allocation should make the control and experimental groups similar at the start of an investigation and ensure that personal judgment and prejudices of the investigator do not influence allocation. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Reabsorption: 1. The act or process of absorbing again, as the selective absorption by the kidneys of substances (glucose, proteins, sodium, etc.) already secreted into the renal tubules, and their return to the circulating blood. 2. Resorption. [EU] Reactivation: The restoration of activity to something that has been inactivated. [EU] 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] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [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] 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] Recur: To occur again. Recurrence is the return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [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] 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] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a specific risk factor to the incidence rate among unexposed individuals; synonymous with risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [NIH] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]

Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal Artery: A branch of the abdominal aorta which supplies the kidneys, adrenal glands and ureters. [NIH] Renal Circulation: The circulation of the blood through the vessels of the kidney. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renal tubular: A defect in the kidneys that hinders their normal excretion of acids. Failure to excrete acids can lead to weak bones, kidney stones, and poor growth in children. [NIH] Renal tubular acidosis: A rare disorder in which structures in the kidney that filter the blood are impaired, producing using that is more acid than normal. [NIH] Replicon: In order to be replicated, DNA molecules must contain an origin of duplication and in bacteria and viruses there is usually only one per genome. Such molecules are called replicons. [NIH] Resected: Surgical removal of part of an organ. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into

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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] 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 Paralysis: Complete or severe weakness of the muscles of respiration. This condition may be associated with motor neuron diseases; peripheral nerve disorders; neuromuscular junction diseases; spinal cord diseases; injury to the phrenic nerve; and other disorders. [NIH] Respiratory System: The tubular and cavernous organs and structures, by means of which pulmonary ventilation and gas exchange between ambient air and the blood are brought about. [NIH] 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] 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] Retinyl palmitate: A drug being studied in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retroperitoneal: Having to do with the area outside or behind the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Retrospective: Looking back at events that have already taken place. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH]

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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] Rhythmicity: Regular periodicity. [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] Riboflavin: Nutritional factor found in milk, eggs, malted barley, liver, kidney, heart, and leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rickets: A condition caused by deficiency of vitamin D, especially in infancy and childhood, with disturbance of normal ossification. The disease is marked by bending and distortion of the bones under muscular action, by the formation of nodular enlargements on the ends and sides of the bones, by delayed closure of the fontanelles, pain in the muscles, and sweating of the head. Vitamin D and sunlight together with an adequate diet are curative, provided that the parathyroid glands are functioning properly. [EU] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risk patient: Patient who is at risk, because of his/her behaviour or because of the type of person he/she is. [EU] Rod: A reception for vision, located in the retina. [NIH] Rutin: 3-((6-O-(6-Deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranosyl)oxy)-2-(3,4dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one. Found in many plants, including buckwheat, tobacco, forsythia, hydrangea, pansies, etc. It has been used therapeutically to decrease capillary fragility. [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] Saphenous: Applied to certain structures in the leg, e. g. nerve vein. [NIH] Saphenous Vein: The vein which drains the foot and leg. [NIH] Saquinavir: An HIV protease inhibitor which acts as an analog of an HIV protease cleavage site. It is a highly specific inhibitor of HIV-1 and HIV-2 proteases. [NIH] Sarcoid: A cutaneus lesion occurring as a manifestation of sarcoidosis. [NIH] Sarcoidosis: An idiopathic systemic inflammatory granulomatous disorder comprised of

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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] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] 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] Scleroderma, Systemic: A chronic, progressive dermatosis characterized by boardlike hardening and immobility of the affected skin, with visceral involvement, especially of lungs, esophagus, kidneys and heart. It may be accompanied by calcinosis, Raynaud's phenomenon, and telangiectasis (CREST syndrome). It includes acrosclerosis and sclerodactyly. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Sclerotherapy: Treatment of varicose veins, hemorrhoids, gastric and esophageal varices, and peptic ulcer hemorrhage by injection or infusion of chemical agents which cause localized thrombosis and eventual fibrosis and obliteration of the vessels. [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] Secretin: A hormone made in the duodenum. Causes the stomach to make pepsin, the liver to make bile, and the pancreas to make a digestive juice. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [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] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Sella: A deep depression in the shape of a Turkish saddle in the upper surface of the body of the sphenoid bone in the deepest part of which is lodged the hypophysis cerebri. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains

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spermatozoa and their nutrient plasma. [NIH] Seminal vesicles: Glands that help produce semen. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senescence: The bodily and mental state associated with advancing age. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] Sensory loss: A disease of the nerves whereby the myelin or insulating sheath of myelin on the nerves does not stay intact and the messages from the brain to the muscles through the nerves are not carried properly. [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] Septicaemia: A term originally used to denote a putrefactive process in the body, but now usually referring to infection with pyogenic micro-organisms; a genus of Diptera; the severe type of infection in which the blood stream is invaded by large numbers of the causal. [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] Seroconversion: The change of a serologic test from negative to positive, indicating the development of antibodies in response to infection or immunization. [EU] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serology: The study of serum, especially of antigen-antibody reactions in vitro. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serotypes: A cause of haemorrhagic septicaemia (in cattle, sheep and pigs), fowl cholera of birds, pasteurellosis of rabbits, and gangrenous mastitis of ewes. It is also commonly found

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in atrophic rhinitis of pigs. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serpins: A family of serine proteinase inhibitors which are similar in amino acid sequence and mechanism of inhibition, but differ in their specificity toward proteolytic enzymes. This family includes alpha 1-antitrypsin, angiotensinogen, ovalbumin, antiplasmin, alpha 1antichymotrypsin, thyroxine-binding protein, complement 1 inactivators, antithrombin III, heparin cofactor II, plasminogen inactivators, gene Y protein, placental plasminogen activator inhibitor, and barley Z protein. Some members of the serpin family may be substrates rather than inhibitors of serine endopeptidases, and some serpins occur in plants where their function is not known. [NIH] Sertraline: A selective serotonin uptake inhibitor that is used in the treatment of depression. [NIH]

Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Sexual Partners: Married or single individuals who share sexual relations. [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] Sicca: Failure of lacrimal secretion, keratoconjunctivitis sicca, failure of secretion of the salivary glands and mucous glands of the upper respiratory tract and polyarthritis. [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] Siderosis: The deposition of iron in a tissue. In the eye, the iron may be deposited in the stroma adjacent to the Descemet's membrane. [NIH] 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] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH]

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Silymarin: A mixture of flavonoids extracted from seeds of the milk thistle, Silybum marianum. It consists primarily of three isomers: silicristin, silidianin, and silybin, its major component. Silymarin displays antioxidant and membrane stabilizing activity. It protects various tissues and organs against chemical injury, and shows potential as an antihepatoxic agent. [NIH] Simvastatin: A derivative of lovastatin and potent competitive inhibitor of 3-hydroxy-3methylglutaryl coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It may also interfere with steroid hormone production. Due to the induction of hepatic LDL receptors, it increases breakdown of LDL-cholesterol (lipoproteins, LDL cholesterol). [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin Pigmentation: Coloration of the skin. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smallpox: A generalized virus infection with a vesicular rash. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Social Behavior: Any behavior caused by or affecting another individual, usually of the same species. [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] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Soybean Oil: Oil from soybean or soybean plant. [NIH] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a

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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] Spectrometer: An apparatus for determining spectra; measures quantities such as wavelengths and relative amplitudes of components. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Spermatozoa: Mature male germ cells that develop in the seminiferous tubules of the testes. Each consists of a head, a body, and a tail that provides propulsion. The head consists mainly of chromatin. [NIH] Sphincters: Any annular muscle closing an orifice. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinal Cord Vascular Diseases: Hypoxic-ischemic and hemorrhagic disorders of the spinal cord. Arteriosclerosis, emboli, and vascular malformations are potential causes of these conditions. [NIH] Spinal Nerves: The 31 paired peripheral nerves formed by the union of the dorsal and ventral spinal roots from each spinal cord segment. The spinal nerve plexuses and the spinal roots are also included. [NIH] Spirochete: Lyme disease. [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] Splenectomy: An operation to remove the spleen. [NIH] Splenic Artery: The largest branch of the celiac trunk with distribution to the spleen, pancreas, stomach and greater omentum. [NIH] Splenic Vein: Vein formed by the union (at the hilus of the spleen) of several small veins from the stomach, pancreas, spleen and mesentery. [NIH] Splenomegaly: Enlargement of the spleen. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Sprue: A non febrile tropical disease of uncertain origin. [NIH] Stabilization: The creation of a stable state. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. [NIH] Status Epilepticus: Repeated and prolonged epileptic seizures without recovery of

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consciousness between attacks. [NIH] Steatosis: Fatty degeneration. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stellate: Star shaped. [NIH] Stereotactic: Radiotherapy that treats brain tumors by using a special frame affixed directly to the patient's cranium. By aiming the X-ray source with respect to the rigid frame, technicians can position the beam extremely precisely during each treatment. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Sterilization: The destroying of all forms of life, especially microorganisms, by heat, chemical, or other means. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] 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] Stomatitis: Inflammation of the oral mucosa, due to local or systemic factors which may involve the buccal and labial mucosa, palate, tongue, floor of the mouth, and the gingivae. [EU]

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] 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] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [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] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH]

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Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] Sulfotransferases: Enzymes which transfer sulfate groups to various acceptor molecules. They are involved in posttranslational sulfation of proteins and sulfate conjugation of exogenous chemicals and bile acids. EC 2.8.2. [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] Sulindac: A sulfinylindene derivative whose sulfinyl moiety is converted in vivo to an active anti-inflammatory analgesic that undergoes enterohepatic circulation to maintain constant blood levels without causing gastrointestinal side effects. [NIH] Superior vena cava: Vein which returns blood from the head and neck, upper limbs, and thorax. It is formed by the union of the two brachiocephalic veins. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] 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] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatology: 1. That branch of medicine with treats of symptoms; the systematic discussion of symptoms. 2. The combined symptoms of a disease. [EU] 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]

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Synovial Membrane: The inner membrane of a joint capsule surrounding a freely movable joint. It is loosely attached to the external fibrous capsule and secretes synovial fluid. [NIH] Synovitis: Inflammation of a synovial membrane. It is usually painful, particularly on motion, and is characterized by a fluctuating swelling due to effusion within a synovial sac. Synovitis is qualified as fibrinous, gonorrhoeal, hyperplastic, lipomatous, metritic, puerperal, rheumatic, scarlatinal, syphilitic, tuberculous, urethral, etc. [EU] Syphilis: A contagious venereal disease caused by the spirochete Treponema pallidum. [NIH]

Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU] Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [NIH] Technetium: The first artificially produced element and a radioactive fission product of uranium. The stablest isotope has a mass number 99 and is used diagnostically as a radioactive imaging agent. Technetium has the atomic symbol Tc, atomic number 43, and atomic weight 98.91. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [NIH] Telomerase: Essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic chromosomes. Telomerase appears to be repressed in normal human somatic tissues but reactivated in cancer, and thus may be necessary for malignant transformation. EC 2.7.7.-. [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] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Tetrahydrocannabinol: A psychoactive compound extracted from the resin of Cannabis sativa (marihuana, hashish). The isomer delta-9-tetrahydrocannabinol (THC) is considered the most active form, producing characteristic mood and perceptual changes associated with this compound. Dronabinol is a synthetic form of delta-9-THC. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss,

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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] Thermal ablation: A procedure using heat to remove tissue or a part of the body, or destroy its function. For example, to remove the lining of the uterus, a catheter is inserted through the cervix into the uterus, a balloon at the end of the catheter is inflated, and fluid inside the balloon is heated to destroy the lining of the uterus. [NIH] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Thioacetamide: A crystalline compound used as a laboratory reagent in place of hydrogen sulfide. It is a potent hepatocarcinogen. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] 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] 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]

Thrombopenia: Reduction in the number of platelets in the blood. [NIH] Thromboplastin: Constituent composed of protein and phospholipid that is widely distributed in many tissues. It serves as a cofactor with factor VIIa to activate factor X in the extrinsic pathway of blood coagulation. [NIH] Thrombopoietin: A humoral factor that controls blood platelet production through stimulation of megakaryocyte populations. Bone marrow megakaryocytes increase in both size and number in response to exposure to thrombopoietin. [NIH] Thromboses: The formation or presence of a blood clot within a blood vessel during life. [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] Thymosin: A family of heat-stable, polypeptide hormones secreted by the thymus gland. Their biological activities include lymphocytopoiesis, restoration of immunological competence and enhancement of expression of T-cell characteristics and function. They have

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therapeutic potential in patients having primary or secondary immunodeficiency diseases, cancer or diseases related to aging. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thymus Gland: A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. [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 concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Thyroiditis: Inflammation of the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tic: An involuntary compulsive, repetitive, stereotyped movement, resembling a purposeful movement because it is coordinated and involves muscles in their normal synergistic relationships; tics usually involve the face and shoulders. [EU] Ticks: Blood-sucking arachnids of the order Acarina. [NIH] Timolol: A beta-adrenergic antagonist similar in action to propranolol. The levo-isomer is the more active. Timolol has been proposed as an antihypertensive, antiarrhythmic, antiangina, and antiglaucoma agent. It is also used in the treatment of migraine and tremor. [NIH]

Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] 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] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxaemia: 1. The condition resulting from the spread of bacterial products (toxins) by the bloodstream. 2. A condition resulting from metabolic disturbances, e.g. toxaemia of

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pregnancy. [EU] 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] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transaminase: Aminotransferase (= a subclass of enzymes of the transferase class that catalyse the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally 2-keto acid). Most of these enzymes are pyridoxal-phosphate-proteins. [EU]

Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] 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] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [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]

Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [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

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protein. It occurs on the ribosome and is unidirectional. [NIH] Translocating: The attachment of a fragment of one chromosome to a non-homologous chromosome. [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] Tremor: Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of Parkinson disease. [NIH] Triad: Trivalent. [NIH] Triage: The sorting out and classification of patients or casualties to determine priority of need and proper place of treatment. [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] Tricyclic: Containing three fused rings or closed chains in the molecular structure. [EU] 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] Tropism: Directed movements and orientations found in plants, such as the turning of the sunflower to face the sun. [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] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tumor 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. 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]

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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] Tungsten: A metallic element with the atomic symbol W, atomic number 74, and atomic weight 183.85. It is used in many manufacturing applications, including increasing the hardness, toughness, and tensile strength of steel; manufacture of filaments for incandescent light bulbs; and in contact points for automotive and electrical apparatus. [NIH] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [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] Ubiquinone: A lipid-soluble benzoquinone which is involved in electron transport in mitochondrial preparations. The compound occurs in the majority of aerobic organisms, from bacteria to higher plants and animals. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [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] Ultrasonography: The visualization of deep structures of the body by recording the reflections of echoes of pulses of ultrasonic waves directed into the tissues. Use of ultrasound for imaging or diagnostic purposes employs frequencies ranging from 1.6 to 10 megahertz. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [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]

Uranium: A radioactive element of the actinide series of metals. It has an atomic symbol U, atomic number 92, and atomic weight 238.03. U-235 is used as the fissionable fuel in nuclear weapons and as fuel in nuclear power reactors. [NIH] 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] Urea Breath Test: A test used to detect Helicobacter pylori infection. The test measures breath samples for urease, an enzyme H. pylori makes. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

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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] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [NIH]

Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urokinase: A drug that dissolves blood clots or prevents them from forming. [NIH] Ursodeoxycholic Acid: An epimer of chenodeoxycholic acid. It is a mammalian bile acid found first in the bear and is apparently either a precursor or a product of chenodeoxycholate. Its administration changes the composition of bile and may dissolve gallstones. It is used as a cholagogue and choleretic. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Uvea: 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] Uveitis: An inflammation of part or all of the uvea, the middle (vascular) tunic of the eye, and commonly involving the other tunics (the sclera and cornea, and the retina). [EU] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vaccinia: The cutaneous and occasional systemic reactions associated with vaccination using smallpox (variola) vaccine. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Varices: Stretched veins such as those that form in the esophagus from cirrhosis. [NIH] Varicose: The common ulcer in the lower third of the leg or near the ankle. [NIH] Varicose vein: An abnormal swelling and tortuosity especially of the superficial veins of the legs. [EU] Variola: A generalized virus infection with a vesicular rash. [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 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] Vasoactive Intestinal Peptide: A highly basic, single-chain polypeptide isolated from the intestinal mucosa. It has a wide range of biological actions affecting the cardiovascular,

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gastrointestinal, and respiratory systems. It is also found in several parts of the central and peripheral nervous systems and is a neurotransmitter. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilatation: A state of increased calibre of the blood vessels. [EU] 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] Vasodilator: An agent that widens blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venereal: Pertaining or related to or transmitted by sexual contact. [EU] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH] Venous Pressure: The blood pressure in a vein. It is usually measured to assess the filling pressure to the ventricle. [NIH] Venous Thrombosis: The formation or presence of a thrombus within a vein. [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] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Verapamil: A calcium channel blocker that is a class IV anti-arrhythmia agent. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Villi: The tiny, fingerlike projections on the surface of the small intestine. Villi help absorb nutrients. [NIH] Villous: Of a surface, covered with villi. [NIH] Viraemia: The presence of virus in blood or blood plasma. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Hepatitis: Hepatitis caused by a virus. Five different viruses (A, B, C, D, and E) most commonly cause this form of hepatitis. Other rare viruses may also cause hepatitis. [NIH] Viral Load: The quantity of measurable virus in the blood. Change in viral load, measured in plasma, is used as a surrogate marker in HIV disease progression. [NIH] Viremia: The presence of viruses in the blood. [NIH] Virion: The infective system of a virus, composed of the viral genome, a protein core, and a protein coat called a capsid, which may be naked or enclosed in a lipoprotein envelope called the peplos. [NIH]

Dictionary 359

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] Virus Diseases: A general term for diseases produced by viruses. [NIH] Virus Replication: The process of intracellular viral multiplication, consisting of the synthesis of proteins, nucleic acids, and sometimes lipids, and their assembly into a new infectious particle. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitamin D: The vitamin that mediates intestinal calcium absorption, bone calcium metabolism, and probably muscle activity. It usually acts as a hormone precursor, requiring 2 stages of metabolism before reaching actual hormonal form. It is isolated from fish liver oils and used in the treatment and prevention of rickets. [NIH] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitreous Hemorrhage: Hemorrhage into the vitreous body. [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] Voluntary Health Agencies: Non-profit organizations concerned with various aspects of health, e.g., education, promotion, treatment, services, etc. [NIH] War: Hostile conflict between organized groups of people. [NIH] Warfarin: An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. [NIH] Weight Gain: Increase in body weight over existing weight. [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] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xanthine: An urinary calculus. [NIH] Xanthine Oxidase: An iron-molybdenum flavoprotein containing FAD that oxidizes hypoxanthine, some other purines and pterins, and aldehydes. Deficiency of the enzyme, an

360 Cirrhosis

autosomal recessive trait, causes xanthinuria. EC 1.1.3.22. [NIH] Xenobiotics: Chemical substances that are foreign to the biological system. They include naturally occurring compounds, drugs, environmental agents, carcinogens, insecticides, etc. [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] Yellow Fever: An acute infectious disease primarily of the tropics, caused by a virus and transmitted to man by mosquitoes of the genera Aedes and Haemagogus. [NIH] Yellow Fever Virus: The type species of the Flavivirus genus. Principal vector transmission to humans is by Aedes spp. mosquitoes. [NIH] Zalcitabine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication at low concentrations, acting as a chainterminator of viral DNA by binding to reverse transcriptase. Its principal toxic side effect is axonal degeneration resulting in peripheral neuropathy. [NIH] Zygote: The fertilized ovum. [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]

361

INDEX A Abdominal Pain, 159, 259, 311, 329, 356 Ablation, 109, 142, 259 Abscess, 118, 259, 345 Absolute risk, 4, 259 Acceptor, 259, 313, 326, 350, 354 Accommodation, 94, 259 Acculturation, 19, 259 Acetaldehyde, 31, 35, 57, 218, 259 Acetaminophen, 35, 259 Acetylcholine, 171, 259, 277, 324 Acetylcholinesterase, 171, 259 Acetylglucosamine, 187, 259, 299 Acidosis, 259 Actin, 31, 259, 320, 321 Acute Disease, 209, 259 Acute renal, 259, 260 Acute tubular, 202, 260 Acyl, 260, 317 Adaptability, 260, 276 Adaptation, 195, 260, 320 Adenine, 260, 338 Adenocarcinoma, 260, 302 Adenoma, 81, 119, 260 Adenosine, 16, 180, 260, 263, 273, 331 Adenovirus, 192, 260 Adenylate Cyclase, 189, 260 Adhesions, 187, 194, 260 Adipocytes, 260, 282, 313 Adipose Tissue, 260, 327 Adjustment, 259, 260 Adrenal Cortex, 260, 261, 284 Adrenal Glands, 260, 263, 341 Adrenergic, 26, 38, 160, 260, 288, 292, 330, 336, 353 Adverse Effect, 69, 133, 219, 244, 260, 346 Aerobic, 260, 318, 356 Aetiology, 73, 176, 260 Afferent, 260, 313 Affinity, 40, 164, 170, 261, 267, 313, 323, 347 Agar, 261, 331 Age of Onset, 261, 356 Agonist, 261, 273, 288, 321, 330 Airway, 194, 261 Alanine, 12, 13, 177, 241, 261 Alanine Transaminase, 13, 261

Albumin, 6, 12, 87, 109, 111, 117, 256, 257, 261, 326, 331 Alcohol-Induced Disorders, 177, 261 Aldosterone, 183, 261 Alertness, 261, 273 Algorithms, 207, 261, 271 Alimentary, 5, 91, 104, 111, 114, 117, 141, 261, 327, 328 Alkaline, 256, 259, 262, 263, 273 Alkaloid, 262, 279, 280 Alleles, 33, 47, 262, 303 Allergen, 262, 345 Allergic Rhinitis, 262, 273 Allogeneic, 72, 262, 299 Allopurinol, 136, 262 Alpha 1-Antichymotrypsin, 262, 346 Alpha 1-Antitrypsin, 208, 262, 346 Alpha Particles, 262, 339 Alpha-1, 26, 208, 231, 262 Alpha-fetoprotein, 85, 103, 262, 294 Alternative medicine, 217, 262 Ambulatory Care, 11, 262 Amino Acid Sequence, 48, 168, 262, 265, 297, 335, 346 Amino-terminal, 263, 335 Amiodarone, 100, 263 Ammonia, 9, 45, 86, 123, 127, 138, 263, 299, 304, 356 Amnestic, 263, 318 Amphetamines, 263, 279 Ampulla, 263, 277, 290, 294 Amyloid, 178, 263, 276 Amyloidosis, 187, 263 Anaesthesia, 263, 307 Anal, 61, 82, 263, 292, 294, 295, 306, 314, 320 Analgesic, 259, 263, 313, 350 Analog, 13, 263, 312, 343 Analogous, 17, 28, 187, 188, 263, 288, 333, 354 Analytes, 241, 263 Anaphylatoxins, 263, 281 Anastomosis, 139, 263, 334 Anatomical, 263, 268, 282, 287, 306, 327, 344 Androgens, 260, 263, 284 Anemia, 9, 45, 235, 254, 264, 329 Anesthesia, 261, 264, 290, 318

362 Cirrhosis

Aneurysm, 78, 234, 264, 358 Angina, 164, 166, 173, 179, 193, 264, 265, 336 Angina Pectoris, 164, 173, 179, 193, 264, 336 Anginal, 264, 265, 323 Angiogenesis, 180, 185, 264, 316 Angiopathy, 264, 276 Angioplasty, 182, 193, 264 Angiosarcoma, 118, 264 Angiotensinogen, 264, 346 Animal model, 23, 25, 28, 34, 59, 64, 68, 70, 135, 183, 198, 213, 264 Anionic, 192, 264 Anions, 261, 264, 311, 346 Annealing, 264, 333 Anomalies, 168, 264 Anorexia, 167, 188, 263, 264, 356 Anoxia, 167, 264 Antagonism, 86, 116, 265, 273 Anterior Cerebral Artery, 265, 276 Antiallergic, 265, 284 Antianginal, 263, 265 Antiarrhythmic, 263, 265, 353 Antibacterial, 265, 348 Antibiotic, 83, 265, 279, 292, 328, 348 Antibiotic Prophylaxis, 83, 265 Antibodies, Anticardiolipin, 265, 266 Antibodies, Antiphospholipid, 265, 266 Anticoagulant, 194, 265, 266, 337, 359 Antidepressant, 265, 278 Antidiuretic, 189, 265, 322 Antidote, 265, 295 Antigen-Antibody Complex, 176, 265, 280 Antihypertensive, 266, 353 Anti-inflammatory, 259, 266, 284, 298, 327, 350 Anti-Inflammatory Agents, 266, 284 Antimetabolite, 266, 343 Antimicrobial, 266, 278 Antineoplastic, 266, 284, 330 Antineoplastic Agents, 266, 284, 330 Antioxidant, 21, 22, 48, 104, 141, 144, 181, 266, 267, 326, 347 Antiphospholipid Syndrome, 174, 265, 266 Antiplasmin, 266, 346 Antipruritic, 266, 277 Antipyretic, 259, 266 Antiviral, 18, 20, 22, 25, 29, 37, 46, 155, 169, 219, 266, 309, 343 Antiviral Agents, 37, 169, 266

Anuria, 266, 312 Anus, 263, 266, 268, 272, 340 Anxiety, 9, 188, 211, 266, 336 Anxiolytic, 266, 273, 318 Aorta, 266, 275, 283, 341, 358 Apoptosis, 26, 42, 59, 66, 182, 266, 275 Aqueous, 267, 269, 285, 304 Arachidonic Acid, 267, 336 Arginine, 23, 180, 263, 267, 324, 331 Aromatic, 267, 270, 330 Arrhythmia, 180, 265, 267, 358 Arteries, 201, 264, 266, 267, 272, 275, 283, 284, 310, 318, 321, 338 Arteriolar, 267, 272, 294 Arterioles, 267, 272, 274, 318, 321, 357 Arteriosus, 267, 338 Arteriovenous, 267, 276, 318 Arteritis, 75, 267 Arthroplasty, 92, 267 Articular, 267, 326 Ascitic Fluid, 5, 267, 329 Ascorbic Acid, 175, 267, 304 Aspartate, 12, 267 Asphyxia, 167, 267 Aspiration, 267, 294 Assay, 43, 50, 70, 230, 267, 306, 339 Asterixis, 45, 267 Astrocytes, 267, 298, 322 Asymptomatic, 7, 10, 11, 69, 268, 326 Ataxia, 235, 268, 303, 352 Atopic, 186, 268 Atresia, 204, 268 Atrial, 94, 263, 268, 283, 355, 359 Atrial Fibrillation, 268, 359 Atrioventricular, 268, 283 Atrium, 268, 283, 355, 358 Atrophy, 9, 179, 235, 268, 313 Attenuated, 32, 62, 268, 287 Attenuation, 32, 268 Atypical, 49, 268 Autoantibodies, 24, 69, 72, 78, 79, 218, 265, 268 Autoantigens, 24, 65, 101, 174, 268 Autodigestion, 268, 326 Autoimmune disease, 4, 7, 10, 24, 38, 65, 69, 172, 173, 174, 186, 197, 265, 268, 320 Autoimmune Hepatitis, 86, 108, 123, 126, 172, 231, 268, 302 Autoimmunity, 23, 77, 78, 86, 98, 99, 107, 115, 174, 268 Autologous, 186, 268 Autolysis, 176, 268

Index 363

Autonomic, 78, 259, 268, 321, 324, 329 Autopsy, 4, 41, 103, 268 Axons, 268, 325, 329 B Bacteria, 186, 203, 260, 265, 269, 270, 279, 282, 290, 291, 293, 294, 296, 300, 310, 314, 318, 332, 340, 341, 345, 348, 354, 356, 357 Bacterial Infections, 102, 269 Bacterial Physiology, 260, 269 Bacterial Translocation, 98, 136, 138, 141, 269 Bactericidal, 269, 293 Bacteriophage, 269, 331, 354 Bacteriostatic, 269, 292 Bacterium, 194, 218, 269, 282 Balloon Occlusion, 213, 269 Basal Ganglia, 46, 81, 268, 269, 276, 305 Basal Ganglia Diseases, 268, 269, 305 Base, 54, 185, 260, 269, 286, 297, 311, 312, 351, 356 Basement Membrane, 269, 293, 312 Basophils, 269, 300, 313 Bed Rest, 5, 269 Benign, 166, 168, 260, 269, 300, 322, 339 Benign prostatic hyperplasia, 166, 269 Benzodiazepines, 270, 273, 295 Benzoic Acid, 270 Benzoylcholine, 171, 270 Beta blocker, 13, 270 Beta-pleated, 263, 270 Beta-Thromboglobulin, 270, 309 Bewilderment, 270, 282 Bile Acids, 14, 32, 71, 143, 270, 297, 349, 350, 351 Bile Acids and Salts, 270 Bile Ducts, 8, 11, 13, 26, 71, 169, 176, 197, 202, 242, 270, 296, 310, 335 Bile Pigments, 270, 311 Biliary Tract, 270, 273, 326 Bilirubin, 6, 12, 71, 177, 241, 256, 261, 270, 296, 304 Binding Sites, 164, 270 Bioavailability, 18, 34, 183, 270, 307 Biogenic Amine Neurotransmitters, 40, 270 Biogenic Amines, 270 Biological Markers, 166, 270 Biological response modifier, 271, 309 Biological therapy, 271, 300 Biological Transport, 271, 287 Biomarkers, 63, 271

Biopsy, 4, 9, 11, 29, 53, 84, 171, 203, 208, 230, 232, 240, 256, 257, 271, 328 Biosynthesis, 16, 267, 271, 314, 336, 345, 347 Biotechnology, 72, 73, 200, 217, 229, 234, 235, 236, 271 Biotransformation, 271 Bladder, 189, 269, 271, 307, 320, 322, 336, 356, 357 Blast phase, 271, 278 Blastocyst, 271, 281 Bloating, 271, 307, 311 Blood Cell Count, 271, 329 Blood Coagulation, 176, 271, 272, 273, 352 Blood Coagulation Factors, 271 Blood Glucose, 272, 301, 308 Blood Platelets, 272, 316, 332, 345, 352 Blood transfusion, 7, 208, 209, 272 Blood Volume, 79, 272, 333 Blood-Brain Barrier, 193, 272 Blot, 65, 272 Body Fluids, 209, 271, 272, 273, 288, 347, 355 Bone Marrow, 219, 271, 272, 278, 299, 304, 306, 309, 315, 316, 321, 333, 347 Bowel, 18, 166, 167, 186, 263, 272, 287, 308, 310, 313, 322, 329, 349, 356 Bowel Movement, 272, 287, 349 Brachytherapy, 272, 310, 311, 339, 360 Bradykinin, 192, 193, 272, 311, 324, 331 Branch, 218, 251, 272, 301, 315, 323, 328, 338, 341, 347, 348, 350, 352 Breakdown, 105, 175, 187, 189, 272, 287, 296, 347 Breath Tests, 124, 127, 272 Bronchi, 272, 292, 354 Bronchial, 210, 272, 303 Bronchiectasis, 210, 272 Bronchitis, 210, 272, 278 Buccal, 273, 315, 349 Budesonide, 105, 158, 273 Burns, 165, 273 Burns, Electric, 273 Buspirone, 35, 273 Bypass, 213, 273 C Cachexia, 186, 273 Caffeine, 31, 147, 273, 338 Calcinosis, 273, 344 Calcium blocker, 173, 273 Calcium channel blocker, 183, 273, 358 Calcium Channel Blockers, 183, 273

364 Cirrhosis

Calculi, 273, 299 Callus, 273, 290 Cannabidiol, 273, 274 Cannabinoids, 164, 273 Cannabinol, 273, 274 Cannula, 274, 327 Capillary, 212, 272, 274, 298, 338, 343, 358 Capillary Permeability, 272, 274 Capsid, 67, 274, 324, 358 Capsules, 274, 297, 298 Carbimazole, 172, 274 Carbohydrate, 34, 171, 187, 274, 284, 298, 299, 333 Carbon Dioxide, 274, 285, 295, 296, 338, 342, 358 Carcinogenesis, 81, 274 Carcinogenic, 274, 308, 325, 335, 349 Carcinogens, 274, 320, 325, 360 Carcinoma, 12, 14, 15, 17, 18, 20, 22, 25, 33, 40, 43, 46, 47, 48, 49, 50, 52, 59, 60, 63, 67, 74, 75, 78, 82, 83, 84, 87, 88, 90, 92, 95, 98, 99, 103, 106, 107, 108, 109, 111, 112, 113, 117, 124, 127, 135, 140, 142, 154, 171, 175, 189, 201, 210, 211, 212, 213, 231, 274, 302 Cardiac arrest, 167, 274 Cardiology, 144, 212, 274 Cardiomyopathy, 45, 178, 184, 274 Cardiopulmonary, 64, 274 Cardiorespiratory, 274, 318 Cardioselective, 274, 336 Cardiotonic, 274, 330 Cardiovascular, 40, 45, 164, 179, 180, 183, 184, 190, 274, 345, 357 Cardiovascular disease, 45, 179, 183, 190, 274 Carnitine, 124, 128, 130, 275 Carotene, 175, 275, 342 Carrier Proteins, 275, 331, 339 Case report, 76, 78, 89, 90, 91, 107, 275, 279 Case series, 11, 275, 279 Case-Control Studies, 33, 275, 292 Caspase, 42, 275 Catabolism, 143, 177, 275 Catalyse, 275, 354 Catecholamine, 275, 288, 330 Catheterization, 264, 275 Cathode, 191, 275, 289 Cations, 275, 311 Caudal, 275, 305, 334 Cause of Death, 16, 26, 30, 32, 38, 209, 244, 275, 285

Celiac Artery, 275, 301 Celiac Disease, 218, 275 Cell Adhesion, 188, 276, 308 Cell Death, 26, 29, 266, 276, 298, 322 Cell Differentiation, 168, 276, 346 Cell Division, 235, 269, 276, 300, 316, 319, 331, 335 Cell membrane, 164, 271, 273, 275, 276, 286, 289, 310, 311, 330, 334 Cell motility, 276, 302 Cell proliferation, 26, 186, 276, 346 Cell Respiration, 276, 318, 342 Cell Survival, 276, 300 Cellular Structures, 276, 319 Ceramide, 56, 181, 182, 276 Cerebellar, 268, 276, 341, 355 Cerebral Hemorrhage, 184, 276 Cerebral Infarction, 166, 167, 184, 276, 304 Cerebrospinal, 276, 303, 346 Cerebrospinal fluid, 276, 303, 346 Cerebrovascular, 269, 273, 275, 276, 352 Cerebrum, 276, 351, 355 Cervix, 276, 352 Character, 264, 277, 286, 299 Chemical Warfare, 191, 277, 286 Chemical Warfare Agents, 191, 277, 286 Chemoembolization, 125, 128, 277 Chemotactic Factors, 277, 281 Chemotherapy, 189, 277, 330 Chenodeoxycholic Acid, 277, 357 Chest Pain, 207, 277 Chest wall, 277, 329 Cholangitis, 23, 57, 68, 73, 102, 111, 158, 188, 204, 231, 277 Cholecystitis, 204, 277 Cholelithiasis, 74, 277 Cholera, 277, 345 Choleretic, 277, 357 Cholestanol, 143, 144, 277 Cholestasis, 8, 32, 66, 74, 134, 153, 177, 198, 202, 210, 277 Cholesterol, 28, 56, 131, 143, 256, 270, 277, 284, 296, 304, 314, 317, 331, 347, 349 Cholesterol Esters, 28, 277 Cholestyramine, 10, 277 Choline, 46, 130, 139, 259, 270, 277 Choroid, 278, 283, 342, 357 Chromatin, 266, 278, 291, 348 Chromosomal, 278, 332, 342 Chromosome, 278, 282, 313, 355 Chronic Disease, 9, 20, 66, 190, 209, 230, 242, 273, 278, 280

Index 365

Chronic Fatigue Syndrome, 186, 278 Chronic lymphocytic leukemia, 278 Chronic myelogenous leukemia, 271, 278 Chronic Obstructive Pulmonary Disease, 168, 210, 278 Chronic phase, 41, 278 Chronic renal, 8, 14, 111, 166, 180, 278, 333, 356 Cicatrix, 278, 311 Ciprofloxacin, 137, 278 Circadian, 9, 159, 188, 278 Circadian Rhythm, 159, 188, 278 CIS, 36, 57, 70, 278, 342 Citalopram, 144, 278 Citrus, 267, 278 Clamp, 34, 279 Clarithromycin, 34, 279 Climacteric, 193, 279 Clinical Medicine, 54, 279, 335 Clinical study, 138, 279, 283 Clinical trial, 11, 15, 24, 57, 63, 69, 71, 153, 161, 190, 198, 229, 279, 283, 288, 337, 340 Clone, 38, 44, 66, 279 Cloning, 23, 44, 48, 51, 52, 164, 198, 271, 279 Coagulation, 72, 96, 266, 272, 279, 281, 301, 331, 352, 359 Coca, 279 Cocaine, 31, 209, 279 Coenzyme, 175, 267, 279, 314, 347 Cofactor, 279, 337, 346, 352 Cohort Studies, 33, 279, 292 Colchicine, 63, 85, 123, 126, 143, 158, 159, 198, 203, 280 Colitis, 57, 204, 280, 311 Collagen disease, 178, 280 Collapse, 272, 280 Colloidal, 261, 280, 346 Colorectal, 119, 280 Combination Therapy, 10, 183, 198, 211, 280 Combinatorial, 72, 170, 280 Common Bile Duct, 32, 70, 280, 284 Comorbidity, 19, 280 Complement, 41, 72, 176, 256, 263, 280, 281, 297, 308, 316, 331, 345, 346 Complement 1, 281, 346 Complement 1 Inactivators, 281, 346 Complement Activation, 176, 263, 281 Complementary and alternative medicine, 133, 134, 149, 281 Complementary medicine, 134, 281

Complete remission, 281, 341 Compress, 281, 301 Computational Biology, 229, 234, 281 Computed tomography, 142, 281 Computerized axial tomography, 281 Computerized tomography, 281 Conception, 219, 281, 283, 294, 349 Concomitant, 3, 81, 179, 282 Confounding, 5, 47, 58, 282 Confusion, 219, 232, 254, 282, 287, 356 Congestion, 179, 184, 282, 285 Congestive heart failure, 23, 40, 166, 168, 183, 188, 218, 282 Conjugated, 170, 270, 277, 282, 285 Conjugation, 271, 282, 350 Conjunctiva, 282, 308, 312 Connective Tissue Cells, 282 Connective Tissue Diseases, 183, 266, 282 Consciousness, 263, 282, 288, 301, 349 Constipation, 207, 282, 311, 329 Constitutional, 282, 320 Constriction, 282, 311, 358 Constriction, Pathologic, 282, 358 Consultation, 7, 282 Consumption, 11, 17, 20, 31, 34, 46, 51, 72, 76, 135, 175, 190, 216, 282, 286, 342 Contamination, 282, 302 Contraceptive, 38, 283 Contractility, 28, 283 Contraindications, ii, 211, 283 Control group, 13, 17, 43, 49, 70, 283, 340 Controlled clinical trial, 159, 283 Controlled study, 23, 283 Conus, 283, 338 Convulsions, 283, 289, 335 Coordination, 283, 320 Cor, 189, 283 Cornea, 283, 312, 344, 349, 357 Coronary, 104, 173, 179, 180, 188, 193, 194, 264, 274, 283, 284, 318, 321 Coronary Arteriosclerosis, 283, 321 Coronary Artery Bypass, 104, 283 Coronary Circulation, 264, 283 Coronary heart disease, 179, 180, 274, 283 Coronary Thrombosis, 284, 318, 321 Coronary Vasospasm, 188, 284 Cortex, 268, 284, 293, 339 Cortical, 184, 284, 344, 351 Corticosteroid, 51, 284, 335 Cortisol, 261, 284 Cost Savings, 15, 284 Coumarins, 284, 337

366 Cirrhosis

Cranial, 284, 300, 322, 325, 329 Cryoglobulinemia, 4, 41, 284 Cues, 27, 284 Cultured cells, 47, 284 Curative, 169, 190, 203, 284, 343, 352 Cutaneous, 182, 186, 284, 305, 315, 357 Cyclic, 260, 273, 284, 300, 324, 330, 334, 336 Cystic Duct, 280, 284 Cytochrome, 17, 34, 42, 166, 190, 284, 326 Cytokine, 29, 42, 43, 44, 53, 60, 61, 66, 70, 105, 141, 182, 190, 285, 309 Cytoplasm, 266, 269, 276, 285, 291, 300, 321, 343 Cytoskeleton, 285, 308 Cytostatic, 182, 285, 320 Cytotoxic, 41, 51, 71, 73, 182, 262, 285, 339, 340, 346 Cytotoxicity, 51, 61, 285 D Data Collection, 285, 295 Databases, Bibliographic, 229, 285 Day Care, 206, 285 Deamination, 285, 356 Death Certificates, 4, 285 Decarboxylation, 270, 285, 303, 339 Decompensation, 14, 231, 285 Decompression, 156, 157, 285 Decompression Sickness, 285 Decongestant, 285, 330 Decontamination, 115, 285 Defense Mechanisms, 286, 309 Degenerative, 178, 192, 283, 286, 298, 301, 325, 342 Deletion, 70, 266, 286 Denaturation, 286, 333 Density, 286, 314, 333 Deoxyguanosine, 49, 286 Depolarization, 42, 286, 346 Depressive Disorder, 286, 314 Dermatitis, 184, 286 Dermatosis, 286, 344 Detoxification, 54, 286 Deuterium, 286, 304 Developed Countries, 190, 286 Developing Countries, 33, 205, 286 Diabetes Insipidus, 23, 286 Diabetes Mellitus, 24, 70, 174, 193, 286, 298, 301 Diabetic Retinopathy, 184, 286, 331 Diagnostic Imaging, 119, 286 Diagnostic procedure, 163, 217, 286, 330

Diaphragm, 287, 332 Diarrhea, 10, 83, 207, 218, 277, 287, 311 Diastole, 287, 335 Diastolic, 287, 304 Diffusion, 110, 271, 274, 287, 307, 310, 323 Digestion, 176, 209, 261, 270, 272, 287, 289, 307, 310, 314, 328, 349 Digestive system, 162, 287, 297 Digestive tract, 177, 243, 287, 347 Dihydroxy, 10, 261, 287, 343 Dilatation, 55, 264, 272, 287, 302, 310, 335, 358 Dilatation, Pathologic, 287, 358 Dilation, 210, 272, 287, 303, 358 Dilator, 62, 287 Dilution, 79, 287, 292, 332 Direct, iii, 23, 25, 27, 37, 38, 40, 44, 50, 51, 59, 64, 144, 172, 180, 182, 221, 279, 287, 288, 341 Disease Progression, 3, 11, 13, 20, 29, 43, 53, 154, 232, 287, 358 Disinfectant, 287, 293 Disorientation, 282, 285, 287 Disparity, 175, 287 Disposition, 17, 35, 287 Dissociation, 261, 287 Distal, 157, 184, 283, 288, 289, 297, 337 Diuresis, 273, 288 Diuretic, 5, 159, 288, 311 Diverticula, 288 Diverticulitis, 204, 288 Diverticulum, 288 Docetaxel, 144, 288 Dominance, 93, 288 Dopamine, 270, 279, 288, 330 Dorsal, 288, 334, 348 Double-blinded, 71, 155, 288 Drive, ii, vi, 4, 6, 7, 8, 10, 11, 14, 26, 30, 34, 64, 121, 207, 209, 211, 230, 288, 311 Drug Design, 37, 223, 288 Drug Interactions, 18, 222, 223, 288 Drug Resistance, 155, 288 Drug Tolerance, 288, 353 Duodenum, 270, 289, 290, 301, 326, 344, 349 Dyes, 263, 269, 289 Dyskinesia, 278, 289 Dysmenorrhea, 188, 289 Dyspepsia, 218, 289, 307 Dysplasia, 235, 289 Dyspnea, 285, 289, 338 Dystrophy, 235, 289

Index 367

E Echocardiography, 79, 289 Eclampsia, 270, 289, 335 Edema, 6, 23, 188, 201, 254, 281, 285, 286, 289, 301, 320, 322, 335, 356 Effector, 24, 67, 259, 280, 289, 323, 330 Efficacy, 6, 17, 23, 30, 31, 85, 112, 143, 154, 156, 158, 159, 160, 173, 273, 288, 289 Effusion, 289, 351 Elastin, 187, 280, 282, 289, 293 Elective, 289 Electrocoagulation, 279, 289 Electrode, 275, 289 Electrolyte, 102, 261, 284, 289, 312, 318, 334, 347, 356 Electrons, 266, 269, 275, 289, 311, 326, 339 Electroporation, 92, 289 Emboli, 289, 290, 348, 359 Embolism, 290, 310, 338, 359 Embolization, 290, 359 Embolus, 290, 307 Embryo, 271, 276, 290, 307, 333 Embryogenesis, 175, 290 Emphysema, 176, 208, 210, 234, 262, 278, 290 Encephalopathy, 8, 9, 15, 39, 45, 69, 160, 201, 230, 290 Endarterectomy, 264, 290 Endemic, 231, 277, 290, 302, 348 Endocrine System, 290, 322 Endogenous Retroviruses, 65, 290 Endometrium, 290, 317 Endopeptidases, 290, 328, 337, 345 Endoscope, 290 Endoscopic, 86, 123, 127, 157, 207, 290, 318 Endoscopy, 39, 101, 290 Endothelial cell, 55, 79, 272, 290, 295, 309, 352 Endothelium, 180, 194, 290, 291, 324 Endothelium, Lymphatic, 290 Endothelium, Vascular, 290, 291 Endothelium-derived, 291, 324 Endotoxemia, 61, 62, 155, 291 Endotoxic, 166, 291 Endotoxin, 61, 62, 124, 127, 164, 291, 355 End-stage renal, 278, 291, 333 Energy balance, 291, 313 Enterohepatic, 291, 350 Enterohepatic Circulation, 291, 350 Environmental Exposure, 33, 271, 291, 325 Environmental Health, 228, 230, 291 Environmental Monitoring, 191, 291

Enzymatic, 64, 168, 170, 176, 190, 270, 273, 275, 280, 291, 295, 303, 333, 342 Enzyme Activation, 65, 291 Eosinophils, 291, 300, 313 Epidemic, 189, 208, 209, 219, 291, 348 Epidemiologic Studies, 271, 291 Epidemiological, 21, 43, 292 Epidermal, 74, 188, 193, 292, 312, 316 Epidermal Growth Factor, 188, 193, 292 Epidermis, 292, 312 Epidural, 118, 292 Epigastric, 292, 326 Epinephrine, 260, 270, 288, 292, 324, 356 Epithelial, 21, 65, 88, 122, 126, 170, 184, 260, 271, 292, 302, 312 Epithelial Cells, 65, 88, 184, 292, 302, 312 Epithelium, 65, 169, 170, 269, 290, 292, 296 Epitope, 23, 292 Erectile, 180, 292 Erection, 292 Erythrocyte Volume, 272, 292 Erythrocytes, 171, 264, 271, 272, 292, 340, 345 Erythromycin, 34, 279, 292 Esophageal, 11, 13, 15, 57, 86, 156, 160, 201, 216, 243, 292, 297, 344 Esophageal Varices, 11, 15, 86, 160, 201, 216, 243, 292, 344 Esophagitis, 207, 293, 297 Esophagus, 160, 194, 201, 204, 207, 268, 287, 292, 293, 297, 300, 314, 330, 341, 344, 349, 357 Essential Tremor, 235, 293 Estrogen, 112, 180, 293 Ethanol, 17, 18, 21, 26, 31, 39, 42, 48, 51, 54, 56, 57, 113, 195, 278, 293 Ethanolamine, 123, 127, 293 Eukaryotic Cells, 293, 307, 356 Evacuation, 282, 293, 313 Evoke, 293, 349 Excrete, 266, 293, 312, 341 Exfoliation, 293, 321 Exhaustion, 265, 293 Exocrine, 293, 326 Exogenous, 41, 55, 56, 186, 192, 271, 293, 337, 345, 350, 356 Extensor, 293, 338 External-beam radiation, 293, 311, 339, 360 Extracellular, 22, 26, 53, 65, 70, 165, 168, 180, 187, 192, 202, 263, 267, 282, 293, 295, 308, 316, 323, 347

368 Cirrhosis

Extracellular Matrix, 22, 26, 53, 65, 70, 165, 187, 192, 282, 293, 295, 308, 316 Extracellular Matrix Proteins, 53, 293, 316 Extracellular Space, 293 Extraction, 58, 293 Extrapyramidal, 101, 288, 294 Eye Infections, 260, 294 F Failure to Thrive, 210, 294 Fallopian Tubes, 194, 294 Family Planning, 229, 294 Fatigue, 7, 10, 69, 84, 104, 141, 177, 198, 203, 209, 278, 294, 300 Fatty acids, 138, 261, 294, 313, 336 Fatty Liver, 35, 70, 94, 103, 167, 170, 180, 218, 241, 294 Fatty Liver, Alcoholic, 218, 294 Febrile, 294, 348 Fecal Incontinence, 207, 294, 307 Feces, 277, 282, 294, 349 Felodipine, 173, 294 Ferritin, 43, 45, 257, 294 Fetoprotein, 256, 294 Fetus, 262, 294, 357 Fibril, 165, 294 Fibrin, 266, 271, 294, 295, 329, 352 Fibrinogen, 294, 331, 332, 337, 352 Fibrinolysis, 83, 176, 295 Fibroblast Growth Factor, 182, 185, 194, 295 Fibroblasts, 31, 165, 172, 185, 282, 295, 309 Fibronectin, 53, 295, 297 Filtration, 140, 295, 312 Fixation, 295, 345 Flatus, 294, 295, 296 Flavivirus, 33, 295, 360 Flumazenil, 69, 295 Focus Groups, 20, 295 Fold, 20, 69, 295, 317, 325 Foramen, 295, 329 Forearm, 272, 295 Fractionation, 37, 295 Frontal Lobe, 46, 265, 276, 295, 319 Fructose, 204, 295, 296, 299, 310 Fructose Intolerance, 204, 296 Fungi, 282, 294, 296, 310, 318, 360 G Galactosemia, 204, 296 Galenical, 190, 296 Gallbladder, 89, 203, 259, 270, 277, 284, 287, 296, 297, 301 Gallstones, 112, 270, 277, 296, 357

Gamma Rays, 296, 320, 339 Gamma-Glutamyltransferase, 87, 296 Ganglia, 46, 259, 269, 296, 322, 329 Gangrene, 200, 296 Gangrenous, 296, 345 Gas, 55, 191, 263, 274, 285, 287, 293, 295, 296, 304, 307, 311, 320, 323, 324, 342, 350, 358 Gas exchange, 55, 296, 342, 358 Gastric, 6, 57, 156, 160, 166, 167, 268, 275, 292, 296, 297, 300, 303, 328, 344 Gastric Juices, 296, 328 Gastric Mucosa, 166, 167, 296, 328 Gastrin, 296, 303 Gastritis, 20, 124, 128, 146, 204, 218, 296 Gastroenterologist, 218, 296 Gastroesophageal Reflux, 204, 207, 297 Gastroesophageal Reflux Disease, 207, 297 Gastrointestinal tract, 202, 218, 269, 293, 297, 345, 355 Gelatin, 297, 299, 352 Gelatinase A, 22, 297 Gene Expression, 29, 35, 41, 42, 57, 62, 64, 70, 84, 103, 151, 185, 236, 297 Genetic Code, 297, 324 Genetic Engineering, 271, 279, 297 Genetic testing, 297, 333 Genetic transcription, 297, 335, 354 Genetics, 74, 122, 126, 208, 218, 282, 288, 297, 319 Genital, 278, 297 Genotype, 37, 41, 45, 47, 68, 297, 330 Germ Cells, 297, 316, 325, 348, 351 Gestation, 297, 328 Giant Cells, 297, 344 Gland, 260, 298, 315, 316, 326, 327, 331, 336, 344, 349, 353 Gliosis, 168, 298 Glomerular, 13, 140, 202, 298, 310, 312, 341 Glomerular Filtration Rate, 202, 298, 312 Glomeruli, 298 Glomerulonephritis, 168, 180, 184, 298, 305 Glomerulosclerosis, 66, 194, 298 Glomerulus, 298, 322 Glucocorticoid, 273, 298, 335 Gluconeogenesis, 296, 298 Glucose, 32, 34, 40, 114, 134, 145, 181, 235, 267, 272, 286, 296, 298, 299, 301, 308, 340 Glucose Intolerance, 32, 34, 286, 298 Glucose tolerance, 34, 134, 298 Glucose Tolerance Test, 34, 298

Index 369

Glutamate, 46, 261, 298 Glutamic Acid, 298, 299, 335 Glutamine, 46, 147, 299 Glutathione Peroxidase, 48, 299, 344 Gluten, 10, 218, 275, 299 Glycine, 270, 277, 299, 345 Glycogen, 110, 181, 189, 299 Glycoprotein, 18, 41, 48, 50, 84, 171, 262, 266, 281, 294, 295, 297, 299, 312, 330, 352, 355 Glycosaminoglycans, 293, 299 Glycoside, 299, 304 Goats, 299, 325 Gout, 184, 280, 299 Governing Board, 299, 334 Government Agencies, 204, 299, 334 Grade, 100, 299 Grading, 231, 299 Graft, 43, 113, 173, 188, 198, 299, 303, 306 Graft Rejection, 173, 188, 299, 306 Grafting, 104, 283, 299, 307 Graft-versus-host disease, 113, 299 Gram-negative, 269, 291, 300 Gram-Negative Bacteria, 291, 300 Granulocytes, 300, 313, 346, 359 Granuloma, 104, 300 Gravidity, 300, 327 Gravis, 174, 300 Group Practice, 206, 300 Growth factors, 165, 168, 175, 182, 185, 188, 193, 194, 300 Guanylate Cyclase, 300, 324 H Haematemesis, 87, 300 Haptens, 261, 300, 339 Headache, 273, 300, 303, 308 Health Education, 244, 300 Health Services, 19, 30, 300 Heart attack, 275, 300 Heart failure, 179, 184, 193, 201, 300, 338 Heartburn, 218, 300, 307 Hematoma, 300, 301 Hematopoiesis, 175, 300, 333 Heme, 64, 270, 284, 301, 326, 333, 334 Hemochromatosis, 33, 45, 92, 179, 216, 218, 244, 301 Hemodialysis, 301, 312 Hemodynamics, 77, 122, 125, 137, 155, 301 Hemoglobin, 104, 264, 271, 292, 301, 334 Hemoglobinuria, 235, 301 Hemorrhage, 13, 30, 38, 166, 177, 243, 289, 300, 301, 349, 359

Hemorrhagic stroke, 167, 301 Hemorrhoids, 301, 344 Hemostasis, 301, 308, 345 Heparin, 301, 332, 346 Hepatic Artery, 96, 301 Hepatic Encephalopathy, 8, 9, 34, 45, 69, 81, 84, 96, 100, 101, 102, 159, 177, 198, 199, 203, 301 Hepatic Veins, 91, 301 Hepatitis A, 20, 33, 50, 60, 91, 108, 119, 167, 170, 205, 207, 218, 232, 243, 301 Hepatitis B, 14, 154, 171, 177, 181, 189, 207, 211, 212, 222, 231, 244, 253, 257, 302 Hepatitis D, 89, 302 Hepatitis Delta Virus, 302 Hepatitis Viruses, 210, 302 Hepatitis, Chronic, 188, 302 Hepatobiliary, 32, 143, 201, 302 Hepatocyte, 26, 29, 39, 42, 49, 51, 59, 71, 76, 88, 92, 124, 127, 175, 188, 277, 302 Hepatocyte Growth Factor, 49, 76, 188, 302 Hepatologist, 7, 97, 302 Hepatoma, 92, 96, 302 Hepatopulmonary Syndrome, 55, 64, 76, 109, 302 Hepatorenal Syndrome, 5, 6, 12, 13, 77, 202, 302 Hepatotoxic, 46, 179, 302 Hepatotoxicity, 48, 302 Hepatovirus, 301, 302 Hereditary, 45, 92, 262, 281, 282, 299, 302, 329, 342 Heredity, 297, 302 Hernia, 159, 302 Heterodimers, 36, 303, 308, 354 Heterogeneity, 43, 97, 261, 303 Heterozygotes, 45, 288, 303 Histamine, 263, 270, 303 Histology, 6, 17, 41, 54, 71, 303, 327 Homeostasis, 21, 22, 23, 40, 45, 303 Homodimer, 303, 354 Homologous, 185, 262, 297, 303, 320, 345, 350, 355 Homozygotes, 33, 288, 303 Hormonal, 268, 284, 303, 329, 359 Hospital Mortality, 72, 303 Hospitals, Public, 303, 306 Host, 33, 43, 44, 47, 48, 50, 51, 59, 60, 67, 188, 231, 269, 294, 303, 306, 342, 357, 359 Humoral, 41, 52, 186, 299, 303, 352 Humour, 303

370 Cirrhosis

Hybrid, 279, 303 Hybridization, 73, 103, 303, 319 Hybridomas, 289, 303, 309 Hydrocephalus, 303, 311 Hydrogen, 182, 259, 269, 274, 286, 293, 299, 304, 313, 319, 323, 324, 326, 330, 337, 352, 360 Hydrogen Bonding, 304, 324 Hydrogen Peroxide, 299, 304, 313 Hydrolases, 64, 304, 331 Hydrolysis, 65, 182, 259, 271, 304, 310, 328, 330, 331, 333, 337 Hydrophilic, 28, 304 Hydrophobic, 10, 71, 304, 311 Hydroxylysine, 280, 304 Hydroxyproline, 280, 304 Hyperammonemia, 96, 97, 116, 198, 199, 304 Hyperbilirubinemia, 13, 203, 304, 311 Hypercholesterolemia, 11, 179, 304 Hyperglycemia, 134, 188, 304 Hyperlipidemia, 18, 70, 304 Hyperplasia, 49, 81, 89, 187, 304 Hypersensitivity, 178, 262, 304, 343, 345 Hypersplenism, 107, 304 Hypertension, Pulmonary, 180, 304 Hypertension, Renovascular, 180, 305 Hyperthyroidism, 305, 336 Hypertrophy, 103, 167, 168, 183, 269, 283, 304, 305, 355 Hyperuricemia, 299, 305 Hypesthesia, 305, 322 Hypnotic, 305, 318 Hypoglycemia, 167, 296, 305 Hypokinesia, 305, 327 Hypotension, 164, 283, 305 Hypotensive, 39, 305, 311 Hypothalamic, 85, 93, 305 Hypothalamus, 305, 331 Hypoxemia, 55, 64, 305 Hypoxia, 64, 305, 352 I Id, 129, 145, 240, 241, 243, 245, 250, 252, 305 Idiopathic, 65, 83, 305, 343 Ileus, 193, 305 Imidazole, 274, 303, 305 Immune Complex Diseases, 266, 305 Immune function, 58, 305, 354 Immune Sera, 305, 306 Immune system, 4, 37, 38, 59, 174, 186, 218, 268, 271, 305, 306, 315, 320, 357, 359

Immunity, 14, 41, 115, 174, 186, 261, 305, 306, 309, 315, 354 Immunization, 206, 207, 244, 306, 345 Immunization Programs, 207, 306 Immunoassay, 53, 171, 230, 265, 306 Immunochemistry, 6, 306 Immunocompromised, 14, 186, 306 Immunodeficiency, 59, 186, 212, 235, 306, 353 Immunodeficiency syndrome, 212, 306 Immunogenic, 52, 73, 306, 339 Immunoglobulin, 66, 152, 265, 306, 319 Immunohistochemistry, 6, 36, 54, 306 Immunologic, 52, 58, 69, 177, 178, 203, 232, 262, 277, 305, 306, 315, 340, 353 Immunology, 25, 50, 52, 54, 98, 122, 123, 125, 126, 127, 128, 138, 261, 306 Immunomodulator, 186, 306 Immunosuppressant, 198, 306 Immunosuppressive, 8, 10, 60, 69, 71, 115, 298, 306 Immunosuppressive therapy, 8, 10, 306 Immunotherapy, 189, 271, 306 Impairment, 9, 12, 21, 31, 74, 110, 171, 183, 202, 268, 270, 277, 289, 294, 306, 317 Imperforate Anus, 204, 306 Implant radiation, 306, 310, 311, 339, 360 Implantation, 281, 307 Impotence, 255, 292, 307 In situ, 36, 54, 307 In Situ Hybridization, 36, 307 In vitro, 25, 28, 32, 37, 41, 44, 47, 51, 52, 64, 66, 67, 169, 171, 182, 190, 262, 307, 333, 345, 353 In vivo, 16, 28, 32, 34, 37, 47, 51, 55, 64, 67, 70, 180, 182, 190, 262, 301, 307, 313, 350 Incision, 307, 310 Incompetence, 297, 307 Incontinence, 303, 307, 321 Incubation, 32, 307 Indicative, 169, 198, 307, 328, 357 Indigestion, 11, 218, 254, 255, 307 Indinavir, 18, 307 Indolent, 68, 307 Induction, 14, 18, 60, 174, 189, 190, 263, 307, 347 Infancy, 33, 135, 307, 343 Infantile, 307, 313 Infarction, 193, 276, 301, 307, 310 Infertility, 193, 307, 311 Infiltration, 66, 169, 298, 307

Index 371

Inflammatory bowel disease, 66, 184, 186, 207, 308 Influenza, 93, 308 Infusion, 55, 155, 186, 308, 344, 354 Ingestion, 21, 43, 47, 114, 133, 170, 192, 296, 298, 308, 333 Inhalation, 308, 333 Initiation, 23, 51, 308, 335, 354 Initiator, 308, 309 Inoperable, 125, 128, 308 Inorganic, 175, 308, 320 Inositol, 46, 308 Inotropic, 288, 294, 308 Insecticides, 308, 360 Insight, 23, 28, 40, 45, 66, 67, 308 Insulator, 308, 320 Insulin, 33, 75, 77, 89, 96, 113, 193, 298, 308, 356 Insulin-dependent diabetes mellitus, 75, 308 Insulin-like, 89, 96, 113, 194, 308 Integrins, 53, 308 Intensive Care, 7, 309 Interferon-alpha, 309 Interleukin-1, 53, 78, 109, 138, 309 Interleukin-10, 53, 78, 309 Interleukin-11, 109, 309 Interleukin-12, 138, 309 Interleukin-2, 309 Interleukin-4, 24, 309 Interleukin-6, 53, 61, 309 Interleukin-8, 60, 61, 309 Intermittent, 82, 231, 309, 314 Internal radiation, 309, 311, 339, 360 Interstitial, 96, 272, 293, 297, 310, 311, 322, 341, 360 Interstitial Collagenase, 297, 310 Intestinal, 34, 90, 97, 114, 115, 136, 143, 156, 269, 275, 277, 298, 310, 316, 357, 359 Intestinal Flora, 136, 310 Intestine, 9, 188, 194, 270, 272, 291, 310, 312 Intoxication, 134, 310 Intracellular, 25, 41, 182, 273, 307, 308, 310, 317, 324, 334, 336, 340, 344, 346, 359 Intracranial Aneurysm, 276, 310 Intracranial Arteriosclerosis, 276, 310 Intrahepatic, 5, 6, 29, 30, 34, 44, 60, 66, 68, 69, 76, 86, 91, 97, 99, 117, 157, 159, 310 Intrahepatic bile ducts, 66, 310 Intramuscular, 310, 327 Intraperitoneal, 310, 329

Intravenous, 12, 34, 59, 155, 207, 209, 212, 308, 310, 327 Intrinsic, 24, 64, 261, 269, 302, 310 Inulin, 298, 310 Invasive, 49, 63, 103, 106, 305, 310, 315 Invertebrates, 170, 310 Involuntary, 269, 293, 294, 310, 321, 353 Iodine, 310, 318 Ion Transport, 26, 310, 318 Ionizing, 262, 291, 311, 339 Ions, 191, 269, 277, 281, 287, 289, 291, 304, 310, 311, 319, 334, 337 Irradiation, 42, 118, 311, 360 Irritable Bowel Syndrome, 204, 207, 311 Ischemia, 166, 167, 184, 188, 268, 301, 311, 320 Isoenzyme, 87, 311 Isoprenoid, 93, 311 Isosorbide, 100, 311 J Jaundice, 11, 75, 167, 177, 203, 206, 207, 210, 218, 255, 302, 304, 311 Joint, 92, 183, 267, 278, 285, 311, 325, 350, 351 K Kallidin, 193, 272, 311 Kallikreins, 311 Kb, 228, 311 Keloid, 165, 192, 311 Keratinocytes, 309, 312 Keratoconjunctivitis, 312, 346 Keratoconjunctivitis Sicca, 312, 346 Keto, 312, 354 Kidney Disease, 23, 153, 154, 156, 157, 158, 159, 160, 162, 228, 235, 241, 244, 312 Kidney Failure, 6, 142, 173, 202, 291, 298, 312 Kidney Failure, Acute, 312 Kidney Failure, Chronic, 312 Kinetic, 40, 311, 312 L Labile, 28, 280, 312 Lacrimal, 312, 346 Lactulose, 9, 159, 312 Laminin, 269, 293, 312 Lamivudine, 14, 83, 85, 140, 155, 312 Laparoscopy, 97, 312 Large Intestine, 287, 310, 312, 340, 347 Latent, 144, 168, 192, 312, 335 Lavage, 21, 22, 313 Laxative, 261, 277, 312, 313 Lectin, 171, 187, 313, 317

372 Cirrhosis

Leptin, 70, 95, 313 Lesion, 169, 283, 298, 300, 313, 314, 343, 351 Lethal, 26, 49, 269, 313, 320 Leucocyte, 262, 313 Leukemia, 235, 278, 313 Leukocytes, 180, 194, 269, 271, 272, 277, 291, 300, 309, 313, 329, 355 Leukocytosis, 313, 333 Levo, 313, 353 Library Services, 250, 313 Life cycle, 25, 296, 313 Ligament, 313, 336 Ligands, 28, 60, 308, 313 Ligation, 32, 70, 313 Linkage, 47, 182, 313, 328 Lipid, 28, 48, 54, 56, 62, 67, 138, 143, 164, 170, 171, 274, 278, 308, 312, 313, 317, 318, 320, 326, 355, 356 Lipid Peroxidation, 28, 48, 54, 62, 313, 326 Lipid Peroxides, 49, 313 Lipodystrophy, 204, 313 Lipophilic, 28, 313 Liposomes, 192, 314 Lithium, 23, 172, 314 Liver Cirrhosis, 5, 8, 18, 30, 36, 46, 49, 52, 57, 62, 72, 73, 74, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 87, 88, 89, 91, 92, 93, 94, 95, 96, 98, 100, 101, 102, 104, 106, 108, 109, 110, 111, 112, 113, 114, 116, 118, 119, 123, 124, 125, 127, 128, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 146, 151, 152, 155, 156, 158, 159, 160, 171, 177, 182, 184, 188, 189, 191, 193, 195, 198, 199, 200, 201, 207, 208, 210, 211, 213, 302, 314 Liver Mitochondria, 56, 314 Liver Regeneration, 178, 314 Lobe, 276, 314 Localization, 40, 193, 306, 314 Localized, 66, 168, 189, 263, 295, 300, 307, 312, 313, 314, 321, 331, 344 Longitudinal study, 61, 314 Long-Term Care, 30, 314 Loop, 28, 57, 302, 314 Lovastatin, 314, 347 Lower Esophageal Sphincter, 218, 297, 314 Luciferase, 44, 314 Lumen, 194, 274, 291, 315 Lupus, 169, 173, 265, 266, 315, 351 Lymph, 169, 170, 202, 269, 290, 303, 315, 344, 349

Lymph node, 169, 170, 269, 315, 344 Lymphatic, 290, 307, 315, 317, 347, 348, 353 Lymphatic system, 315, 347, 348, 353 Lymphocyte, 265, 315, 316 Lymphocytic, 169, 315 Lymphoid, 265, 313, 315, 353 Lymphokines, 71, 315 Lymphoma, 33, 169, 235, 315 Lymphoscintigraphy, 90, 315 Lysine, 304, 315, 335 Lytic, 315, 345 M Macrophage, 28, 29, 61, 66, 309, 315 Macrophage Activation, 29, 66, 315 Magnetic Resonance Imaging, 117, 315 Maintenance therapy, 11, 315 Major Histocompatibility Complex, 309, 316 Malabsorption, 8, 146, 235, 275, 316 Malignancy, 83, 133, 189, 219, 316 Malignant, 173, 174, 189, 235, 260, 266, 314, 316, 322, 339, 351 Malignant tumor, 189, 316 Malnutrition, 48, 58, 73, 142, 179, 261, 268, 273, 316, 320 Mammary, 185, 283, 316 Manic, 314, 316 Maple Syrup Urine Disease, 204, 316 Mastitis, 316, 345 Matrix metalloproteinase, 88, 316 Mediate, 51, 52, 56, 172, 288, 316 Mediator, 70, 309, 316, 332, 345 Medical Records, 4, 316 Medical Staff, 288, 316 Medicament, 176, 184, 316 MEDLINE, 229, 234, 235, 316 Megakaryocytes, 309, 316, 352 Meiosis, 316, 320, 350 Melanin, 316, 330, 356 Melanocytes, 316, 317 Melanoma, 235, 317 Membrane Fluidity, 56, 317 Membrane Glycoproteins, 317 Membrane Proteins, 314, 317 Memory, 24, 104, 180, 188, 189, 264, 317 Menarche, 38, 317 Meninges, 276, 317 Menopause, 38, 317, 334, 336 Menstrual Cycle, 23, 317 Menstruation, 289, 317 Mental Disorders, 22, 162, 305, 317, 338

Index 373

Mental Health, iv, 15, 162, 212, 228, 233, 317, 338 Mentors, 42, 70, 317 Mesenchymal, 292, 317 Mesenteric, 269, 317, 334 Mesothelial, 187, 317 Meta-Analysis, 4, 5, 86, 317 Metabolic disorder, 201, 210, 286, 299, 304, 317 Metabolite, 31, 35, 46, 57, 271, 314, 317 Metastasis, 176, 184, 316, 317 Methimazole, 172, 274, 318 Methionine, 56, 94, 175, 318, 350 MI, 73, 85, 87, 104, 136, 138, 141, 144, 145, 166, 219, 258, 318 Microbe, 318, 354 Microbiology, 25, 50, 51, 52, 98, 260, 268, 318 Microcirculation, 18, 62, 314, 318 Microgram, 193, 318 Microorganism, 279, 318, 327, 359 Micro-organism, 38, 318, 345 Microscopy, 18, 54, 65, 169, 269, 318 Midazolam, 34, 318 Migration, 24, 315, 318, 323 Milk Thistle, 133, 148, 149, 244, 318, 347 Milligram, 318 Mineralocorticoids, 260, 284, 318 Mitochondria, 42, 56, 177, 318 Mitochondrial Swelling, 318, 322 Mitosis, 267, 319 Mitotic, 288, 319 Mitotic inhibitors, 288, 319 Mobility, 43, 44, 70, 191, 319 Mobilization, 28, 319 Modeling, 26, 61, 288, 319 Modification, 297, 319, 339, 360 Modulator, 37, 319 Molecular Probes, 16, 289, 319 Molecular Structure, 40, 319, 355 Monitor, 14, 18, 25, 94, 219, 242, 319, 324 Monoclonal, 170, 171, 303, 311, 319, 339, 360 Monocyte, 66, 319 Mononuclear, 43, 67, 105, 141, 300, 319, 355 Monotherapy, 154, 211, 319 Morphological, 171, 290, 316, 319 Morphology, 119, 315, 319 Motility, 105, 114, 319, 345 Motion Sickness, 319, 321 Motor Cortex, 41, 319, 341

Mucins, 320, 343 Mucosa, 269, 275, 296, 315, 320, 349, 357 Mucus, 320, 356 Multidrug resistance, 74, 320, 330 Multiple sclerosis, 24, 173, 174, 184, 320 Multivalent, 52, 320 Multivariate Analysis, 99, 108, 320 Muscle Contraction, 218, 320 Muscle Fibers, 320, 321 Muscular Atrophy, 235, 320 Muscular Dystrophies, 289, 320 Musculature, 305, 320, 337 Mustard Gas, 320 Mutagen, 37, 320 Mutagenesis, 37, 70, 320 Myalgia, 308, 320 Myasthenia, 174, 320 Mydriatic, 287, 320, 330 Myelin, 320, 323, 345 Myelitis, 117, 320 Myelofibrosis, 321, 333 Myocardial infarction, 166, 179, 184, 193, 270, 284, 318, 321, 336, 359 Myocardial Ischemia, 166, 193, 264, 321 Myocarditis, 178, 184, 321 Myocardium, 178, 264, 318, 321 Myofibrils, 109, 321 Myosin, 320, 321 Myotonic Dystrophy, 235, 321 N Naloxone, 321 Naltrexone, 31, 321 Narcotic, 259, 321 Nasal Mucosa, 308, 321 Natural killer cells, 309, 321 Nausea, 11, 13, 255, 307, 321, 356 NCI, 1, 157, 161, 227, 278, 321 Necrolysis, 74, 321 Necrosis, 95, 179, 186, 202, 230, 266, 276, 302, 307, 318, 321, 344 Needle Sharing, 208, 322 Neoplasia, 187, 235, 322 Neoplasm, 322, 356 Neoplastic, 55, 303, 315, 322 Nephritis, 168, 322 Nephrogenic, 23, 322 Nephron, 184, 298, 322 Nephropathy, 152, 180, 184, 312, 322 Nephrosis, 302, 322 Nephrotic, 23, 172, 188, 322 Nephrotic Syndrome, 23, 172, 188, 322

374 Cirrhosis

Nerve, 194, 260, 264, 268, 316, 320, 322, 325, 327, 334, 342, 343, 344, 348, 349, 355 Nervous System, 79, 174, 180, 189, 235, 259, 260, 261, 263, 273, 276, 279, 296, 298, 300, 303, 316, 320, 322, 323, 325, 329, 345 Neural, 171, 260, 263, 294, 303, 322, 329 Neural tube defects, 294, 322 Neuralgia, 322, 334 Neuritis, 184, 322 Neuroendocrine, 26, 108, 322 Neuroglia, 298, 322 Neurologic, 45, 303, 323 Neuromuscular, 9, 171, 259, 323, 342, 356 Neuromuscular Junction, 259, 323, 342 Neuronal, 278, 322, 323, 329 Neurons, 270, 279, 296, 323, 350 Neuropathy, 78, 184, 323, 360 Neuropeptide, 188, 323 Neurophysiology, 286, 323 Neuropsychological Tests, 45, 69, 159, 323 Neuropsychology, 96, 97, 323 Neurotoxicity, 9, 323 Neurotransmitters, 270, 323 Neutrons, 262, 311, 323, 339 Neutrophil, 61, 262, 323 Neutrophil Infiltration, 61, 323 Nifedipine, 173, 323 Nitric Oxide, 40, 55, 62, 86, 87, 88, 102, 122, 125, 143, 155, 179, 180, 184, 323 Nitrogen, 122, 126, 145, 182, 262, 264, 285, 293, 295, 299, 312, 324, 355 Norepinephrine, 260, 270, 288, 324 Nuclear, 28, 36, 61, 88, 101, 112, 143, 144, 269, 282, 289, 293, 296, 322, 324, 356 Nuclei, 262, 265, 282, 289, 297, 315, 319, 323, 324, 325, 337 Nucleic acid, 65, 67, 169, 174, 176, 185, 274, 297, 303, 307, 324, 338, 343, 359, 360 Nucleic Acid Hybridization, 66, 303, 324 Nucleocapsid, 67, 324 Nucleotidases, 304, 324 O Observational study, 119, 324 Occupational Exposure, 38, 324 Odds Ratio, 4, 5, 324, 341 Office Management, 203, 325 Ointments, 325, 327 Oliguria, 312, 325 Oltipraz, 190, 325 Omentum, 301, 325, 348 Oncogene, 49, 84, 185, 235, 302, 325

Oncogenic, 189, 309, 325 Oocytes, 40, 325 Operon, 325, 335 Optic Disk, 283, 286, 325 Optic Nerve, 325, 342, 344 Orf, 195, 325, 327 Organ Culture, 325, 353 Organ Transplantation, 14, 71, 91, 95, 184, 325 Osmolality, 23, 201, 325 Osmoles, 325 Osmotic, 261, 311, 319, 325, 346 Osteoarthritis, 184, 325 Osteoporosis, 7, 10, 27, 104, 145, 151, 180, 184, 198, 326 Outpatient, 153, 326 Ovalbumin, 326, 346 Ovaries, 294, 326 Overexpress, 18, 67, 326 Ovum, 297, 313, 326, 360 Oxidation, 94, 180, 259, 266, 271, 284, 299, 313, 318, 326 Oxidative Phosphorylation, 39, 326 Oxidative Stress, 22, 29, 39, 48, 54, 88, 122, 125, 138, 326 Oxygenase, 64, 326 Oxygenation, 285, 301, 302, 305, 326 P P53 gene, 33, 326 Palate, 326, 349 Palliative, 326, 352 Pancreas, 169, 259, 271, 287, 297, 301, 308, 326, 344, 348, 355 Pancreatic, 108, 235, 275, 297, 326 Pancreatic cancer, 235, 326 Pancreatic Juice, 297, 326 Pancreatitis, 20, 122, 125, 184, 193, 207, 218, 326 Panniculitis, 210, 327 Paracentesis, 5, 117, 159, 327 Paraffin, 49, 327 Parapoxvirus, 195, 327 Parasite, 327 Parasitic, 172, 179, 327 Parenchyma, 171, 327 Parenteral, 12, 58, 136, 139, 327 Paresis, 322, 327 Paresthesias, 322, 327 Parietal, 46, 265, 327, 329, 332 Parietal Lobe, 46, 265, 327 Parity, 38, 327 Parkinsonism, 80, 327

Index 375

Parotid, 327, 344 Paroxysmal, 235, 264, 327 Partial remission, 327, 341 Particle, 65, 116, 327, 354, 359 Patch, 27, 283, 327 Pathogen, 307, 327 Pathologic, 5, 23, 37, 66, 82, 99, 259, 267, 271, 273, 283, 304, 328, 338 Pathologic Processes, 267, 328 Pathologies, 36, 41, 174, 328 Pathophysiology, 26, 36, 46, 57, 124, 128, 201, 202, 208, 328 Patient Education, 11, 211, 218, 242, 248, 250, 258, 328 Peer Review, 121, 232, 328 Pelvic, 328, 336 Penicillin, 265, 328 Pepsin, 328, 344 Pepsin A, 328 Peptic, 5, 184, 207, 328, 344 Peptic Ulcer, 5, 184, 207, 328, 344 Peptic Ulcer Hemorrhage, 328, 344 Peptide, 63, 94, 176, 184, 188, 194, 279, 290, 295, 296, 304, 313, 328, 332, 333, 335, 336, 337 Peptide Chain Elongation, 279, 328 Peptide Hydrolases, 290, 304, 328 Percutaneous, 50, 113, 193, 328 Perfusion, 54, 104, 109, 141, 305, 328, 353 Pericarditis, 165, 328 Pericardium, 328, 351 Perinatal, 167, 328 Periodicity, 329, 343 Peripheral blood, 43, 91, 105, 141, 309, 329 Peripheral Nerves, 194, 329, 348 Peripheral Nervous System, 270, 329, 350, 358 Peripheral stem cells, 299, 329 Peripheral Vascular Disease, 164, 329 Peritoneal, 5, 267, 310, 329 Peritoneal Cavity, 5, 267, 310, 329 Peritoneovenous Shunt, 5, 329 Peritoneum, 325, 329, 342 Peritonitis, 5, 30, 73, 95, 114, 146, 203, 329 Pernicious, 122, 125, 329 Pernicious anemia, 122, 125, 329 Peroxidase, 313, 318, 329 Petroleum, 327, 329 P-Glycoprotein, 35, 330 Pgp, 18, 330 PH, 92, 103, 109, 142, 166, 330 Pharmacodynamic, 105, 330

Pharmacokinetic, 330 Pharmacologic, 28, 36, 157, 264, 330, 353, 354 Pharmacotherapy, 83, 330 Pharynx, 297, 308, 330 Phenotype, 66, 271, 330 Phenyl, 173, 330 Phenylalanine, 105, 124, 127, 328, 330, 356 Phenylephrine, 26, 330 Phlebotomy, 34, 330 Phosphodiesterase, 182, 330 Phospholipases, 330, 346 Phospholipids, 265, 266, 294, 308, 317, 330 Phosphoric Monoester Hydrolases, 304, 331 Phosphorous, 172, 331 Phosphorus, 273, 331 Phosphorylated, 70, 279, 331 Phosphorylation, 32, 40, 54, 180, 331 Photocoagulation, 279, 331 Physical Examination, 72, 331 Physiologic, 23, 32, 36, 71, 133, 261, 271, 279, 286, 305, 310, 317, 331, 336, 340, 355 Physiology, 71, 79, 105, 122, 126, 208, 209, 271, 274, 297, 323, 331 Pigment, 270, 316, 317, 331 Pilot study, 57, 115, 331 Pituitary Gland, 189, 284, 295, 331 Plant sterols, 143, 331 Plants, 262, 274, 277, 278, 279, 298, 299, 310, 313, 319, 324, 331, 333, 343, 346, 354, 355, 356 Plaque, 10, 264, 331 Plasma cells, 265, 331 Plasma Kallikrein, 193, 311, 331 Plasma protein, 261, 290, 331, 335, 337, 346 Plasma Volume, 272, 318, 332 Plasmid, 44, 332, 358 Plasminogen, 266, 331, 332, 346 Plasminogen Inactivators, 332, 346 Platelet Activation, 332, 346 Platelet Aggregation, 180, 189, 263, 324, 332 Platelet Count, 12, 112, 332 Platelet Factor 4, 309, 332 Platelet-Derived Growth Factor, 194, 332 Platelets, 180, 194, 270, 324, 332, 352 Platinum, 314, 332 Pleura, 332 Pleural, 110, 317, 332 Pleural cavity, 332 Pleural Effusion, 110, 332

376 Cirrhosis

Poisoning, 30, 172, 310, 314, 321, 333 Policy Making, 299, 333 Pollen, 333, 339 Polyarthritis, 312, 333, 346 Polycystic, 23, 235, 333 Polycythemia Vera, 112, 330, 333 Polyethylene, 102, 333 Polymerase, 37, 93, 185, 230, 266, 333, 335 Polymerase Chain Reaction, 185, 230, 333 Polymorphism, 44, 333 Polypeptide, 262, 263, 280, 292, 294, 303, 328, 333, 335, 337, 352, 357, 360 Polyposis, 204, 333 Polysaccharide, 265, 333, 337 Polyunsaturated fat, 28, 136, 139, 140, 144, 333 Porphyria, 204, 330, 333, 334 Porphyria Cutanea Tarda, 330, 334 Porphyrins, 333, 334 Portacaval, 6, 139, 334 Portal Pressure, 39, 100, 160, 334 Portal Vein, 78, 90, 92, 118, 156, 160, 210, 334 Portosystemic Shunt, 34, 69, 117, 334 Posterior, 189, 263, 267, 268, 278, 288, 326, 334, 344 Postherpetic Neuralgia, 184, 334 Postmenopausal, 99, 180, 326, 334 Postprandial, 100, 334 Postsynaptic, 334, 346 Potassium, 40, 64, 261, 318, 334 Potassium Channels, 40, 64, 334 Potentiate, 309, 334 Potentiation, 334, 346 Practice Guidelines, 233, 243, 334 Precipitating Factors, 9, 334 Precipitation, 69, 174, 334 Precursor, 70, 264, 267, 277, 288, 289, 291, 324, 330, 332, 335, 337, 354, 355, 356, 357, 359 Predictive factor, 89, 112, 335 Predisposition, 59, 62, 174, 335 Prednisolone, 203, 335 Preeclampsia, 166, 335 Prekallikrein, 331, 335 Preload, 31, 335 Prevalence, 8, 9, 12, 14, 19, 33, 34, 42, 48, 52, 59, 66, 119, 207, 216, 324, 335 Probe, 16, 335 Procollagen, 168, 335 Proenzyme, 291, 335 Prognostic factor, 30, 108, 206, 207, 335

Proline, 182, 280, 304, 335 Promoter, 36, 70, 78, 335 Promotor, 180, 335 Prone, 65, 165, 218, 335 Prophase, 320, 325, 335, 350 Prophylaxis, 13, 82, 91, 195, 211, 266, 336, 357, 359 Proportional, 325, 336 Propranolol, 39, 106, 336, 353 Prospective Studies, 10, 336 Prospective study, 21, 113, 314, 336 Prostaglandin, 61, 336 Prostaglandins A, 336 Prostate, 235, 269, 271, 311, 336, 355 Prostatic Hyperplasia, 336 Protease, 17, 169, 176, 262, 280, 307, 332, 336, 343 Protease Inhibitors, 17, 176, 336 Protective Agents, 273, 337 Protein Binding, 337, 353 Protein C, 23, 193, 261, 262, 269, 294, 337, 356, 358 Protein Conformation, 262, 337 Protein S, 26, 32, 37, 54, 165, 176, 200, 235, 236, 266, 271, 279, 292, 297, 337, 343 Proteinuria, 298, 322, 335, 337 Proteoglycans, 165, 269, 293, 337 Proteolytic, 176, 193, 262, 280, 294, 311, 337, 346 Prothrombin, 6, 257, 337, 352 Prothrombin Time, 6, 337 Protocol, 114, 153, 337 Protons, 262, 304, 311, 337, 339 Proximal, 94, 288, 337, 345 Prune Belly Syndrome, 204, 337 Pruritus, 8, 69, 71, 153, 156, 160, 177, 198, 337, 356 Pseudocholinesterase, 171, 337 Psoriasis, 219, 320, 337 Psychiatric, 61, 114, 271, 317, 338 Psychiatry, 19, 60, 61, 90, 114, 212, 295, 338 Psychic, 279, 338, 344 Psychology, 30, 287, 323, 338 Psychophysiology, 323, 338 Psychotropic, 164, 338 Public Health, 19, 50, 59, 190, 208, 209, 213, 233, 338 Public Policy, 229, 338 Publishing, 72, 202, 204, 338 Pulmonary Artery, 40, 272, 338, 358 Pulmonary Circulation, 64, 304, 338 Pulmonary Edema, 312, 338

Index 377

Pulmonary Embolism, 338, 359 Pulmonary Fibrosis, 27, 187, 194, 240, 338 Pulmonary Gas Exchange, 64, 338 Pulmonary hypertension, 166, 167, 283, 338 Pulse, 159, 319, 338 Pupil, 283, 287, 320, 338 Purines, 338, 345, 359 Purulent, 259, 338 Putrefaction, 296, 339 Pyramidal Tracts, 294, 339 Pyridoxal, 339, 354 Pyruvate Dehydrogenase Complex, 122, 126, 170, 339 Q Quality of Life, 11, 12, 20, 30, 57, 96, 134, 210, 339 Quercetin, 137, 339 Quiescent, 53, 339 R Race, 17, 38, 52, 318, 339 Radiation, 116, 118, 172, 189, 264, 291, 293, 295, 296, 310, 311, 339, 360 Radiation therapy, 293, 295, 310, 311, 339, 360 Radioactive, 285, 304, 306, 307, 309, 311, 315, 319, 324, 325, 339, 351, 356, 360 Radioimmunoassay, 23, 270, 339 Radioimmunotherapy, 339, 340 Radiolabeled, 311, 339, 360 Radiological, 45, 240, 328, 339 Radiotherapy, 118, 272, 311, 339, 349, 360 Random Allocation, 340 Randomization, 39, 340 Randomized clinical trial, 30, 82, 157, 340 Reabsorption, 23, 189, 291, 340 Reactivation, 231, 340 Reactive Oxygen Species, 42, 49, 340 Reagent, 293, 315, 340, 352 Receptors, Serotonin, 340, 345 Recombinant, 25, 32, 52, 66, 93, 109, 119, 125, 128, 151, 168, 191, 192, 212, 222, 230, 340, 358 Rectal, 123, 127, 340 Rectum, 266, 272, 280, 287, 295, 296, 307, 308, 312, 336, 340 Recur, 165, 329, 340 Recurrence, 10, 43, 99, 109, 110, 115, 154, 198, 278, 329, 340 Red blood cells, 218, 292, 326, 334, 340 Red Nucleus, 268, 340 Reductase, 314, 341, 347

Refer, 1, 204, 273, 280, 295, 296, 314, 323, 339, 341 Reflux, 218, 297, 341 Refraction, 341, 348 Refractory, 5, 30, 106, 116, 117, 159, 289, 341 Regeneration, 50, 59, 76, 140, 295, 341 Regimen, 13, 71, 111, 160, 289, 330, 341 Regurgitation, 297, 300, 341 Relapse, 61, 341 Relative risk, 15, 259, 341 Reliability, 22, 341 Remission, 14, 315, 340, 341 Renal Artery, 305, 341 Renal Circulation, 202, 341 Renal failure, 9, 13, 188, 202, 302, 341 Renal tubular, 202, 341 Renal tubular acidosis, 202, 341 Replicon, 37, 46, 341 Resected, 49, 341 Resection, 99, 108, 137, 189, 213, 341 Respiration, 274, 319, 341, 342 Respiratory distress syndrome, 21, 184, 342 Respiratory Paralysis, 259, 342 Respiratory System, 342, 358 Response rate, 4, 10, 52, 342 Restoration, 340, 342, 352, 359 Retina, 185, 278, 283, 286, 323, 325, 342, 343, 357, 359 Retinal, 286, 287, 325, 342 Retinoblastoma, 235, 342 Retinoid, 36, 64, 124, 128, 342 Retinol, 65, 342 Retinopathy, 180, 286, 342 Retinyl palmitate, 65, 342 Retroperitoneal, 213, 260, 342 Retrospective, 4, 342 Retrovirus, 65, 169, 342 Rheumatism, 187, 343 Rheumatoid, 24, 66, 174, 184, 186, 280, 343 Rheumatoid arthritis, 66, 174, 184, 186, 280, 343 Rhinitis, 193, 343, 346 Rhythmicity, 28, 343 Ribavirin, 10, 22, 37, 52, 154, 155, 156, 157, 209, 343 Riboflavin, 22, 343 Ribose, 260, 343 Ribosome, 343, 355 Rickets, 343, 359 Rigidity, 327, 331, 343

378 Cirrhosis

Risk patient, 63, 343 Rod, 269, 279, 291, 343 Rutin, 339, 343 S Saliva, 218, 343 Salivary, 65, 169, 287, 326, 343, 346, 349 Salivary glands, 65, 170, 287, 343, 346 Saphenous, 283, 343 Saphenous Vein, 283, 343 Saquinavir, 18, 343 Sarcoid, 91, 343 Sarcoidosis, 186, 204, 343 Sclera, 278, 282, 283, 344, 357 Scleroderma, 24, 27, 69, 169, 344 Scleroderma, Systemic, 169, 344 Sclerosis, 6, 235, 280, 310, 320, 344 Sclerotherapy, 86, 123, 127, 215, 344 Screening, 13, 45, 63, 86, 90, 112, 208, 210, 217, 218, 219, 230, 279, 344 Scrotum, 344, 357 Secondary tumor, 317, 344 Secretin, 26, 344 Secretion, 26, 29, 33, 54, 278, 284, 292, 303, 308, 312, 318, 320, 344, 346, 354 Secretory, 26, 344 Sedative, 295, 318, 344 Segmental, 125, 128, 298, 344 Seizures, 153, 327, 344, 348 Selenium, 48, 125, 128, 130, 136, 137, 138, 140, 144, 175, 344 Sella, 331, 344 Semen, 336, 344, 345 Seminal vesicles, 345, 357 Semisynthetic, 279, 345 Senescence, 182, 345 Senile, 326, 345 Sensitization, 62, 72, 345 Sensor, 9, 191, 345 Sensory loss, 321, 345, 351 Sepsis, 21, 22, 80, 102, 269, 345 Septal, 71, 202, 265, 345 Septic, 112, 164, 166, 345 Septicaemia, 345 Sequence Homology, 65, 345 Sequencing, 24, 44, 48, 73, 185, 333, 345 Serine, 176, 182, 290, 311, 345, 346 Serine Endopeptidases, 290, 345, 346 Serine Proteinase Inhibitors, 345, 346 Seroconversion, 41, 231, 345 Serologic, 53, 306, 345 Serology, 6, 345

Serotonin, 69, 270, 273, 278, 330, 340, 345, 346, 355 Serotypes, 91, 345 Serous, 267, 290, 332, 346 Serpins, 176, 346 Sertraline, 156, 346 Serum Albumin, 201, 339, 346 Sex Determination, 235, 346 Sexual Partners, 207, 346 Shock, 164, 166, 184, 291, 346, 355 Shunt, 5, 6, 30, 69, 78, 79, 84, 98, 109, 117, 157, 346 Sicca, 65, 346 Side effect, 10, 13, 37, 156, 170, 206, 207, 211, 219, 221, 223, 260, 271, 278, 305, 346, 350, 354, 360 Siderosis, 28, 346 Signal Transduction, 42, 70, 174, 181, 182, 308, 346 Signs and Symptoms, 184, 341, 346, 356 Silymarin, 137, 138, 143, 190, 318, 347 Simvastatin, 189, 347 Skeletal, 93, 264, 279, 320, 321, 347 Skeleton, 259, 311, 336, 347 Skin Pigmentation, 11, 347 Skull, 322, 347, 351 Small intestine, 9, 270, 277, 284, 289, 303, 310, 347, 358 Smallpox, 347, 357 Smooth muscle, 31, 40, 64, 180, 189, 263, 273, 282, 294, 303, 311, 347, 350 Social Behavior, 189, 347 Social Environment, 339, 347 Sodium, 5, 184, 199, 202, 203, 261, 299, 318, 340, 347 Soft tissue, 272, 347 Solid tumor, 264, 347 Solvent, 293, 325, 347 Somatic, 279, 290, 303, 316, 319, 329, 347, 351 Soybean Oil, 333, 347 Spastic, 311, 347 Specialist, 7, 246, 287, 347 Specificity, 6, 27, 261, 290, 346, 348, 353 Spectrometer, 191, 348 Spectrum, 210, 348 Spermatozoa, 345, 348, 357 Sphincters, 294, 348 Spinal cord, 267, 276, 277, 292, 317, 320, 322, 323, 329, 339, 342, 348 Spinal Cord Vascular Diseases, 320, 348 Spinal Nerves, 329, 348

Index 379

Spirochete, 348, 351 Spleen, 106, 164, 167, 201, 263, 269, 315, 333, 344, 348 Splenectomy, 213, 304, 348 Splenic Artery, 213, 348 Splenic Vein, 334, 348 Splenomegaly, 201, 304, 333, 348 Sporadic, 334, 342, 348 Sprue, 9, 204, 348 Stabilization, 70, 348 Staging, 117, 231, 348 Standard therapy, 9, 348 Status Epilepticus, 167, 348 Steatosis, 51, 56, 94, 144, 294, 349 Steel, 279, 349, 356 Stellate, 16, 28, 29, 31, 35, 36, 46, 53, 57, 64, 70, 94, 349 Stereotactic, 118, 349 Sterility, 307, 349 Sterilization, 194, 349 Steroid, 270, 284, 347, 349 Stimulant, 273, 303, 311, 349 Stimulus, 180, 182, 283, 288, 289, 309, 327, 349, 352 Stomatitis, 52, 349 Stool, 114, 307, 311, 312, 349 Strand, 44, 333, 349 Stress, 4, 7, 29, 48, 62, 64, 105, 180, 189, 211, 255, 275, 284, 311, 321, 326, 335, 343, 349 Stroke, 162, 166, 179, 188, 228, 275, 301, 349 Stroma, 327, 346, 349 Subacute, 69, 103, 307, 349 Subarachnoid, 166, 300, 349 Subclinical, 8, 159, 307, 344, 349 Subcutaneous, 210, 260, 289, 296, 313, 327, 329, 349 Submaxillary, 292, 349 Subspecies, 348, 350 Substance P, 292, 317, 344, 350 Substrate, 34, 176, 304, 350 Suction, 295, 350 Sulfotransferases, 35, 350 Sulfur, 222, 293, 312, 318, 350 Sulindac, 115, 350 Superior vena cava, 329, 350 Supplementation, 35, 56, 104, 123, 127, 134, 138, 140, 141, 145, 350 Support group, 258, 350 Suppression, 31, 58, 103, 182, 198, 219, 284, 350

Suppressive, 186, 350 Surfactant, 21, 293, 350 Survival Rate, 6, 141, 231, 350 Symphysis, 336, 350 Symptomatic, 7, 10, 11, 112, 134, 159, 177, 184, 326, 350 Symptomatology, 12, 350 Synaptic, 346, 350 Synergistic, 12, 48, 350, 353 Synovial, 350, 351 Synovial Membrane, 351 Synovitis, 184, 351 Syphilis, 179, 351 Systemic disease, 174, 178, 351 Systemic lupus erythematosus, 24, 65, 174, 184, 265, 266, 280, 305, 351 Systolic, 304, 351 T Tardive, 278, 351 Taurine, 97, 270, 277, 351 Technetium, 144, 351 Telangiectasia, 235, 351 Telencephalon, 269, 351 Telomerase, 88, 351 Temporal, 16, 56, 351 Testis, 185, 351 Tetrahydrocannabinol, 164, 273, 351 Thalamic, 268, 351 Thalamic Diseases, 268, 351 Therapeutics, 5, 16, 91, 104, 111, 114, 117, 141, 223, 352 Thermal, 113, 287, 323, 333, 352 Thermal ablation, 113, 352 Thigh, 193, 352 Thioacetamide, 122, 126, 136, 139, 352 Thorax, 259, 350, 352 Threonine, 182, 345, 352 Threshold, 304, 352 Thrombin, 83, 294, 332, 337, 352 Thrombocytes, 332, 352 Thrombocytopenia, 75, 109, 152, 352 Thrombomodulin, 337, 352 Thrombopenia, 266, 352 Thromboplastin, 335, 337, 352 Thrombopoietin, 142, 152, 352 Thromboses, 266, 352 Thrombosis, 90, 118, 176, 179, 188, 270, 308, 310, 337, 344, 349, 352 Thrombus, 284, 307, 321, 332, 352, 358 Thymosin, 14, 155, 352 Thymus, 306, 315, 352, 353 Thymus Gland, 352, 353

380 Cirrhosis

Thyroid, 13, 174, 182, 305, 310, 318, 353, 356 Thyroid Gland, 305, 353 Thyroid Hormones, 318, 353, 356 Thyroiditis, 13, 65, 69, 124, 128, 169, 353 Thyroxine, 100, 261, 330, 346, 353 Tic, 33, 353 Ticks, 295, 353 Timolol, 39, 160, 353 Tissue Culture, 52, 187, 353 Tissue Distribution, 40, 168, 353 Tolerance, 174, 260, 298, 353 Tomography, 69, 134, 353 Tooth Preparation, 260, 353 Topical, 222, 293, 304, 327, 353 Torsion, 307, 353 Toxaemia, 335, 353 Toxicity, 27, 54, 124, 128, 144, 160, 190, 198, 219, 288, 354 Toxicokinetics, 354 Toxicology, 122, 126, 230, 354 Toxins, 9, 181, 242, 265, 291, 307, 339, 353, 354 Trace element, 176, 354 Trachea, 272, 330, 353, 354 Traction, 279, 354 Transaminase, 166, 177, 354 Transcriptase, 169, 312, 342, 351, 354, 360 Transcription Factors, 57, 70, 354 Transduction, 27, 70, 174, 182, 192, 346, 354 Transfection, 27, 271, 289, 354 Transfer Factor, 306, 354 Transforming Growth Factor beta, 42, 193, 354 Transfusion, 3, 219, 302, 354 Translation, 44, 292, 354 Translocating, 269, 355 Translocation, 269, 279, 292, 355 Transmitter, 259, 267, 288, 316, 323, 324, 355 Trauma, 98, 167, 187, 194, 269, 276, 293, 300, 303, 322, 327, 352, 355 Tremor, 327, 353, 355 Triad, 64, 82, 302, 355 Triage, 7, 355 Tricuspid Atresia, 283, 355 Tricyclic, 278, 355 Triglyceride, 170, 355 Tropism, 50, 51, 355 Tryptophan, 280, 345, 355 Tuberculosis, 282, 315, 355

Tuberous Sclerosis, 235, 355 Tumor marker, 262, 271, 355 Tumor Necrosis Factor, 42, 52, 61, 172, 182, 355 Tumor suppressor gene, 59, 326, 355 Tumour, 95, 356 Tungsten, 275, 356 Type 2 diabetes, 34, 356 Tyrosine, 86, 124, 127, 288, 356 U Ubiquinone, 176, 356 Ubiquitin, 54, 356 Ulceration, 325, 356 Ulcerative colitis, 107, 186, 308, 356 Ultrasonography, 81, 118, 356 Unconscious, 286, 305, 356 Uraemia, 327, 356 Uranium, 351, 356 Urea, 6, 312, 356 Urea Breath Test, 6, 356 Uremia, 312, 341, 356 Ureters, 341, 356, 357 Urethra, 194, 269, 336, 356, 357 Uric, 262, 299, 305, 338, 357 Urinary, 4, 7, 11, 23, 38, 74, 96, 273, 278, 303, 307, 325, 337, 356, 357, 359 Urinary tract, 4, 7, 11, 38, 337, 357 Urinary tract infection, 4, 7, 11, 38, 357 Urokinase, 49, 332, 357 Uterus, 276, 290, 294, 317, 326, 352, 357 Uvea, 357 Uveitis, 77, 357 V Vaccination, 24, 97, 207, 211, 230, 231, 357 Vaccine, 25, 48, 50, 52, 93, 222, 337, 357 Vaccinia, 195, 357 Vagina, 277, 317, 357 Vaginal, 4, 193, 357 Varices, 13, 15, 30, 34, 38, 57, 87, 98, 103, 106, 123, 127, 156, 157, 160, 357 Varicose, 344, 357 Varicose vein, 344, 357 Variola, 357 Vas Deferens, 194, 357 Vascular Resistance, 189, 263, 294, 357 Vasculitis, 327, 357 Vasoactive, 26, 85, 86, 155, 194, 357 Vasoactive Intestinal Peptide, 26, 357 Vasoconstriction, 6, 62, 64, 164, 202, 292, 358 Vasodilatation, 55, 86, 93, 311, 358 Vasodilation, 62, 64, 172, 180, 216, 358

Index 381

Vasodilator, 36, 62, 64, 272, 288, 303, 323, 358 Vector, 29, 354, 358, 360 Vein, 156, 160, 264, 267, 269, 310, 324, 327, 329, 330, 334, 343, 348, 350, 358 Venereal, 351, 358 Venous, 78, 81, 91, 97, 184, 266, 267, 270, 271, 276, 285, 301, 329, 332, 334, 337, 355, 358, 359 Venous blood, 271, 276, 332, 358 Venous Pressure, 81, 91, 97, 184, 334, 358 Venous Thrombosis, 270, 358, 359 Ventricle, 268, 283, 305, 338, 351, 355, 358 Ventricular, 168, 178, 180, 263, 283, 304, 355, 358 Venules, 272, 274, 290, 318, 358 Verapamil, 173, 183, 358 Vesicular, 52, 347, 357, 358 Veterinary Medicine, 229, 358 Villi, 304, 358 Villous, 9, 275, 358 Viraemia, 14, 358 Viral Load, 44, 48, 49, 155, 358 Viremia, 44, 47, 358 Virion, 302, 324, 358 Virulence, 268, 354, 359 Virus Diseases, 266, 359 Virus Replication, 16, 50, 91, 359 Viscera, 203, 347, 359 Visceral, 329, 344, 359 Vitamin A, 65, 124, 128, 308, 342, 359

Vitamin D, 7, 343, 359 Vitreous Body, 342, 359 Vitreous Hemorrhage, 286, 359 Vitro, 25, 301, 359 Vivo, 16, 32, 62, 182, 187, 359 Voluntary Health Agencies, 306, 359 W War, 277, 320, 359 Warfarin, 20, 359 Weight Gain, 118, 294, 359 White blood cell, 265, 271, 278, 313, 315, 319, 320, 321, 323, 331, 359 Windpipe, 330, 353, 359 Wound Healing, 165, 168, 278, 295, 308, 316, 359 X Xanthine, 262, 359 Xanthine Oxidase, 262, 359 Xenobiotics, 38, 77, 190, 360 Xenograft, 264, 360 X-ray, 256, 257, 275, 281, 296, 311, 320, 324, 339, 349, 360 X-ray therapy, 311, 360 Y Yeasts, 296, 310, 330, 360 Yellow Fever, 295, 360 Yellow Fever Virus, 295, 360 Z Zalcitabine, 312, 360 Zygote, 282, 360 Zymogen, 291, 335, 337, 360

382 Cirrhosis

Index 383

384 Cirrhosis

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