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

LIVER DISEASE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Liver Disease: 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: 0-597-84011-3 1. Liver Disease-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 liver disease. 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 LIVER DISEASE .......................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Liver Disease ............................................................................... 13 E-Journals: PubMed Central ....................................................................................................... 75 The National Library of Medicine: PubMed ................................................................................ 76 CHAPTER 2. NUTRITION AND LIVER DISEASE .............................................................................. 123 Overview.................................................................................................................................... 123 Finding Nutrition Studies on Liver Disease.............................................................................. 123 Federal Resources on Nutrition ................................................................................................. 125 Additional Web Resources ......................................................................................................... 126 CHAPTER 3. ALTERNATIVE MEDICINE AND LIVER DISEASE ........................................................ 129 Overview.................................................................................................................................... 129 The Combined Health Information Database............................................................................. 129 National Center for Complementary and Alternative Medicine................................................ 130 Additional Web Resources ......................................................................................................... 132 General References ..................................................................................................................... 141 CHAPTER 4. DISSERTATIONS ON LIVER DISEASE .......................................................................... 143 Overview.................................................................................................................................... 143 Dissertations on Liver Disease................................................................................................... 143 Keeping Current ........................................................................................................................ 144 CHAPTER 5. CLINICAL TRIALS AND LIVER DISEASE..................................................................... 145 Overview.................................................................................................................................... 145 Recent Trials on Liver Disease................................................................................................... 145 Keeping Current on Clinical Trials ........................................................................................... 153 CHAPTER 6. PATENTS ON LIVER DISEASE ..................................................................................... 155 Overview.................................................................................................................................... 155 Patents on Liver Disease ............................................................................................................ 155 Patent Applications on Liver Disease ........................................................................................ 182 Keeping Current ........................................................................................................................ 202 CHAPTER 7. BOOKS ON LIVER DISEASE ........................................................................................ 203 Overview.................................................................................................................................... 203 Book Summaries: Federal Agencies............................................................................................ 203 Book Summaries: Online Booksellers......................................................................................... 206 The National Library of Medicine Book Index ........................................................................... 212 Chapters on Liver Disease.......................................................................................................... 214 Directories.................................................................................................................................. 218 CHAPTER 8. MULTIMEDIA ON LIVER DISEASE.............................................................................. 221 Overview.................................................................................................................................... 221 Video Recordings ....................................................................................................................... 221 Bibliography: Multimedia on Liver Disease............................................................................... 222 CHAPTER 9. PERIODICALS AND NEWS ON LIVER DISEASE........................................................... 225 Overview.................................................................................................................................... 225 News Services and Press Releases.............................................................................................. 225 Newsletter Articles .................................................................................................................... 227 Academic Periodicals covering Liver Disease ............................................................................ 230 CHAPTER 10. RESEARCHING MEDICATIONS ................................................................................. 231 Overview.................................................................................................................................... 231 U.S. Pharmacopeia..................................................................................................................... 231 Commercial Databases ............................................................................................................... 234

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APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 237 Overview.................................................................................................................................... 237 NIH Guidelines.......................................................................................................................... 237 NIH Databases........................................................................................................................... 239 Other Commercial Databases..................................................................................................... 244 The Genome Project and Liver Disease...................................................................................... 244 APPENDIX B. PATIENT RESOURCES ............................................................................................... 249 Overview.................................................................................................................................... 249 Patient Guideline Sources.......................................................................................................... 249 Associations and Liver Disease .................................................................................................. 260 Finding Associations.................................................................................................................. 260 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 263 Overview.................................................................................................................................... 263 Preparation................................................................................................................................. 263 Finding a Local Medical Library................................................................................................ 263 Medical Libraries in the U.S. and Canada ................................................................................. 263 ONLINE GLOSSARIES................................................................................................................ 269 Online Dictionary Directories ................................................................................................... 270 LIVER DISEASE DICTIONARY ................................................................................................ 271 INDEX .............................................................................................................................................. 363

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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 liver disease 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 liver disease, 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 liver disease, 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 liver disease. 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 liver disease, 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 liver disease. 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 LIVER DISEASE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on liver disease.

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

Model for End-Stage Liver Disease (MELD) and Allocation of Donor Livers Source: Gastroenterology. 124(1): 91-96. January 2003. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Website: www.gastrojournal.org. Summary: A consensus has been reached that liver donor allocation should be based primarily on liver disease severity and that waiting time should not be a major determining factor. This article reports on a study that assessed the capability of the Model for End Stage Liver Disease (MELD) score to correctly rank potential liver recipients according to their severity of liver disease and mortality risk on the OPTN liver waiting list. The MELD model predicts liver disease severity based on serum creatinine, serum total bilirubin, and INR (international normalized ratio) and has been

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shown to be useful in predicting mortality in patients with compensated and decompensated cirrhosis (liver scarring). In this study cohort with chronic liver disease (n = 3,437), 412 patients (12 percent) died during the 3 month follow up period. Waiting list mortality increased directly in proportion to the listing MELD score. Patients having a MELD score less than 9 experienced a 1.9 percent mortality, whereas patients having a MELD score greater than 40 had a mortality rate of 71.3 percent. The authors conclude that the MELD score is able to accurately predict 3 month mortality among patients with chronic liver disease on the liver waiting list and can be applied for allocation of donor livers. 3 figures. 4 tables. 14 references. •

Autoimmune Liver Disease in Children Source: Journal of Gastroenterology and Hepatology. 16(6): 674-677. 2001. 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: Autoimmune liver disease (AILD) in children progresses to cirrhosis (liver scarring) and liver failure if not diagnosed and managed in time. In this article, the authors report on their prospective analysis of their patients with liver disease for autoimmune etiology and their outcome with treatment. All patients with liver disease were evaluated with liver function tests, abdominal ultrasonography, endoscopy, liver biopsy, viral markers, and investigations for Wilson's disease. Immunoglobulin (Ig) M hepatitis A virus, hepatitis E virus (HEV) and IgM hepatitis B core antibody were tested if acute viral hepatitis was suspected. Antinuclear antibody (ANA), antismooth muscle antibody (SMA), and liver kidney microsomal antibody (anti LKM1) were done in all cases. Autoimmune liver disease was diagnosed when one or more autoantibodies tested positive and no other etiology of liver disease was identified. Cases diagnosed to have AILD were treated with immunosuppressive drugs. AILD constituted 3.9 percent of chronic liver disease cases (6 of 153 patients; median age and duration of illness 8.5 years and 3 months, respectively). Four patients had acute hepatitis-like presentation. Three of the patients achieved remission with combination therapy of oral prednisolone (OP) and azathioprine (AZT), and one with only OP. The other two patients were not treated. Two of the patients in remission have been weaned off from immunosuppressive therapy, and one is in a withdrawal phase. Another patient, while in biochemical remission developed superimposed anicteric (without jaundice) acute HEV infection. The authors conclude that although AILD is uncommon in children, its search is rewarding, as remission is achieved with immunosuppressive therapy. Superimposed acute viral hepatitis can occur in endemic areas (the authors report from Lucknow, India). 1 figure. 2 tables. 14 references.

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Cholestatic Liver Disease Source: Practical Gastroenterology. 25(1): 28, 30, 32-35. January 2001. Contact: Available from Shugar Publishing. 12 Moniebogue Lane, Westhampton Beach, NY 11978. (516) 288-4404. Fax (516) 288-4435. Summary: Cholestatic liver disease remains a rare but increasingly recognized cause of illness affecting adults worldwide. Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the two major cholestatic liver diseases. This article provides an overview of adult cholestatic liver disease and the options available to clinicians in the management of these patients. The author discusses epidemiology, pathologic features, clinical features, diagnosis, medical therapy, management of

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complications, and prognosis of each disease. While there is much current evidence supporting an underlying immunologic process for both PBC and PSC, no unifying hypothesis exists to allow for the development of target specific therapies. Because of advances in technology and the refinement of diagnostic modalities, an increasing number of individuals are being identified at earlier stages of disease who may benefit from existing treatment options. In the majority of patients with PBC, a progressive clinical course resulting in fibrosis and eventual cirrhosis (scarring) is observed. Pruritis (itching) as a frequently complication creates difficult management options as significant impairments in quality of life are observed. Individuals undergoing orthotopic liver transplantation (OLT) for PBC have the highest rates of graft and patient survival over 5 years. Disease progression in PSC as a result of chronic bile duct obliteration eventually leads to biliary cirrhosis, hepatic (liver) failure, and complications from portal hypertension. Despite improvements in the management of complications from end stage liver disease and excellent long term results from liver transplantation, a continued understanding of the clinicopathologic processes responsible for cholestatic liver disease remains important. 23 references. •

Complementary and Alternative Medicine in Chronic Liver Disease Source: Hepatology. 34(3): 595-603. September 2001. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Chronic liver disease is a major cause of mortality and morbidity in the United States. Medical therapies for these diseases are often difficult to handle and limited in effectiveness and, therefore, affected patients often seek other treatments, either to complement or to replace standard care. This article reviews the types of complementary and alternative medical (CAM) therapies used, which encompass a wide range of approaches, including prayer, meditation, hypnosis, biofeedback, herbal medicals, chiropractic, diet, and lifestyle modifications. The authors note that at least 42 percent of the general population and a similar proportion of liver disease patients use some form of CAM on a regular basis. Herbal preparations are used by 20 percent of liver disease patients, typically without the advice or even knowledge of their physician. Current impediments to progress in developing reliable information on the safety and efficacy of botanicals are the incomplete understanding of their modes of action, the lack of standardization in their manufacture, and the complexity of the chemical ingredients in the average herbal extract. The authors conclude with four recommendations, including the advice that physicians should routinely and nonconfrontationally ask patients about use of CAM, and should become knowledgeable about CAM products, their traditional indications, and potential toxicities. 2 tables. 81 references.

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Liver Disease in the Elderly Source: Gastroenterology Clinics of North America. 30(2): 547-563. June 2001. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32821-9816. (800) 654-2452. Summary: Despite several morphologic and functional changes that have been described in the aging liver, most relevant studies fail to identify a significant age related deficit in liver function in humans. This article, from a special issue on gastrointestinal (GI) disorders in the elderly, addresses liver disease in this population. One of the important age related changes is a decrease in regenerative capacity, which may partly explain the impaired recovery after severe viral and toxic injury in the

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elderly. Nevertheless, livers from older subjects are used successfully for transplantation. Substantial morbidity (illness or disease) and mortality (death) in the elderly is attributable to liver diseases, and the number of patients older than 65 years of age with chronic liver disease is increasing rapidly. Although there are no liver diseases specific to advanced age, the presentation (symptoms), clinical course, and management of liver diseases in the elderly may differ in important respects from those of younger individuals. The authors specifically consider hepatitis in older patients, notably hepatitis A, hepatitis B, and hepatitis C; drug induced liver disease; cirrhosis (liver scarring) and portal hypertension; primary biliary cirrhosis; autoimmune hepatitis; and hepatocellular carcinoma (liver cancer). 4 figures. 1 table. 115 references. •

Burden of Liver Disease in the United States: Summary of a Workshop Source: Hepatology. 36(1): 227-242. July 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Disease burden is a term that encompasses a number of aspects of the impact of a disease on the health of a population, ranging from the frequency of the disease, as measured by incidence and prevalence, to its effect on longevity, such as case-fatality rate and years of life lost due to premature death, morbidity including decrease in health status and quality of life, and finance, including direct health care expenditures and indirect costs related to lost income from premature death or disability. This article summarizes a workshop conducted by the American Association for the Study of Liver Disease in May 2001. The goal of the workshop was to assemble available data on epidemiology and burden of liver disease in the United States and identify areas in which further research is needed. The authors conclude that liver disease is an important cause of morbidity (illness) and mortality (death) in the United States: currently, up to 2 percent of all deaths are attributable to liver disease. To improve the understanding of the epidemiology and impact of liver disease and to enhance effective means of diagnosis, therapy and prevention of liver disease at the population level, there are key factors required: objective and generalizable research data, appropriate personnel with necessary qualifications and expertise, and research infrastructure and funding. 5 figures. 5 tables. 72 references.

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Is Severe Liver Disease a Common Outcome for People with Chronic Hepatitis C? Source: Journal of Gastroenterology and Hepatology. 17(4): 423-430. April 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. Summary: For people with chronic hepatitis C, an assessment of their risk of progression to advanced liver disease is a major priority. Early studies of the natural history of chronic hepatitis C suggested that development of cirrhosis (liver scarring) was a relatively common outcome, even in the first 20 years of infection. More recent studies indicate that liver disease progression is generally slow, and that a minority of people with chronic hepatitis C will develop advanced liver disease. This article reports on a Markov model of liver disease progression that the authors developed based on an extensive review of studies reporting on chronic hepatitis C natural history. This model estimates that the risk of progression to cirrhosis in 7 percent and 20 percent after 20 and 40 years of infection, respectively. Corresponding estimates for hepatitis C related mortality (death) are 1 percent and 4 percent. However, liver disease progression is

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highly variable, and certain subgroups of people with chronic hepatitis C are at increased risk of advanced liver disease. Those groups include people with a heavy alcohol intake, those who have coinfection with HIV or HBV, and those who have already progressed to moderate to severe hepatic fibrosis. 6 figures. 2 tables. 61 references. •

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

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Liver Disease in Pediatric Patients with Cystic Fibrosis is Associated with Glutathione S-Transferase P1 Polymorphism Source: Hepatology. 36(4 Part 1): 913-917. October 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Liver disease in patients with cystic fibrosis (CF) is inconstant and has not yet been clearly related to any specific risk factor. Among liver detoxifying enzymes, the glutathione S-transferases (GSTs) play a key role in the protection against oxidative stress. This article reports on a study that provides the first demonstration of a significant association between GST gene polymorphism and the development of liver disease in patients with CF. The authors hypothesize that the major role of GSTs as detoxifying enzymes is probably emphasized in CF disease by the frequent use of antibiotics and other drugs in these patients. Identification of GSTP1 polymorphism may have prognostic significant in pediatric patients with CF and may direct more targeted therapy toward children with an increased risk of liver disease. 3 tables. 25 references.

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Pediatric Liver Disease in the United States: Epidemiology and Impact Source: Journal of Gastroenterology and Hepatology. 17 (5): 521-525. May 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. Summary: Liver diseases which affect children are different than those that affect adults. Diseases such as inborn errors of metabolism are fertile grounds for investigation (research). Study of these 'experiments of nature' will provide insight into hepatobiliary (liver and bile system) function and lead to new treatment options. Successful treatment or prevention of liver diseases in children will have long term implications. This article describes the current burden of pediatric liver disease and offers approaches to intervention. Topics include epidemiology, burden of disease, biliary atresia, intrahepatic cholestasis, metabolic liver disease, nonalcoholic steatohepatitis, viral hepatitis, acute liver failure in children, and immune diseases of the liver and biliary tract. 1 table. 16 references.

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Nonalcoholic Fatty Liver Disease Source: New England Journal of Medicine. 346(16): 1221-1231. April 18, 2002. Summary: Nonalcoholic fatty liver disease (NAFL) is an increasingly recognized condition that may progress to end stage liver disease. This review article considers the epidemiology, clinical manifestations (symptoms), pathogenesis (development), diagnosis, natural history, and management of NAFL. Insulin resistance and oxidative stress have critical roles in the pathogenesis of NAFL. Liver biopsy remains the most sensitive and specific means of providing important prognostic information. Simple steatosis may have the best prognosis within the spectrum of NALF, but it has the potential to progress to Steatohepatitis, fibrosis, and even cirrhosis (scarring of the liver). No effective medical therapy is currently available for all patients with nonalcoholic fatty liver disease. Weight reduction, when achieved and sustained, may improve the liver disease. Drug therapy aimed at the underlying liver disease holds promise, however, questions remain regarding the use of drug therapy and the effect of recommended dietary measures. Liver transplantation is a therapeutic alternative for some patients with decompensated, end stage NALF disease, but NALF may recur or develop after liver transplantation. 5 figures. 3 tables. 95 references.

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Nonalcoholic Fatty Liver Disease: An Agenda for Clinical Research Source: Hepatology. 35(4): 746-752. April 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Nonalcoholic steatohepatitis (NASH) is a pathological condition often seen in obese women with diabetes in the absence of significant alcohol use and hepatic histology consistent with alcoholic hepatitis. NASH is part of a larger spectrum of conditions comprising nonalcoholic fatty liver (NAFL) that also includes hepatic steatosis alone and hepatic steatosis with nonspecific inflammation. This review article summarizes the epidemiologic impact of NAFL, risk factors and determinants of severity of NAFL, the theories of pathogenesis (development) of NASH, and treatment options. There is no universally effective treatment for NASH, and therapeutic strategies have been largely empirical because the pathogenesis remains unknown. Treatments discussed include modification of the clinical conditions associated with NASH (treating

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the underlying diabetes, hyperlipidemia, and obesity), weight reduction, the use of ursodeoxycholic acid (UDCA), clofibrate, betaine, N-acetylcysteine, gemfibrozil, atorvastatin, troglitazone, and vitamin E. The authors note that current evidence supports the notion that NASH has the potential to progress to cirrhosis (scarring of the liver) and liver-related mortality (death) and morbidity (complications). 2 figures. 56 references. •

Efficacy of Granulocyte-Macrophage Colon-Stimulating Factor or Lamivudine Combination with Recombinant Interferon in Non-Responders to Interferon in Hepatitis B Virus-Related Chronic Liver Disease Patients Source: Journal of Gastroenterology and Hepatology. 17(7): 765-771. 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. Summary: Non-response to interferon (IFN) monotherapy is a major therapeutic problem in the management of chronic hepatitis B virus (HBV) infection. This article reports on a study in which the effectiveness of combination therapy to enhance the immunomodulatory effect of IFN by combining GMCSF (granulocyte-macrophage colony stimulating factor) or decreasing viral load by adding an antiviral agent such as lamivudine was evaluated prospectively. The study included 24 patients with chronic hepatitis B who were non-responders to previous IFN therapy were randomized to receive an IFN and GMCSF (group A, n = 10) or IFN and lamivudine (group B, n = 14) combination for 6 months. All patients successfully completed both the treatment schedules. At the end of treatment, there was a significant decrease in mean ALT levels. The HBV-DNA and HBeAg loss was seen in six of 10 (60 percent) patients in group ! and seven of 15 (50 percent) patients in group B. During follow up, two of six patients (33 percent) in group A and three of seven (43 percent) patients in group B relapsed with HBV-DNA and HBeAg positivity, which meant an overall sustained response of 40 percent and 28 percent respectively. None of the factors such as HBV viral load, ALT levels or liver histology could predict the non-response to combination therapy or occurrence of relapse. The authors conclude that larger studies using such combination therapies would be helpful in improving treatment strategies for chronic hepatitis B. 4 tables. 34 references.

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Alterations of Chemosensory Function in End-Stage Liver Disease Source: Physiology and Behavior. 66(2): 203-207. April 1999. Contact: Available from Elsevier Science. P.O. Box 945, New York, NY 10159-0945. (888) 437-4636 or (212) 633-3730. Fax (212) 633-3680. E-mail: [email protected]. Summary: Taste and smell dysfunction have been documented in patients with both acute and chronic liver disease. This article reports on a study undertaken to determine if chemosensory function is improved after restoration of hepatic function with liver transplantation. Nine subjects (seven women and two men) with end stage liver disease participated in the study. Taste and smell detection and recognition thresholds were determined before and after transplantation. A significant improvement in detection of the taste of sodium chloride (table salt) and the odor of phenethyl alcohol was found after transplantation. These findings may have clinical significance in food choices and nutritional status of these patients. Smell and taste play an important role in appetite and food intake. Specifically, the inability to taste salt is of potential importance in controlling the disordered salt and fluid balance often present in patients with end stage

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liver disease. Also, the chemosensory alterations demonstrated in this study may play a role in the anorexia and weight loss often seen in end stage liver disease and the improvement of nutritional status after transplantation. 2 figures. 2 tables. 15 references. (AA-M). •

Drug-Induced Liver Disease in Older Adults Source: Practical Gastroenterology. 25(3): 43, 47, 50, 52, 54, 56, 58, 60. March 2001. Contact: Available from Shugar Publishing. 12 Moniebogue Lane, Westhampton Beach, NY 11978. (516) 288-4404. Fax (516) 288-4435. Summary: The elderly population consumers more prescription and over the counter (OTC) medications than any other segment of the population. As a result, they are more prone to adverse drug events and are more susceptible to drug induced liver injury. Further, age related changes in the liver also influence drug metabolism, contributing to an increased risk of adverse effects. This article explores drug induced liver disease in older adults, which can vary from frequently noted mild abnormality of liver function tests to occasional severe injury, resulting in death. In the elderly, drugs must be considered as the most likely basis for abnormal liver function. Age related hepatic changes that may increase risk of liver injury include decrease in hepatic blood flow, decrease in hepatic microsomal enzyme activity, and decrease in serum albumin. Management is usually supportive. Early recognition of a toxic drug reaction with prompt discontinuation of the offending agent is paramount to limiting the amount of hepatic damage. This is usually followed by clinical and biochemical improvement. Rechallenge with the drug should be considered only if the need for the drug clearly outweighs the risks or if the initial reaction was observed was highly questionable. The authors conclude that to minimize the risk of adverse hepatic (liver) drug reactions in the elderly, physicians must be aware of age related pharmacokinetic and pharmacodynamic alterations, presence of comorbidity (other illnesses), and the many medications that the patient may be consuming. Close monitoring and review of the drug regimen and liver function tests will reduce the magnitude of this problem. A brief posttest is appended to the article. 4 tables. 24 references.

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Oxidative Damage in Alcoholic Liver Disease Source: European Journal of Gastroenterology and Hepatology. 13(1): 49-53. January 2001. Contact: Available from Lippincott Williams and Wilkins. 241 Borough High Street, London SE1 1GB, UK 44(0)20-7940-7502. Fax: 44(0)20-7940-7574. Website: http://www.eurojgh.com/. Summary: The metabolic effects of alcohol are due both to its direct action and to that of its first metabolite, and can also be connected with the changes in redox state. Differences in ethanol distribution, bioavailability, and hepatic (liver) metabolism can provide insight into the protective and predisposing factors in alcoholism, as well as gender differences of alcohol toxicity. Oxidative stress occurs following various conditions of ethanol consumption. This article reports on a study of oxidative damage in patients with alcoholic liver disease. The study included 26 Caucasian patients with alcoholism and 32 health, abstinent controls of both sexes who were investigated with special regard to reduction-oxidation status and ad hoc free radical antioxidant balance. Patients with alcoholism showed a decrease of free SH-group concentration, hydrogendonating ability, and an increase of reducing power property in plasma. A decreased total scavenger capacity of erythrocytes and plasma of alcoholic patients, combined with

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gender differences, could be detected. The authors conclude that alcoholic dependence causes gradual exhaustion of the antioxidant capacity of erythrocytes, therefore this non invasive measurement may be useful as a follow up of the evolution of alcoholic liver disease. The results also suggest a gender susceptibility of alcohol toxicity. 2 tables. 27 references. •

Genetic Liver Disease in Adults: Early Recognition of the Three Most Common Causes Source: Postgraduate Medicine. 107(2): 147-152, 155, 158-159. February 2000. Contact: Available from McGraw-Hill, Inc. 1221 Avenue of the Americas, New York, NY 10020. (612) 832-7869. Summary: This article is the final entry in a four article symposium that provides a practical approach to the diagnosis and management of common hepatic disorders encountered by primary care physicians. In this article, the authors review the early recognition and diagnosis of the three most common causes of genetic liver disease in adults: Wilson's disease, hereditary hemochromatosis (HHC), and alpha1 antitrypsin deficiency. Although advances in molecular biology have led to the identification and characterization of the genetic defects in these disorders, gene testing has its strengths and limitations. The longstanding techniques of serum (blood) testing and histologic assessment can be combined with genetic evaluation to clarify the diagnosis. Genetic testing is probably most helpful in HHC because of the high frequency of the homozygous C282Y mutation among patients of northern European descent and the relatively high penetrance of the mutation with regard to clinical expression. Genetic testing is much less helpful in the other genetic liver diseases because of the high number of possible mutations and variable clinical expression. However, noninvasive phenotype based screening tests and specific treatments are available for most genetic liver diseases. A patient care algorithm is included. 1 figures. 4 tables. 19 references.

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Utility of Radiological Imaging in Nonalcoholic Fatty Liver Disease Source: Gastroenterology. 123(3): 745-750. September 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Website: www.gastrojournal.org. Summary: This article reports on a prospective study that evaluated the role of radiological modalities in establishing the diagnosis of nonalcoholic steatohepatitis (NASH). Consecutive patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) were enrolled in the study. Each patient underwent liver biopsy, limited abdominal ultrasonography (US), computerized tomography (CT), and magnetic resonance imaging (MRI). Patients with NASH had greater aspartate aminotransferase levels, greater ferritin levels, more hepatocyte ballooning, and more fibrosis. None of the radiological features distinguished between NASH and other types of NAFLD. No radiological modality detected the presence of hepatocyte ballooning, Mallory's hyaline, or fibrosis, which are important features in the diagnosis of NASH. The presence of more than 33 percent fat on liver biopsy was optimal for detecting steatosis on radiological imaging. 3 tables. 35 references.

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Non-Alcoholic Fatty Liver Disease: An Overview Source: Journal of Gastroenterology and Hepatology. 17(11): 1136-1143. November 2002.

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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 reviews non-alcoholic fatty liver disease (NAFL), a condition that includes a spectrum of clinicopathological conditions and that is seen with increasing prevalence in the developed world. Although steatosis alone seems to have a benign course, those patients with the diagnosis of non-alcoholic steatohepatitis (NASH) can have a progressive course. Additionally, there is now evolving indirect evidence that some of the patients with cryptogenic cirrhosis (liver scarring) may be the result of 'burned-out' NASH. Although NAFL and NASH are associated with insulin-resistance syndrome, some patients with NAFL may have no obvious risk factors. Despite preliminary data from a number of pilot studies, no established therapies can be offered to patients with NASH. Over the next few years, a number of research projects dealing with the epidemiology as well as the pathogenesis of NAFL are expected to be completed. The authors anticipate that through a better understanding of NAFL, more effective treatment protocols can be developed targeting only those patients with NASH who are at the highest risk for progression to cirrhosis and liver failure. 2 table. 94 references. •

Liver Disease: Fat Inflames the Liver Source: Harvard Health Letter. 26(4): 4. February 2001. Contact: Harvard Health Letter. P.O. Box 420300, Palm Coast, FL 32142-0300. (800) 8299045. Website: www.health.harvard.edu/newsletters/subinfo.html. Summary: This health education newsletter article describes nonalcoholic steatohepatitis (NASH), a common form of chronic liver disease in which the liver has excess fat cells and those cells cause inflammation. The author contends that NASH is another result of the epidemics of obesity and diabetes sweeping the United States. NASH is found most often in people who are 10 to 40 percent of their ideal body weight, or have diabetes, or both. At the cellular level, the changes produced by NASH resemble the liver tissue inflammation caused by alcohol. For up to 20 percent of people with NASH, the condition is the beginning of a dangerous cycle that leads to fibrosis (a buildup of fibrous tissue in the liver) and that can lead to life threatening cirrhosis (scarring of the liver). Most people with NASH have no symptoms, or vague symptoms, such as fatigue, an achy feeling on the right side of the abdomen, and malaise (generally feeling bad). Liver function tests (blood tests) can show the first signs of trouble, but a liver biopsy must be used to confirm the diagnosis of NASH. Treatment involves weight loss, close monitoring of blood glucose levels in patients with diabetes, and cessation of alcohol consumption. Present research studies are investigating the role of vitamin E and ursodeoxycholic acid as possible drug therapies for NASH.

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Non-alcoholic Fatty Liver Disease Source: Journal of Gastroenterology and Hepatology. 17 (Supplement): S186-S190. February 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. Summary: This review article considers nonalcoholic fatty liver disease (NAFLD), a chronic liver disease that affects a high proportion of the world's population. Insulin

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resistance and oxidative stress play a critical role in the pathogenesis (development) of NAFLD. Clinical, biochemical and imaging studies are of value in the diagnostic evaluation of patients with NAFLD, but liver biopsy remains the most sensitive and specific means of providing important diagnostic and prognostic information. Simple steatosis (fatty liver) has the best prognosis within the spectrum of NAFLD, but NAFLD has the potential to progress to steatohepatitis, fibrosis, and even cirrhosis (liver scarring). No effective medical therapy is currently available for all patients with NAFLD. In patients with diabetes mellitus and hyperlipidemia (high levels of blood fats), appropriate metabolic control is always recommended, but rarely effective in resolving the liver disease. Weight reduction, when achieved and sustained, may improve the liver disease, although the results with weight loss have been inconsistent. Drug therapy aimed at the underlying liver disease holds promise. Several medications with different mechanisms of action and potential benefit are currently being evaluated in clinical trials. Liver transplantation is a life-extending treatment choice for patients with end stage NAFLD, but NAFLD may recur after liver transplantation. 43 references. •

Outcome of Hospital Care of Liver Disease Associated with Hepatitis C in the United States Source: Hepatology. 33(1): 201-206. 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: This study describes mortality and resource utilization for inpatient (hospital) care of hepatitis C (HCV) in comparison to alcohol induced liver disease (ALD) in the United States. The study also identifies factors that affect outcomes. The Healthcare Cost and Utilization Project database, a national inpatient sample was used to identify hospitalization records with diagnoses related to liver disease from HCV and ALD. Outcomes of hospitalizations was analyzed in terms of inhospital deaths and health care resource utilization. For 1995, the authors estimate that there were 26,700 hospitalizations and 2,600 deaths in acute, nonfederal hospitals in the United States for liver diseases caused by HCV. Total charges for these hospitalizations were $514 million. In comparison, ALD was associated with 101,200 hospitalizations; 13,400 deaths, and $1.8 billion in charges. Simultaneous HCV and alcohol abuse was associated with younger ages at the time of hospitalization and death compared with HCV or ALD alone. In analyses, alcohol abuse and HIV infection were associated with an increased risk of death among those with HCV. Liver transplantation and patient death were associated with the largest increase in hospitalization charges. Major complications of cirrhosis (such as variceal bleeding, encephalopathy, and hepatorenal syndromes) and sociodemographic factors (such as race and health insurance) were also significantly associated with the risk of death and hospitalization charges, which were similar in HCV and ALD. The authors provide new estimates regarding the public health impact of HCV, for use in health policy decision and cost effectiveness analyses of preventive and therapeutic interventions. 6 tables. 21 references.

Federally Funded Research on Liver Disease The U.S. Government supports a variety of research studies relating to liver disease. These studies are tracked by the Office of Extramural Research at the National Institutes of

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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 liver disease. 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 liver disease. The following is typical of the type of information found when searching the CRISP database for liver disease: •

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 COHORT Principal Investigator & Institution: Freise, Chris; Surgery; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122

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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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Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2009 Summary: (provided by applicant): Cadaveric liver transplantation is recognized as the optimal therapy for end stage liver disease, with marked improvement in results over the last two decades. With the increasing success of this treatment, the demand for suitable donor organs has also risen, resulting in a large discrepancy between the number of transplantable organs and the number of patients waiting. This imbalance has led to the development of living donor liver transplantation (LDLT) as an additional method to increase organ supply. The exact indications for this procedure as well as long-term results and potential impact on the healthy donor are questions that remain unanswered. These issues form the basis for this research protocol, which proposes a longitudinal cohort study of live donor liver transplant recipients and their donors across eight transplant centers with an extended period of follow-up. The aims of this cohort study will be the formation of a core database containing information collected pre-transplant, intraoperatively and post-transplant. At least 250 living liver donor/recipient pairs and an equal or greater number of cadaveric recipients will be followed for a minimum of two years to provide critically needed information on the safety and efficacy of living donor liver transplantation, the potential impact on disease progression and recurrence, and ultimately to better define the specific role of living donor liver transplantation in the management of end stage liver disease.In addition to core data collection, this cohort study will offer an opportunity to address specific research questions unique to the setting of LDLT. The first project focuses on patients with hepatitis C, the most common indication for transplantation in the U.S. The kinetics of recurrent hepatitis C viral load post-transplantation will be compared in living donor and matched cadaveric recipients, and the effect of pre-transplant interferon treatment on the tempo and severity of recurrence evaluated. The second project focuses on optimization of pain control in living donors, comparing the use of preemptive thoracic epidural catheter analgesia delivery with patient controlled intravenous analgesia, and using pain scores and quality of life instruments to evaluate the impact of these treatments on long and short-term outcomes.We anticipate that the study will provide the necessary information to aid physicians in the counseling of patients regarding transplant options, and help prospective donors and recipients to better understand the risks and benefits of the procedure. Additionally, the information gained through this cohort study can be expected to impact the entire living donor transplantation procedure itself, by identifying factors that can be modified pre-transplantation, intraoperativiely, and post-transplantation to improve donor and recipient outcomes. 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

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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 •

Project Title: ALCOHOL EFFECTS ON LIVER DISEASE IN HCV AND HIV COINFECT Principal Investigator & Institution: Schmidt, Warren N.; Assistant Professor; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2001; Project Start 25-SEP-2000; Project End 31-JUL-2003 Summary: (Applicant's Abstract) Hepatitis C (HCV) and Human Immunodeficiency virus (HIV) cause chronic infections of worldwide importance. Because they share parenteral factors for transmission, over one third of patients with HIV are usually coinfected with HCV and nearly 400,000 individuals in the United States are positive for both viruses. Patients with co-infection have more aggressive liver disease and increased incidence of cirrhosis than patients with HCV only. While the reasons for this are unclear, it is possible that co-existent alcoholism in this population is at least partially responsible. Alcohol may further modulate host immune suppression and have specific effects on host immune defenses resulting in increased viral replication and mutational pressure on HCV. The overall goal of this proposal is to study and clarify the effects of alcohol on HCV and progressive liver disease in patients who are co-infected with HIV. The specific aims are: 1) We will evaluate a cohort of HCV/HIV positive patients and identify the sociodemographic, histological, and clinical variables of these individuals that are affected by excess alcohol consumption and most likely to be important for progressive liver disease. 2) We will then sequence and compare important genomic regions of HCV isolated from these patients and determine the significance of quasispecies diversity for HCV pathology. 3) We will study the effects of antiviral therapy on the composition and diversity of HCV genomic regions and determine their importance for patient prognosis and response to therapy. Our work will clarify the epidemiology, natural history, and pathology of alcohol in these patients. It will also provide an increased understanding of progressive liver disease in this population that will aid in future management and antiviral therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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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

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

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

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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 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: CELLULAR IMMUNITY TO HEPATITIS C VIRUS IN HIV Principal Investigator & Institution: Graham, Camilla S.; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: (Provided by Applicant) The epidemics of HIV and hepatitis C virus (HCV) infections meet in individuals with parenteral exposure to blood, including injecting drug users (IDU) and persons with hemophilia, where rates of coinfection range from 60-90 percent. Coinfected individuals have a significantly increased risk of progression to end-stage liver disease, though mechanisms by which HIV modifies the course of HCV are poorly understood. It is paradoxical that HIV, an immunosuppressive state, leads to an accelerated progression of liver disease, and that HAART is associated with liver failure as well. Our central hypothesis is that both peripheral and intrahepatic HCV-specific cellular immune responses are qualitatively and quantitatively different in patients coinfected with HIV compared with those with HCV monoinfection, and that this is not solely a function of the degree of immunosuppression. Our goals are to determine whether coinfected individuals have an altered cellular immune response to HCV, to determine if immune reconstitution impacts HCV-specific cellular immunity, and if cellular immune responses to HCV are associated with improved outcome with anti-HCV therapy. To address these hypotheses we are examining HCV-specific cellular immune responses in three groups: 1) individuals with HCV/HIV versus HCV alone, 2) individuals with HIV/HCV prior to HAART and during immune reconstitution, and 3) individuals with HIV/HCV who are entering a protocol of interferon-ribavirin therapy. We are using ELISPOTS to characterize secretion of interferon-gamma, tumor necrosis factor alfa, and interleukin-10 at the single cell level in peripheral mononuclear cells and liver-infiltrating lymphocytes in these populations. We are complementing these

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functional assays with flow cytometry to phenotypically characterize lymphocyte populations. Determining alterations in cellular immune responses to HCV in individuals with HIV may help us to understand the pathophysiology underlying the accelerated progression of severe liver disease as well as help define subgroups of persons with HIV who may benefit from treatment of hepatitis C. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHIMERIC VIRUS PRIMATE MODEL OF HEPATITIS C Principal Investigator & Institution: Lemon, Stanley M.; Professor & Dean, Sch. of Medicine; Clinical Research Center; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-JAN-2006 Summary: (Provided by the applicant): Chronic HCV infection is a major threat to the public health. Current therapies have limited efficacy, but the search for more effective treatments is hampered by the lack of available animal models of HCV infection. The chimpanzee (Pan troglodytes) is the only animal species permissive for infection with this virus. This deficiency will be addressed by developing a small nonhuman primate model of hepatitis C involving the closely related, unclassified flavivirus GBV-B. GBV-B replicates to high titers, is hepatotropic, and causes liver disease in susceptible tamarins (Saquinus sp.). Since tamarins are more readily available than chimpanzees for such studies, GBV-B infection of these animals represents a potentially useful surrogate for studies of hepatitis C. However, although GBV-B among all animal viruses has the closest phylogenetic relationship to HCV, its proteins still share only approximately 25% identity at the amino acid level. Moreover, unlike HCV, GBV-B does not appear capable of establishing persistent infection in these animals. These features of GBV- B limit its usefulness. To overcome these limitations, the applicants will construct chimeric genome-length GBV-B cDNA clones in which specific functional domains of HCV are inserted in lieu of homologous GBV-B sequence. The hypothesis is that the close phylogenetic relationship between GBV-B and HCV will allow the rescue of viable chimeric viruses from these clones, and that these viruses will represent uniquely valuable resources to the research community since they will allow the in vivo evaluation of candidate inhibitors of critical HCV replication functions in a readily available and relatively inexpensive small, nonhuman primate species. Under Aim 1, the investigators have constructed a fulllength, infectious cDNA copy of the GBV-B genome. The infectivity of RNA transcribed from this clone has been demonstrated following intrahepatic injection of the RNA in a susceptible tamarin. In Aim 2, the investigators are constructing infectious chimeric flavivirus cDNAs containing the following HCV domains within a GBV-B background: the internal ribosome entry site (IRES), the major proteinase (NS3) with its cofactor molecule (NS4A), the RNA helicase (NS3) and the RNA dependent, RNA polymerase (NSSB). In Aim 3, chimeras in which the structural proteins of GBV-B and HCV are placed within the genetic background of the alternate virus will be constructed. For both Aims 2 and 3, the applicants will assess the ability of RNAs transcribed from these chimeric cDNA clones to induce infection in tamarins following intrahepatic inoculation, and determine the extent to which the viruses rescued from these clones cause acute or chronic liver disease on subsequent passage in these nonhuman primates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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

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Project Title: CINCINNATI DEVELOPMENT (CGD

DDRDC:

CENTER

FOR

GROWTH

AND

Principal Investigator & Institution: Cohen, Mitchell B.; Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2003; Project Start 08-MAY-2003; Project End 31-MAR-2008 Summary: OVERALL (provided by applicant): The overall goal of the Cincinnati DDRDC: Center for Growth and Development (CGD) is to promote research that will yield insights into the fundamental processes of growth and development in the digestive tract and lead to novel or improved therapies. The specific goals of the CGD derive from the central theme that understanding the molecular mechanisms that control development of the gastrointestinal tract and liver will result in strategies to

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correct intestinal, nutritional and liver disease. Furthermore, our working model of interdisciplinary collaboration and our strong research environment will continue to lead to productive investigation in digestive diseases. The 28 full members and 6 associate members come from 9 different divisions within the Department of Pediatrics and a total of 6 Departments within the University of Cincinnati College of Medicine. These investigators are grouped into four working areas that all impact growth and development: Differentiation, Absorption and Secretion, Inflammation, and Regeneration and Repair. The Aims of the Cincinnati DDRDC:CGD are: 1) To promote research in basic and translational science areas relevant to understanding of gastrointestinal and liver growth and development, as well as digestive disease, by studying differentiation, absorption and secretion, inflammation, and regeneration and repair; 2) To promote interactions among scientists with diverse backgrounds, 3) To attract basic investigators to the study of gastrointestinal and liver growth and development, and 4) To foster translational research in digestive disease. The specific aims of the Center will be achieved primarily through three inter-related Biomedical Research Cores. 1) The Microarray Core will perform high quality state of the art experiments to identify novel genes expressed in the digestive organs of humans and in animal models of disease. 2) The Bioinformatics Core will provide design assistance and statistical and computational analysis for the complex experiments performed in the Microarray Core. 3) The Integrative Morphology Core will provide consultation and technical support for morphology studies, including in situ hybridization to localize gene expression identified by microarray analysis. Thus, at many levels, there is strong synergy among the research base and among the Biomedical Research Cores. This synergy will increase efficiency, promote new research directions, and foster collaborations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLIN. & HISTOLOGIC SPECTRUM OF HCV LIVER DISEASE IN IDU Principal Investigator & Institution: Edlin, Brian R.; Associate Professor of Medicine and Publ; Family and Community Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2002 Summary: Injection drug users (IDUs) have the highest hepatitis C (HCV) infection rates of any risk group in the United States; fully 70-96 percent of IDUs have been infected. Natural history studies of transfusion recipients have suggested that HCV infection represents a slowly progressive disease culminating in cirrhosis and liver cancer after decades. But while active IDUs represent the largest single group of persons infected with HCV, there are no studies to date describing the prevalence and severity of HCVrelated liver disease among street-recruited, actively injecting IDUs. Because most IDUs acquired HCV when they began injecting decades ago, many are at imminent risk for life-threatening complications. We propose a cross-sectional study of 1000 active, streetrecruited IDUs who test positive for HCV antibody in the Urban Health Study's ongoing program of HIV and hepatitis testing in inner-city neighborhoods in San Francisco. Indepth epidemiological, clinical and laboratory evaluations of HCV-positive participants will be conducted to assess signs, symptoms, and correlates of liver disease. A subset of 200 HCV-positive participants will undergo liver biopsies. Specifically, this study aims to: 1) to describe the clinical and laboratory spectrum of HCV-related liver disease among 1000 active, street-recruited IDUs in San Francisco, 2) to determine the correlates of advanced liver disease among active IDUs, including demographic factors, injection and other behaviors, comorbidities, and viral markers. Advanced liver disease will be

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Liver Disease

defined as Child-Pugh score B or greater, 3) to describe the histologic spectrum of HCVrelated liver disease in a subset of 200 active IDUs who will undergo liver biopsy, and 4) to determine the correlates of progressive liver disease among the 200 IDUs who undergo biopsy. Progressive liver disease will be defined as fibrosis stage 3 or 4 on liver biopsy. In addition, contact information will be collected so that this cross-sectional study can serve as a baseline for future cohorts to examine the incidence of clinical and histological disease in this cohort. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLINICAL IMPACT ON HCV & ALCOHOL IN HIV INFECTED PERSONS Principal Investigator & Institution: Samet, Jeffrey H.; Professor of Medicine; Boston Medical Center Gambro Bldg, 2Nd Fl, 660 Harrison Ave, Ste a Boston, Ma 02118 Timing: Fiscal Year 2001; Project Start 26-SEP-2000; Project End 31-JUL-2005 Summary: (Applicant's Abstract) The complex relationships between alcohol use, HCV disease, and HIV disease progression have not been well characterized. The cooccurrence of these conditions is common. Both alcohol and HIV infection accelerate the development of HCV complications. The impact of alcohol and HCV infection on the course of HIV infection is less clear. The objective of this project, the HIV Longitudinal Interrelationships of Viruses and Ethanol Study (the HIV-LIVE Study), is to test whether alcohol consumption and HCV, separately and together, are associated with worse HIVrelated disease outcomes, and to determine the magnitude and importance of the effects. We will draw upon an existing cohort to enroll 400 subjects with both alcohol diagnoses and HIV infection from a diverse population with a HCV combined prevalence of 50 percent at Boston Medical Center and the Beth Israel-Deaconess Medical Center. The cohort will be assessed at baseline regarding alcohol diagnosis and consequences, recent and lifetime consumption, drug use and addiction severity, CD4 cell counts, HIV viral load, HCV antibody, viral RNA and genotype, liver disease, HIV disease severity, health-related quality of life, and comorbidity using standard measures. Subjects will be followed twice a year for 3.5 years to determine the primary outcomes, disease progression as determined by CD4 count and incident opportunistic infections. Additional outcomes include clinical progression of liver disease, acute care hospitalization, mortality, health-related quality of life, HIV viral load, and HIV and HCV medication use. Using data from this cohort and the literature, we will develop a comprehensive computer simulation model that will delineate the magnitude of impact that alcohol, HCV and other important determinants such as drug use, other comorbidity, antiretroviral therapy and opportunistic infection prophylaxis have on HIV disease progression. This HIV/HCV policy model will provide a framework for the understanding of the policy implications of a wide range of interventions and will allow the extrapolation of the cohort study data beyond the end of the study. The main hypotheses to be tested are that HCV-infected persons have worse HIV-related outcomes than those without HCV, hazardous alcohol consumption leads to worse HIVrelated outcomes, and subjects with both HCV and alcohol diagnoses have the worst outcomes. The results of this study will provide crucial information needed for the development and prioritization of interventions for coinfected persons with addictions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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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: CORE--MICROARRAY & VIROLOGY Principal Investigator & Institution: Katze, Michael G.; Professor; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2007 Summary: In the Microarray & Virology Core, we have brought together a diverse group of NIH-funded investigators from basic science and clinical medicine. These investigators have a common interest in using state-of-the-art technologies to better understand the molecular mechanisms underlying the progression from HCV infection to end-stage liver disease. Our goal is to use DNA microarrays to provide a molecular blueprint of the changes in cellular gene expression that occur at multiple points along the continuum from virus infection to liver disease, including cirrhosis and hepatocellular carcinoma. Our Specific Aims are the following: Aim 1: Supply biological samples for microarray and proteomic analyses and provide molecular biology and

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virology support. Investigators associated with this core will provide the biological samples used for microarray and proteomic analyses. These samples will come from a variety of in vitro and in vivo systems, including HCV replicon cell lines, cultured primary human hepatocytes, liver biopsy material from patients with recurrent HCV after liver transplantation, and liver biopsy material from patients co-infected with HCV and human immunodeficiency virus (HIV). Aim 2: Use DNA microarrays to profile changes in cellular gene expression that occur during HCV infection and HCVassociated liver disease. This core will leverage the capabilities of a pre-existing microarray facility, the Center for Expression Arrays, to apply the technologies of global gene expression analysis to the study of HCV infection and liver disease. This technology infrastructure will be coupled with expertise in hepatitis C virology, virushost interactions (including extensive experience in the use of global gene expression profiling), and liver disease and transplantation. Data obtained from these analyses will be provided to the Bioinformatics & Biostatistics core for analysis and integration with data generated by the Proteomics & Modeling core. The information is likely to yield improved diagnostic methods, markers of disease progression, and novel approaches for therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--MOLECULAR BIOLOGY FACILITY Principal Investigator & Institution: Wu, Gary D.; Associate Professor of Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 15-JUL-2002; Project End 30-JUN-2007 Summary: Description (provided by applicant) The purpose of the Molecular Biology Core as stated in the original Center Application in 1996 was to provide advice, equipment and technical applications for molecular cellular experimental approaches specific to digestive and liver disease. The major components of the Services of the Molecular Biology Core included: A) Digestive Disease regents, B) DNA Sequencing, C) Image analysis, D) Molecular and Cellular Biology Techniques, and E) Education. Many components of this Core have been highly successful under the directorship of Dr. Rebecca Taub. Enhancing the availability of reagents and protocols specifically targeted to digestive and liver research is of vital importance in attracting both current and potential Digestive Disease Center investigators. In this regard, components A-C have been instrument to the success of the Molecular Biology Core and the overall Center. They will be retained and expanded in the following fashion: A) Digestive Disease Reagents: We have expanded this repository of reagents to include significant additions to the stock of cDNA libraries, cDNA probes antibodies, Tab polymerase, expression vectors, and general purpose vectors already available through this core. A new component of the Molecular Biology Reagent Bank is a Human RNA Source Bank; B) DNA oligonucleotide synthesis and DNA sequencing. New components include: Direct PCR product sequencing, direct sequencing of cosmids/P1/BAC/ and PAC clones, walking strategy, and site directed mutagenesis; and c) Image Analysis: The Molecular Biology Core will continue to support the use of a Molecular Dynamics be a fully equipped workstation to analyze both custom gene arrays as well as commercially available arrays through Affymetrics (GeneChip Analysis Suite) and Genemax (Informax). The last two components of the Molecular Biology Core, D) Molecular and Cellular Biology Techniques and E) Education, have been redesigned and expanded to incorporate the analysis of gene expression at the level of mRNA through the use of array technology. At the time of the initial Center grant submission, many of the molecular techniques in item D were new to many investigators involved in digestive

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disease research. These include cDNA library construction, bacterial expression of proteins, and yeast two-hybrid cloning. However, with time, these techniques have become more widely used by many investigators, in part through the success of the Molecular Biology Core under Dr. Taub's direction. As a result, the need for many of the services in components D and E has diminished. In contrast, there has been considerable interest by Center Members to have services that would permit utilization of emerging technologies in the analysis of gene expression. Therefore, components D and E of the Molecular Biology Core will be replaced by a new Gene Expression Facility. This was met with great enthusiasm by the Executive Committee and the External Advisory Committee. The ability to examine and quantify alterations in gene expression is fundamental to the understanding of molecular mechanisms that determine biological processes. High density gene arrays are now a technical reality. The cost of this technology, although previous prohibitive for most investigators, has very recently become affordable for most investigators, has very recently become affordable This facility will have 2 components: 1) Digestive organ custom arrays, Affymetrix commercial arrays, and the Genomax Bioinformatics Workstation, and 2) Real-Time Quantitative PCR. The Gene Expression Facility will be highly interactive, not only with the other Cores of the Center, but also with the Clinical Investigators from both the Division of Gastroenterology and the Department of Surgery. Examples of these interactions include: 1) Interact with the transgenic/chimeric core facility by assisting in the analysis of murine tissues from wild-type and genetically engineered mice; 2) Complement the analysis of gene expression performed by the Morphology Core through in situ hybridization; 3) Assist in the analysis of in vitro cell culture model systems developed by the Cell Culture Core; and 4) Interact in a translational fashion with patient oriented research through the analysis of gene expression in human tissues. The services provided by the Gene Expression Facility are designed to provide access to several important components in the analysis of gene expression at the level of mRNA. Patterns of mRNA expression, acquired from various sources by interacting with the other Core facilities in the Digestive Disease Center, can be determined by gene array analysis either using custom gene arrays (murine) or Affymetrix arrays (murine and human). Bioinformatics and computational biology are critical components to the analysis of the data obtained from these array experiments and will be supported by the Molecular Biology Core through various Data Analysis tools provided by the Core, principally Genomax. Ultimately, with the identification of specific target genes of interest, quantification of target gene expression in a large number of samples can be performed by Quantitative Real-Time PCR and cellular localization can be determined by in situ hybridization. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYCLOOXYGENASE 2 AND ALCOHOLIC LIVER DISEASE Principal Investigator & Institution: Nanji, Amin A.; Director; University of Hong Kong Pokfulam Rd Hong Kong, Timing: Fiscal Year 2001; Project Start 17-SEP-2001; Project End 31-AUG-2002 Summary: Conventional treatment options for alcoholic liver disease have, in general, not been successful either in reversing liver injury or preventing progression in patients who continue to abuse alcohol. Current understanding of alcoholic liver injury revolves around the roles of endotoxin and oxidative stress. These stimuli acting in concert lead to upregulation of cyclooxygenase-2 (Cox-2). Based on studies in Cox-2 deficient mice and the intragastric feeding rat model for alcoholic liver disease, induction of Cox-2 appears to be a final common pathway for alcoholic liver injury. The studies proposed

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Liver Disease

will evaluate the role of Cox-1 and Cox-2 in alcoholic liver injury and test the role of specific Cox inhibitors in preventing and reversing established alcohol-induced liver injury. A specific Cox-2 inhibitor and a non-specific Cox inhibitor (indomethacin) will be administered to rats fed ethanol intragastrically and their effects on the development of pathological changes, endotoxin levels, lipid peroxidation and cytokines will be evaluated. Based on our preliminary studies that show that Indomethacin aggravates liver injury, another drug with higher Cox-2 selectivity (Meloxicam) will be used in the prevention/treatment studies. Additionally, the effects of the drugs will be tested in a model (CCI4) in which extensive fibrosis is seen. The effect of the Cox inhibitors (Cox-2 and Meloxicam) in reversing established alcoholic liver injury will also be tested in rats by simulating an in-hospital alcoholic hepatitis setting and an outpatient alcoholic liver disease setting. In the first set of experiments (in-hospital model), rats will be fed a fish oil- ethanol diet for 6 weeks to induce liver injury. After discontinuing ethanol, the Cox2 inhibitor or Meloxicam will be administered for two weeks with fish oil and dextrose. In the outpatient model, rats will be fed the fish oil-ethanol diet for 6 weeks followed by two weeks of treatment with the Cox-2 inhibitor or Meloxicam with continued ethanol administration. In both models, reversal of inflammatory and fibrotic changes will be evaluated. The prevention and treatment of alcoholic liver injury by Cox-2 inhibitors in these experiments should provide data for the testing of these drugs in patients with alcoholic liver disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHENOTYPE

DETERMINANTS

OF

SINUSOIDAL

ENDOTHELIAL

CELL

Principal Investigator & Institution: Deleve, Laurie D.; Associate Professor; Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 30-JUN-2007 Summary: (provided by applicant): Capillarization precedes fibrosis in alcoholic liver disease. In capillarization, sinusoidal endothelial cells (SEC) lose fenestrae and form a basement membrane, a loss of phenotype that has not been examined previously. We propose to examine determinants of SEC phenotype in a series of in vitro and in vivo experiments. In vitro, isolated cells will be examined in homotypic culture and in coculture with other liver cells to determine whether SEC phenotype is regulated by paracrine regulation or by heterotypic contact. The in vitro studies will utilize cells isolated from normal rats and from liver disease models, notably models of steatosis, alcoholic liver disease and fibrosis using thioacetamide. Studies in SEC from liver disease models will examine changes in response to determinants of normal SEC phenotype by heterotypic cells. Studies in hepatocytes and stellate cells from liver disease models will look for changes in factors that determine SEC phenotype. A proteomic approach will be used to identify and examine proteins involved in paracrine regulation. In vivo studies will provide confirmation of the relevance of the soluble factors implicated as determinants of SEC phenotype using continuous intraportal infusions of the soluble factors or their inhibitors in normal rats or rats from the above mentioned liver disease models by monitoring changes in liver histology. Differences in gene expression between SEC from normal and liver disease model rats will be characterized to understand what regulates SEC phenotype. These studies will be used to identify markers of SEC that are altered in the models, to confirm the findings of the proteomic studies and to identify common pathways that regulate expression of genes that are expressed in normal SEC, but not in SEC isolated from liver disease models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIGESTIVE DISEASES RESEARCH CORE CENTERS Principal Investigator & Institution: Boyer, James L.; Professor; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 30-SEP-1984; Project End 31-AUG-2004 Summary: This is a renewal application for support of the Yale University Digestive Disease Research Core Center, a multi-disciplinary Center whose research focus is Liver Structure, Function and Disease. Thirty-five independently funded investigators comprise a research based of approximately $8.5 million. Current research programs in the Center are distributed in 10 departments of the University including Biology, Cell Biology, Cellular and Molecular Physiology, Epidemiology and Public Health, Human Genetics, Medicine, Pathology, Pediatrics, Pharmacology and Surgery. The research based focuses on six major areas: 1) Cellular and Molecular Biology of the Liver, 2) Hepatic Transport Mechanisms, 3) Basic Biology of Disease Processes, 4) Studies of the Hepatic and Splanchnic Circulation, 5) Clinical Hepatology, and 5) Liver Immunology. The research programs in the Center are quite broad and range from fundamental studies of the biology of liver research programs in the Center are quite broad and range from fundamental studies of the biology of liver cells to clinical therapeutic trials of immediate clinical relevance to the diagnosis and treatment of chronic liver cells to clinical therapeutic trials of immediate clinical relevance to the diagnostic and treatment of chronic liver cells to clinical therapeutic trials of immediate clinical relevance to the diagnosis and treatment of chronic liver cells to clinical therapeutic trials of immediately clinical relevance to the diagnosis and treatment of chronic liver disease in patients with these disorders. The major goals of the Center continue to be: 1) to stimulate multidisciplinary interactions between basic and clinical faculty and departments, 2) to provide in-depth training environment, 3) to efficiently organize time consuming, often costly techniques and procedures in core facilities for use by multiple investigators, 4) to stimulate basic scientists to direct their talents and technologies to specific areas of research interest in the Center, 5) to promote important new research and training opportunities through a pilot feasibility project program, and 6) to create an intellectual environment within opportunities through a pilot feasibility project program, and 6) to create an intellectual environment within the institution in the field of Hepatology and to foster collaborations both within and outside the institution. To achieve these goals the Center is organized into five Core Facilities including both within and outside the institution. To achieve these goals the Center is organized into five Core Facilities including: 1) Administrative Core, 2) Cell Isolation, Culture and Organ Perfusion Core, 3) Molecular Biology Core, and 4) Imaging Core. A Pilot Feasibility Program supports small 1-2 year grants for new scientific initiatives. An Enrichment program consists of a seminar program, journal clubs, symposia, retreats and Center newsletters. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DRUG METABOLISM AND CHRONIC LIVER DISEASE Principal Investigator & Institution: Branch, Robert A.; Professor/Director; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 30-JUN-2006 Summary: (provided by applicant): This is a resubmission of a proposal whose goal is to use pharmacogenetic principles to better understand the influence of liver disease associated with hepatitis C on drug disposition and develop new tools to evaluate hepatic function. We propose to address the following specific hypotheses: In Specific Aim 1: Hepatitis C influences the clearance of drugs that undergo metabolism in

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Liver Disease

comparison to matched controls. Furthermore, the extent of change in clearance is different for drugs that are metabolized by different drug metabolizing enzymes and is associated with the severity of the liver disease. Specific Aim 2: Selective decreases in drug metabolism in patients with hepatitis C without hepatic decompensation is associated with enzyme specific down-regulation of hepatic expression of mRNA for that enzyme and increased circulating levels of the cytokines, Interleukin-6 and Tumor Necrosis Factor- ?. Specific Aim 3: The measurement of activity of multiple drug metabolizing enzymes can be interpreted in the context of a sequential, progressive model of hepatic dysfunction to provide an integrated assessment of hepatic function and prognosis in patients with hepatitis C. We propose to study patients with hepatitis C (n= 112) associated with chronic persistent hepatitis, chronic active hepatitis and cirrhosis with or without hepatic decompensation and age, sex matched controls (n=48) on two occasions. Each study subject will participate in three pharmacokinetic (PK) studies that uses drugs selected as probes of substrates metabolized predominantly or exclusively by an individual drug metabolizing enzyme. Part 1: A cocktail to include: caffeine (CYP1A2), flurbiprofen (CYP2C9), mephenytoin (CYP2C19), debrisoquine (CYP2D6), chlorzoxazone (CYP2E1) and dapsone (acetylation). Part 2: Semisimultaneous oral:intravenous administration with midazolam to measure intestinal and hepatic contributions to CYP3A metabolism and Part 3: oral administration of acetaminophen (UGT1A6) simultaneously with intravenous morphine (UGT2B7). When feasible, liver tissue obtained at the time of diagnostic liver biopsy as part of routine patient care will have concentrations of mRNA for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, UGT1A6 and UGT2B7 measured. Patients with hepatitis C-associated liver disease will be followed at 6 monthly intervals until liver transplantation, death or duration of funding. The study will be repeated either after a change in clinical status or at 2 years in patients with liver disease and after one or 12 months in control subjects. Collectively, these studies will provide a consolidated base of information within the same cohort of patients with hepatitis C and normal subjects to better understand the influence of hepatitis C-associated live disease on drug metabolizing enzymes. This information has potential to create new integrated indices to evaluate hepatic function and prognosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EARLY DETECTION OF LIVER CANCER AND HEPATITIS Principal Investigator & Institution: Block, Timothy M.; Professor and Director; Biochem & Molecular Pharmacol; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: The goal of this proposal is to develop methods for the early detection of hepatocellular carcinoma (HCC) and hepatitis. The hypothesis that changes in the amount or modification of serum polypeptides correlate with the onset of HCC or hepatitis will be determined. Individuals chronically infected with hepatitis B or C virus (HBV, HCV) are at high risk for the development of HCC and hepatitis, with disease progression occurring after many years. Serum polypeptides from individuals at different stages in the disease continuum will be resolved by "Proteomic" 2-dimensional gel analysis. Our preliminary evidence and the work of others demonstrate that 2D gel technology has advanced to the point where expressed protein profiles of biological samples can be reproducibly resolved. Polypeptides that correlate (by their appearance, disappearance or post translational modification) with disease status will be identified. Correlating polypeptides will be characterized by a variety of methods available to us:

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data base reference, immunological methods or micro sequencing. Identification of biomarkers that help in the diagnosis and prediction of liver disease in this high-risk population will have enormous public health benefit, given the limitations on current methods. It will also provide insights about the mechanisms of progression of this disease family and offer a platform technology for the use of proteome diagnostics in other areas of cancer detection and liver decompensation. 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: END-STAGE LIVER DISEASE/PREVALENCE & TREATMENT VARIATION Principal Investigator & Institution: Bryce, Cindy L.; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 15-SEP-2000; Project End 31-AUG-2005 Summary: (adapted from the application) The primary purpose of this proposal is to provide the applicant with means and structure for achieving two goals. The immediate goal is to evaluate the effect of gender, race and income on access to liver transplant services. The long-term goal is to gain independence as a health services researcher by

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developing methodological expertise in decision sciences and multivariate statistical modeling and research expertise in organ transplantation and health policy evaluation. The applicant will obtain further instruction in computer simulation, geographic information systems, and advanced statistical analysis; in addition, she will receive clinical education to better understand the liver transplantation process and overall delivery of patient care. This training will be provided through formal coursework, directed readings, seminars and conferences, a clinical preceptorship, and research. Most activities will take place at the University of Pittsburgh's School of Medicine, Graduate School of Public Health, and Center for Research on Health Care. The applicant's research project evaluates the role of gender, race, and income in determining access to liver transplantation and explaining variation in liver transplant rates. To date, most studies on access to transplantation have focused on renal transplant services; few researchers have studied hepatic transplantation because of serious data limitations. Whereas the federal government maintains a comprehensive database of persons with renal disease from the time they receive dialysis, there is no centralized, population-based registry for persons with end-stage liver disease (ESLD). Most information on ESLD patients is collected on liver transplant candidates by the United Network for Organ Sharing. The hypothesis of this project is that demographic and economic factors significantly affect early access to transplant services, namely referral rates to transplant centers and listing rates by transplant centers. To address this issue, better information is needed. Therefore, the project will satisfy two aims: (1) develop and validate a population-based methodology for identifying and tracking a cohort of "transplant potential" patients with ESLD; and (2) estimate the effect of gender, race and income on movement through the transplantation process. This project will collect new information on patients with ESLD and combine it with existing data resources made available through The Optimal Timing of Liver Transplantation Project (AHCPR, R01 HS09694-02). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EPIDEMIOLOGY AND IMPACT OF HEPATITIS C IN THE COMMUNITY Principal Investigator & Institution: Kim, W R.; Assistant Professor; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2003; Project Start 15-MAR-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the US: an estimated 2.7 million Americans have been infected with the virus. Although the prevalence of HCV infection in the population is well established, the public health impact of liver disease caused by HCV remains uncertain. Based on established resources for population-based research in Olmsted County (the Rochester Epidemiology Project), we have already established a registry of all community residents presently diagnosed with HCV. In this study, we propose to screen community residents for HCV and then determine the impact of HCV infection in the community. In Aim 1, we will measure the prevalence of HCV which has not previously been diagnosed by screening the serum of Olmsted County residents of ages 30 to 49 years for HCV. For screening, we will utilize an established method to obtain serum samples from the majority of the target population in the community. In Aim 2, we will compare the prevalence and severity of liver disease, health status, quality of life and comorbidity profile among three groups of community residents, namely those with established HCV diagnosis, those with HCV infection discovered only by screening, and those without HCV infection. In Aim 3, based on these three groups, we

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will measure community-wide healthcare resource utilization related to HCV, independent of effects of comorbid conditions, particularly substance abuse and mental health problems. The results of this work will address the substantial gap between patient outcome data derived from referral patient samples and prevalence data based on population surveys, by providing key information about the impact of HCV on morbidity and health of the majority of Americans whose HCV infection remains undetected. My long-term goal is to establish a comprehensive patient-oriented research program in viral hepatitis and liver disease, encompassing epidemiology, survival statistics, quality of life, and health services research. Resources created by the current project, namely detailed clinical information and biologic specimens from a large cohort of community residents with HCV, will provide future opportunities to study natural history, virologic and host prognostic determinants of progression, and effectiveness of community-based interventions on HCV outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EPIDEMIOLOGY OF HEPATOCELLULAR CARCINOMA Principal Investigator & Institution: Ko, Cynthia W.; Medicine; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2002; Project Start 06-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): The goals of the proposed research project are: 1) to prepare and train the candidate for a career in academic gastroenterology by providing the necessary environment, education, and research support, and 2) to gain insight into the epidemiology of hepatocellular carcinoma in the United States. The candidate is a clinically trained gastroenterologist with additional training in basic epidemiology and biostatistics. As part of this proposal, she will be provided with more advanced training in both general and applied epidemiology and biostatistics. The candidate will be supported and mentored by Dr. John Potter. Her progress will be monitored by the sponsor and the Division of Gastroenterology. The Department of Medicine and Division of Gastroenterology will provide full commitment and support toward the development of the candidate's independent research career. The focus of the scientific portion of this proposal is on hepatocellular carcinoma, a common tumor worldwide the incidence of which is also rising in the United States. Much of this increase can be attributed to the current epidemic of hepatitis C. The epidemiology of hepatocellular carcinoma has not been extensively studied in this country, and few studies have recruited population-based cases and controls. Well-recognized environmental risk factors for hepatocellular carcinoma include chronic viral hepatitis, other chronic liver diseases, and exposure to aflatoxins. However, risk factors that predispose patients with chronic liver disease to hepatocellular carcinoma are not well defined. It is likely that genetic risk factors for hepatocellular carcinoma exist, since familial and ethnic clustering of the tumor are well documented, iron is a recognized co-factor for the development of malignancy in other sites. Hemochromatosis is an inherited disorder in which excess iron accumulates in the liver, heart, pancreas, and other organs. A gene for hemochromatosis, HFE, has recently been identified. Patients with hemochromatosis are at up to 200-fold increased risk of developing hepatocellular carcinoma. We hypothesize that HFE mutations are risk factors for HCC in patients either with or without underlying liver disease. Thus, the specific aims of tills proposal are: 1) to determine whether mutations in the HFE gene are a risk factor for hepatocellular carcinoma; and 2) to recruit a cohort of patients with chronic hepatitis C for prospective studies of the epidemiology of hepatocellular carcinoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE THERAPY FOR ALCOHOLIC LIVER DISEASE Principal Investigator & Institution: Lemasters, John J.; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 27-DEC-2002; Project End 30-NOV-2007 Summary: (provided by applicant): Alcoholic liver disease is associated with an increase in oxidative stress and inflammatory mediators such as TNFalpha. Recently, work by this group has clearly demonstrated an essential role of oxidant production and TNFalpha signaling in the liver pathogenesis due to chronic ethanol consumption in a intragastric ethanol-feeding model in mice. Two primary approaches have been employed thus far to elucidate the mechanisms of alcohol-induced liver injury: viral vector-mediated gene transfer and mutant (i.e., knockout and transgenic) mouse technology. The work proposed here will continue to rely on the strengths of these approaches and build on our recent finding to test the unifying hypothesis that Kupffer cell-derived oxidants initiate a cascade of inflammatory responses including NFkappaB activation and TNFalpha production which subsequently induces mitochondrial dysfunction and oxidative stress in hepatocytes leading to tissue damage. First, isolated liver perfusion and superoxide production by cytochrome c reduction from transgenic and knock out mice following 4 weeks of intragastric ethanol feeding will be used to identify sources or oxidants (i.e., NADPH oxidase, CYP2E1, myeloperoxidase, iNOS, etc) and critical pathways responsible of hepatic oxidative stress due to alcohol (Aim 1). Next, in order to specifically target cellular and subcellular sources of oxidants, cellspecific gene delivery vectors will be used. Using recombinant adeno-associated viral (rAAV) serotypes and cell-specific promoter elements for Kupffercells or hepatocytes, optimized gene transfer to both Kupffer cells and hepatocytes in vivo will be achieved (Aim 2). Finally, using rAAV serotypes and cell-specific promoter elements, the over expression of cytosolic Cu/Zn-SOD, mitochondrial Mn-SOD and dominant-negative IkappaBalpha in each cell type will be evaluated in the mouse enteral ethanol feeding model to test the hypothesis that Kupffer cell-derived oxidants are initially responsible for activating an inflammatory cascade leading to mitochondrial oxidative stress and dysfunction and ultimately tissue damage (Aim 3). The experiments outlined in this proposal will not only provide important mechanistic data related to oxidant production and transcription factor activation involved in acute ethanol-induced liver injury, provide novel experimental tools that can be used to address numerous questions related to basic biology and disease of liver and potentially provide an effective therapeutic approach to treatment of alcoholic liver disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE THERAPY FOR ERYTHROPOIETIC PROTOPORPHYRIA Principal Investigator & Institution: Mathews-Roth, Micheline M.; Associate Professor of Medicine; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2003 Summary: Erythropoietic protoporphyria (EPP) is a genetic disease in which ferrochelatase, the enzyme that inserts iron into protoporphyrin, is defective. In EPP, protoporphyrin accumulate in erythrocytes, leaks into about 5% of patients. Since it has been demonstrated that the vast majority of the protoporphyrin found in plasma, skin and liver derives from the erythrocytes, we propose that gene therapy directed at the bone marrow could cure EPP. This would be especially beneficial for patients with severe photosensitivity or incipient liver disease resistant to pharmacological treatment. Using a mouse model of EPP (homozygous recessive mutation), we have recently

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demonstrated that transplantation of bone marrow from normal syngeneic Balb/C donors into irradiated EPP recipients completely cures the disease phenotype. We have also shown that retrovirus-mediated transfer of human ferrochelatase cDNA into peripheral blood BFU-E from human EPP patients corrects the specific protoporphyrinmediated fluorescence. In addition, we are developing improved gene transfer methods for hematopoietic stem cells by means of Lentiviral vectors and in vivo selection protocols, which will be validated and optimized in the EPP gene therapy model. Based on these preliminary results, our Specific Aims are as follows: Specific Aim 1: To demonstrate that retroviral transfer of human ferrochelatase cDNA into hematopoietic stem cells of EPP donor mice followed by their transplantation into EPP recipient mice will cure or significantly ameliorate the disease phenotype. Specific Aim 2: To compare the efficiencies of Murine Leukemia Virus-verus HIV-1 Lentivirus-based vectors to transduce murine hematopoietic stem cells and correct the EPP phenotype by bone marrow transplantation. Specific Aim 3: To evaluate the efficacy of gene therapy protocols for EPP that combine minimal myeloablation prior to bone marrow transplantation, Multi-drug Resistance (MDR) or Dihydrofolate Reductase (DHFR) retroviral vectors and corresponding in vivo selection regimens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENERAL CLINICAL RESEARCH CENTER Principal Investigator & Institution: Boat, Thomas F.; Director; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2001; Project Start 30-DEC-1993; Project End 30-NOV-2001 Summary: This is a proposal for the renewal of a multi-categorical General Clinical Research Center at the Children's and University Hospitals. Major areas of research include: 1. Pediatric Liver Disease. Studies are defining the pathophysiology and treatment of new inborn errors of bile acid metabolism and peroxisomal disorders and the pathogenesis of bone disease and growth failure in cholestatic liver disease. 2. Bone Health. Studies will examine the effect of maternal age during lactation on bone demineralization and the value of progestins in ameliorating the loss. Studies will evaluate the role of calcium supplementation on bone accretion in prepubertal children, the role of exercise in bone accretion in preschoolers and the pathogenesis and management of bone disease in juvenile rheumatoid arthritis. 3. Cancer. Using resources available through a proposed Tissue Procurement Facility supported by the GCRC, basic science and clinical investigators will obtain tumors for investigations of the cell biology and molecular mechanisms of malignancies. Studies will investigate thyroid cancer, neural tumors, breast cancer, and the APC and Bloom's Syndrome genes. 4. Gaucher Disease. Despite the availability of enzyme research for Gaucher Disease, disability from bone disease persists. Studies will evaluate the potential value of bisphosphonates as an adjunct to enzyme replacement for the treatment of bone disease in Gaucher Disease. 5. Cystic Fibrosis. Studies are defining the safety of a replicationdeficient recombinant adenovirus construct to deliver the CF transmembrane conductance gene to the nasal epithelium. 6. Cholesterol Synthesis. Studies are evaluating the potential effect of the cholesterol content in breast milk or infant formulae and cholesterol synthesis rates to determine if early exposure to cholesterol in the human infant may have an "imprinting" effect on cholesterol synthesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETICS OF AUTOSOMAL DOMINANT POLYCYSTIC LIVER DISEASE Principal Investigator & Institution: Somlo, Stefan; Associate Professor; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2001; Project Start 30-SEP-1995; Project End 31-MAR-2003 Summary: Autosomal dominant polycystic liver disease without kidney cysts (ADPLD) is a genetically distinct, heritable disease characterized by the presence of multiple, scattered cysts in the liver parenchyma not associated with cyst formation in the kidney. We have performed a genome-wide scan for linkage using several ADPLD families and identified a major locus for the disease confined to a approximately 10 centiMorgan interval on human chromosome 19p13.2. The overall goals of our program for studying polycystic liver disease (PLD) are (1) phenotypic characterization of individuals with PLD and families with ADPLD, (2) identification of the gene (PLD1) mutated in human ADPLD, (3) elucidation of the mechanisms by which mutations result in the observed phenotype, (4) discovery of the factors that modify the expression of the ADPLD phenotype, (5) understanding the role of PLD1 in human cystic diseases in general and, (6) discovery of approaches for modulating the phenotypic effects of mutations in PLD1. The present proposal focuses on the characterization of the ADPLD phenotype and the identification of responsible human disease gene by positional cloning. We propose to undertake a comprehensive characterization of the clinical phenotype of ADPLD to determine whether patients with ADPLD have extrarenal manifestations that overlap with those of patients with autosomal dominant polycystic kidney disease (ADPKD) and establish whether the severity of the liver cystic disease in ADPLD correlates with the same factors known to influence the severity of the liver cystic disease in ADPKD. We plan to establish whether most patients with a presentation of polycystic liver disease (PLD) without renal involvement have familial ADPLD. We will use positional cloning to identify PLD1. Positional cloning will require refinement of the recombinatorial boundaries of the ADPLD genetic interval by definition of "critical recombinants" and construction of a detailed physical map of the interval. This physical map will be used to isolate all expressed sequences from the refined ADPLD candidate region. Candidate genes will be scanned to identify disease related mutations. Once identified, we will characterize the nature of the ADPLD mutations, study the genomic organization of the PLD1 gene, and determine if there is a relationship between genotype and phenotype in ADPLD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENOMIC DETERMINANTS OF NONALCOHOLIC FATTY LIVER DISEASE Principal Investigator & Institution: Merriman, Raphael B.; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by candidate): Nonalcoholic fatty liver disease (NAFLD) is a group of diseases characterized by hepatic steatosis without significant alcohol use, often associated with hyperlipidemia, obesity and insulin resistance. Nonalcoholic steatohepatitis (NASH) is part of the spectrum of NAFLD, with steatosis and added necroinflammation and fibrosis. NASH is common and may progress to cirrhosis. The pathogenesis of NAFLD is unknown but may incorporate a polygenic susceptibility with a phenotype strongly influenced by environmental factors. Disorders of lipid homeostasis underlie all forms of hepatic steatosis. Fat accumulation as triglyceride (TG)

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in the hepatocyte is the critical first step in the development of NAFLD. The central hypothesis of this proposal is that the pathogenesis of NAFLD is based upon increased flux of TG precursors (fatty acids, FA) with increased synthesis or decreased mobilization of TG in the hepatocyte, leading to fat accumulation. We postulate that NAFLD evolves to NASH when genetic abnormalities of fatty acid flux and environmental factors converge. Triglyceride accumulation may relate to increased peripheral FA mobilization, regulated in part by peroxisome proliferator-activated receptor gamma (PPARgamma). Alternatively, FA within the hepatocyte may be misdirected from oxidative pathways to TG synthesis: genomic variants in PPARalpha are likely candidates. Impaired lipidation and hepatocyte VLDL secretion would also potentiate steatosis and variants in Microsomal Triglyceride Transfer Protein (MTP) and apo-B render these as further prime candidate genes. Clinical and tissue databases at UCSF will be utilized and further characterized. The specific aims are (1) To perform mutation analysis on key genes of lipid metabolism, PPARalpha, PPARgamma, MTP and apo-B, for known and novel mutations in patients with NASH. We aim to extend our preliminary data showing increased prevalence of genomic variants of PPARalpha in patients with NASH, supporting our postulate that these are important in disease progression (2) To genotype polymorphisms detected, permitting screening of case control sample populations (3) To assess the contribution to NASH of genomic variants uncovered, in kindred identified with NASH, using cosegregation analysis (4) To determine the biochemical effects of mutants using in-vitro transfection studies. These projects will increase our understanding of NASH and with mentoring and coursework will foster the candidate's development as an independent researcher. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GLYPICAN-3: A NOVEL MARKER FOR HEPATOCELLULAR CARCINOMA Principal Investigator & Institution: Filmus, Jorge E.; Sunnybrook & Women's Coll Hlth Scis Ctr Health Sciences Centre Toronto, Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Human hepatocellular carcinoma (HCC) is usually asymptomatic at early stages. As a result, HCC is generally at an advanced stage when discovered, and the therapeutic options very limited. HCC is associated with chronic liver injury, primarily chronic viral hepatitis and alcoholic liver disease. The risk of developing HCC is 50 - 100 fold greater in individuals with chronic hepatitis B virus infection than in non-infected individuals, and the incidence of HCC in cirrhotic carriers of hepatitis C virus (HCV) may be as high as 5% per year. In principle, therefore, screening protocols are justified for chronic HBV carriers and cirrhotic HCV patients. The only molecular marker that has been widely used for the diagnosis and detection of HCC is alfafetoprotein (AFP). However, AFP expression is significantly increased in a considerable number of patients with non-malignant chronic liver diseases. Thus, more specific markers for HCC are required. Results recently obtained in this laboratory have shown that a protein called glypican-3 (GPC3) can be detected in most HCC tissue sections but it is undetectable in normal liver or benign liver disease. In addition, examination of a limited number of patients has shown that whereas GPC3 is undetectable in the serum of healthy individuals, its levels are significantly elevated in a large proportion of HCC patients. These results suggest, therefore, that GPC3 could be a better marker than AFP for the diagnosis and detection of HCC. The main goal of this study is to test this hypothesis. To this end, serum GPC3 and AFP will be measured in a cohort of 100 patients with HCC, and in patients with benign liver disease. The

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specificity and sensitivity of both markers will then be compared. GPC3 levels will also be assessed in 50 additional tissue sections from HCC patients, and a similar number of sections from various benign liver diseases. Another objective of this project is to investigate whether GPC3 could be used as a marker of tumor burden in experimental cancer. If this is the case this study will provide a tool that will simplify the search of novel treatments for HCC, and may open the possibility of using GPC3 measurement for the follow-up of HCC patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HBV-ETHANOL INTERACTIONS IN LIVER DISEASE Principal Investigator & Institution: Feitelson, Mark A.; Associate Professor; Pathology, Anat/Cell Biology; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Chronic alcoholism and hepatitis B virus (HBV) infection are associated with chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) in millions of people worldwide. Epidemiologic evidence shows a higher frequency of HBV markers among chronic alcoholics compared to the general population, and more severe liver disease among chronically infected alcoholics compared to patients suffering from chronic alcoholism or HBV infection alone. The applicant laboratory has recently developed an HBV transgenic mouse on a severe combined immunodeficient (SCID) host, which supports consistent levels of virus gene expression and replication. Since the SCID host is not tolerant to the virus, adoptive transfer of unprimed syngeneic splenocytes resulted in the development either acute or chronic hepatitis, with either complete or partial clearance of virus markers from serum and liver, respectively. Interestingly, the introduction of ethanol in a liquid LieberDiCarli diet strongly up-regulated HBV gene expression and replication in these mice, and that when ethanol fed mice were adoptively transferred with 5 x 107 splenocytes, which usually results in acute hepatitis, they develop chronic liver disease (CLD) instead. Since the pathogenesis of hepatitis B is immune mediated, and T cells play a central role in the clearance of virus infected hepatocytes, the objective of this work is to identify the changes in anti-viral T cell immunity that are responsible for the ethanol mediated changes in pathogenesis. This will be addressed by asking whether the shift from acute to chronic liver disease is associated with changes in the presence, frequency, and distribution of T cell responses to one or more virus antigens (aim 1). Experiments will also be conducted to ask whether chronic hepatitis could be converted back to acute, resolving hepatitis by (1) polarizing the immune response toward Thl, or (2) adoptively transferring primed splenocytes to one or more virus antigens (aim2). Together, these experiments will identify the T cell subsets and specificities associated with the ethanol mediated shift from acute to chronic hepatitis, and then therapeutically manipulate T cell immunity so as to prevent the development of CLD in ethanol fed, adoptively transferred mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HCV & ALCHOOL-- 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

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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 •

Project Title: HCV GENOMIC VARIABILITY IN HIV INFECTED HEMOPHILIACS Principal Investigator & Institution: Sherman, Kenneth E.; Associate Professor; Internal Medicine; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: Hemophiliacs with symptomatic disease are multiply exposed to blood products including factor concentrates to correct the Internet clotting factor deficiencies. Prior to routine use of heat inactivation and screening of donor blood for specific viral pathogens, hemophilia patients were routinely exposed to, and infected with, viruses such as hepatitis B (HBV), hepatitis C (HCV) and human immunodeficiency virus (HIV). Cohort studies in hemophiliacs suggest several clinically and scientifically important findings that warrant further detailed investigation including; a) Liver disease progression may be altered in hemophiliacs infected with HCV with more rapid progression to liver failure and death; b) The source of infection from large pools of concentrate that were potentially infected by multiple discreet donors leads to a high risks of mixed infection represented by both genotype and quasi species heterogeneity; c) The HIV coinfected hemophiliacs may have different clinical outcomes and an altered

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immune response may facilitate our understanding of the underlying process of mutant virus selection, and the associated clinical outcomes. The overall goals of this proposal include the study and characterization of the genomic RNA of HCV in infected hemophilic patients with and without confection with HIV. In the retrospective Phase 1, we utilize the NCI Multi center Hemophiliac Cohort Study serum bank database to study the relationship between progression to decompensated liver disease and quasi species variability in the viral envelope hyper variable and core domain. Heteroduplex analysis will be used to rapidly screen samples from index patients and matched controls using samples longitudinally collected over a 10 year or longer period of time. Peptides will be produced from unique quasi species and these peptides will be evaluated for their function as CTL epitomes. Phase 2 involves the initiation and performance of a clinical intervention trial designed to determine variable kinetic response rates to PEG-interferon+ribavirin between hemophiliacs with HCV alone vs HCV/HIV coinfected subjects. Quasi species populations will be modified/cloned, sequencing will be performed to generate families of closely related core peptides that will be studied for their ability to bind and stimulate an immune response. Treatment nonresponders will be followed in a prospective cohort study for up to 3 additional years so that the evolution of the virus, and its associated immune response in this group can be evaluated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HCV INFECTION--RISK FACTORS FOR PROGRESSION Principal Investigator & Institution: Stuver, Sherri O.; Assistant Professor; Epidemiology; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02460 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): For individuals who are infected with hepatitis C virus (HCV), knowledge of co-factors affecting the occurrence of liver disease is crucial. However, the mechanisms of HCV-associated pathogenesis, particularly with regard to the role of the virus and the host immune response, remain unclear. The primary goal of the proposal is to elucidate the natural history of HCV infection with respect to progression to hepatocellular carcinoma (HCC) and other health outcomes in a Japanese community-based population in which infection with HCV is highly endemic. As part of an annual ultrasonographic tomography screening program in this population, nearly 1,000 adult residents with HCV have been under surveillance for liver cancer since 1994. The proposed study will extend the observation of this cohort, with the additional collection and analysis of virologic, epidemiologic, and clinical data. The specific aims of the research are: to determine the predictive value of markers of HCV infection in the development of liver damage and HCC; to estimate the effect of host-related factors, including heavy alcohol consumption, cigarette smoking, and diet, on HCV-induced liver disease progression and hepatocarcinogenesis; to examine the role of co-infection with hepatitis B virus and human T-lymphotropic virus type I in the natural history of HCV; to characterize the function of host immune status and response in the persistence of HCV infection as well as in the progression of liver disease and HCC among HCV carriers; to evaluate the utility of serologic markers of liver damage in predicting the development of HCC in individuals infected with HCV; to identify predictors of extrahepatic morbidity and mortality among HCV carriers. The uniqueness of the study population and the richness of the data parameters combined with the extensive experience of the assembled multi-disciplinary team provide an important opportunity to increase our understanding of the natural history of HCV and to contribute to our

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ability to identify and potentially treat those carriers who are at increased risk of an adverse outcome related to their HCV infection. 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 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: HCV-HIV COINFECTION: IMPACT OF IMMUNE DYSFUNCTION Principal Investigator & Institution: Sterling, Richard K.; Internal Medicine; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): This proposal for the Mentored Clinical Research Award (K-23) is to provide supervised experience in patient oriented clinical research. The candidate is an Associate Professor of Medicine in the Division of Gastroenterology and Hepatology at Virginia Commonwealth University Health System/Medical College of Virginia campus (VCUHS/MCV). His career goals are: (1) to be an outstanding clinician and (2) to be a leading scientist in patient-oriented research in liver disease. During the period of support, the applicant will be primarily mentored by Dr. Arun J. Sanyal with support from other faculty from Hepatology (Dr. Mitchell L. Shiffman), Infectious Disease (Dr. Evelyn Fisher), Biostatistics (Dr. Chris Gennings), and Quality Health Care (Dr. Wally Smith). Effective therapy for human immunodeficiency virus (HIV) infection has markedly prolonged survival in infected individuals. As a result, other comorbid conditions in these patients are becoming more clinically important. Approximately 30% of HIV infected patients are also infected with hepatitis C virus (HCV) which is now the leading co-morbid disease in HIV-infected individuals. The

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histologic severity and natural history of HCV has been reported to be accelerated in those co-infected with HIV. It is hypothesized that: 1) the severity and progression of hepatic fibrosis in patients with HIV-HCV co-infection is directly related to the immunologic competence of the individual, and 2) the virologic response to anti-HCV treatment is directly related to the degree of immunologic competence. These will be tested by the following specific aims: 1) to perform a longitudinal prospective cohort study of subjects with HIV-HCV co-infection and to define the change in the distribution of hepatic fibrosis scores and the relationship between these changes and the immunologic status, and 2) to prospectively define the relationship between the immunologic status and the sustained virologic response to anti-HCV therapy. The institution and departmental environment as well as the facilities and resources are excellent for career development in academic medicine. The K-23 award will protect this candidates time and help him mature into a senior investigator in Hepatology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEPATITIS C VIRUS PROTEINS AND ETHANOL Principal Investigator & Institution: Polyak, Stephen J.; Assistant Professor, Research; Laboratory Medicine; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): This revised R21 exploratory proposal focuses on the interaction of alcohol with hepatitis C virus (HCV) proteins in the pathogenesis of HCV liver disease. HCV infection is a significant clinical problem and is a major cause of liver disease worldwide. The prevalence of HCV infection is significantly higher in alcohol abusers, who are also at greatly increased risk for development of liver diseases that include fibrosis, cirrhosis and hepatocellular carcinoma. Moreover, the incubation period for development of liver disease is much shorter in HCV-infected alcohol abusers. HCV infected patients who abuse alcohol also have reduced responses to interferon (IFN) therapy. Alcohol and HCV proteins have separately been shown to induce a plethora of changes in signal transduction cascades in human cells, including inhibition of the IFN system and increased expression of pro-inflammatory cytokines and chemokines, such as TNF-alpha and IL-8. Our preliminary data indicate that the HCV NS5A protein induces IL-8 to inhibit the IFN system, while the HCV core protein activates the IFN system. However, very little is known about how alcohol affects cellular signal transduction pathways in the context of HCV protein expression, and the resultant effects on liver cell horneostasis. We hypothesize that alcohol and HCV proteins induce pro-inflammatory cytokine and chemokine expression, inhibit IFN signal transduction, and perturb the expression of other cellular proteins and signal transduction pathways in human hepatocytes. Using human hepatocyte cell lines stably expressing the HCV NS5A and core proteins under tetracycline regulation, this exploratory application will address two specific aims. Specific Aim 1 will determine the effects of physiological concentrations of ethanol with HCV core and NS5A protein expression on pro-inflammatory cytokine and chemokine expression, and IFN signal transduction. Specific Aim 2 will characterize the global transcriptional changes in human hepatocytes induced by HCV core and NS5A proteins, ethanol, and IFN by CDNA microarray analysis. These studies will provide mechanistic information on how alcohol interacts with the HCV-infected patient to promote liver disease, and may lead to strategies to counteract the deleterious effects of these agents on the liver. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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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 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

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Project Title: HIV HCV COINFECTION--ANTIVIRAL THERAPY AND FIBROSIS Principal Investigator & Institution: Thomas, David L.; Associate Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 20-SEP-2000; Project End 31-JUL-2005 Summary: (Applicant's Abstract) Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections occur with alarming frequency in persons who misuse alcohol and illicit drugs. In East Baltimore, 80 percent of HIV-infected injection drug users also have HCV infection and one-half acknowledges regular, heavy alcohol use. This disease cluster may cause cirrhosis since HIV infection and heavy alcohol use are the two conditions that accelerate progression of hepatitis C. Recently the significance of these cofactors has been magnified by improved anti-retroviral treatments that dramatically reduce other opportunistic infections but may themselves

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cause liver toxicity. Accordingly, the 1999 US Public Health Service guidelines for management of HIV opportunistic infections considered hepatitis C but withheld recommendations for medical management because of the paucity of supporting data. In this investigation, we hypothesize that treatment of HIV and HCV infections will reduce progression of liver disease, after controlling for alcohol use. To test the hypothesis, we will first examine the success of prior anti-retroviral use with respect to liver fibrosis and then the change in fibrosis over three years of anti-retroviral experience. In addition, we will examine the effect of alfa-interferon based treatment for HCV infection with respect to fibrosis changes and eradication of HCV. Innovative tools will be tested to assess liver fibrosis (morphometrics), predict liver fibrosis (markers), and measure use of alcohol and medical adherence (A-CASI). Given the experience of the investigative team and the extensive preliminary data, we anticipate providing data that will directly affect forthcoming guidelines for the medical management of HIVHCV coinfected persons. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HUMAN POLYCYSTIC KIDNEY DISEASE Principal Investigator & Institution: Schrier, Robert W.; 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-APR-1985; Project End 30-JUN-2006 Summary: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common potentially lethal genetic diseases. It occurs worldwide and affects about 1 in 500 to 1000 Americans. The costs for treatment of end- stage renal disease (ESRD) are estimated to exceed 1.5 billion US dollars per year, not including the cost for treatment of other renal and extrarenal manifestations. Over the last 15 years this Program Project Grant (PPG), which is the largest study of ADPKD manifestations in children and adults in the world, has contributed significantly to our understanding of the natural history of this disease. The long-term objective for the competitive renewal is to develop strategies to prevent disease progression. This application focuses on ADPKD kidney and liver disease. Combining a clinical trial with investigations into genetic mechanisms of disease severity and with basic research in an animal model and cell culture systems will be the overall strategy to achieve the goal. The competitive renewal of the PPG continues to take advantage of the unique adult and child population, which has been assembled as a result of the 15-year PPG. This patient population will e used in the first Project-A randomized trial of anti-hypertensive therapy in children, adolescents and young adults with ADPKD- and in the second Project- Identification of modifying gene sin ADPKD. The premise is that identifying genes that promote disease severity will not only help to understand the pathophysiology, but will also allow development of new treatments and section of high-risk patients for treatment trials. The third and fourth will complement the two clinical investigations by performing basic science studies, which have clinical implications for patients with ADPKD. The third Project investigates the role of apoptosis and caspase (apoptosis) inhibitors in the progression to ESRD in the Han:SPRD rat model of ADPKD and in the Pkd2/WS25 mouse model provided by Dr. Somlo, and the fourth Project examines the pathogenesis of hepatic cystic disease. Very little is known about the pathogenesis of liver cysts and thus focused interventions are not possible. Study of the liver will also contribute to our understanding of the factors that cause ESRD in ADPKD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNITY TO HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS Principal Investigator & Institution: Koziel, Margaret J.; Assistant Professor; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-JUN-1997; Project End 31-MAY-2002 Summary: (Adapted from the applicant's abstract) Hepatitis C virus (HCV) is a significant cause of end stage liver disease in the United States, and in most transplant centers is a major indication for transplantation. Following liver transplantation, HCV viremia occurs in nearly 100% of HCV-infected individuals. Approximately half of infected liver transplant recipients will develop clinically significant hepatitis, which has a more rapid progression than HCV hepatitis in the immunocompetent host. A subset of HCV infected transplant recipients may have rapid graft loss and impaired survival. The only currently licensed therapy for HCV infection, interferon-alpha (IFN-a), has a low sustained response rate and increases the risk of chronic rejection in allograft recipients. Given the impact of HCV on transplant recipients, there is a need for a greater understanding of pathogenesis of this infection. Neither the viral nor the host factors which determine outcome are defined. At present, there is no small animal model for HCV infection; so examination of host responses in infected individuals is critical to understanding the possible role of host factors in determining clinical outcome. Cellular immune responses are a crucial component of host defenses in most viral infections and are attenuated in transplant recipients. In particular, cytotoxic T lymphocytes (CTL) are an important element of protective host immunity, but under certain circumstances may induce host tissue damage without clearing viral infection. By comparing the immune response against HCV in immunocompetent hosts and transplant recipients, it may be possible to determine which host factors are important in controlling viremia and which host factors may be responsible for accelerated disease. The goal of this proposal is understanding the role of cytotoxic T lymphocytes in limiting viral replication. The specific aims of this proposal are to: 1) define HCVspecific cellular immune responses in transplant recipients; 2) correlate the spectrum of HCV-specific CTL responses with disease activity in transplant recipients; and 3) characterize the role of cytokines in HCV-specific CTL responses in transplant recipients. These studies will provide the necessary scientific background for the development of vaccines or immunotherapies. 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 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

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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: INCIDENCE OF DRUG-INDUCED LIVER INJURY Principal Investigator & Institution: Chan, Kin-Wei A.; Epidemiology; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02460 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): This is a new application of an epidemiology study among five health maintenance organizations (HMOs) to evaluate the incidence of druginduced liver injury that results in hospitalizations and to assess the association between exposure to specific drugs and liver outcomes not attributable to non-drug cause. The proposed study will be based on collaborative research infrastructure that has already been established at the HMO Research Network, which is funded as a Center for Education and Research on Therapeutics by the Agency for Healthcare Research and Quality. Five HMOs in different regions of the U.S. will participate. They are Fallon Community Health Plan in central Massachusetts, Harvard Pilgrim Health Care in Eastern Massachusetts, Kaiser Permanente Colorado in Denver area, Kaiser Permanente Northwest in Oregon, and Lovelace Clinic in New Mexico, with a combined health plan population of more than two million. Automated hospital discharge data from the HMOs will be used to identify all patients hospitalized with acute liver disease in 2001. Medical records of potential cases will be reviewed and the liver disease attributed to pre-defined causes. Cases not clearly attributed to a non-drug cause will be independently reviewed by two hepatologists to determine their severity and etiology. Cases of probably drug-induced acute liver injury, possibly drug-induced acute injury, idiopathic acute liver disease, and those whose liver events did not have enough information to evaluate causality will be described. Population-based incidence of these acute liver events will be calculated, and they will form the case series in a case-control analysis designed to evaluate the strength of association between drug exposure and these liver events. Two control series (hospital controls and health plan controls) will be identified. This proposed study will serve as a long term valuable data source for the study of drug-induced liver injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INDUCTION OF AP1 AND NFKB BY ETHANOL Principal Investigator & Institution: Brenner, David A.; Professor; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 27-DEC-2002; Project End 30-NOV-2007 Summary: (provided by applicant): Alcoholic liver disease in patients appears to progress from steatosis to alcoholic hepatitis, fibrosis, and finally cirrhosis. Recent studies in rodents have elucidated many of the pathways by which chronic alcoholic intake leads to steatosis and steatohepatitis. However, the progression to hepatic fibrosis and cirrhosis is largely unknown. The overall goal of this project is to define the

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mechanism by which steatohepatitis leads to fibrosis in alcoholic liver disease. We will perform studies using the intragastric lavage model in mice to take advantage of mouse genetics and using primary cultures of hepatic stellate cells. This proposal is based on several underlying hypotheses: 1. Activation of the hepatic stellate cell (HSC) is the key mediator of the progression of alcoholic liver disease from steatohepatitis to fibrosis. 2. Activation of HSCs in culture recapitulates critical components of activation and hepatic fibrosis in vivo. 3. Lipopolysaccharide (LPS) is a critical factor in alcohol-induced fibrosis. 4. Female mice are more susceptible to alcoholic fibrosis than male mice. The specific aims to be addressed in this project are: 1. To determine if NF-rJ3 transcriptional activity is an early marker of HSC activation. 2. To determine if HSC activation and proliferation proceeds type 1 collagen expression in alcoholic liver disease. 3. To determine if fibrogenesis exceeds matrix degradation in activated HSCs in alcoholic liver disease. The experimental design will use three novel transgenic mice that were created in our laboratory. The trangenic lines express reporter genes driven by the collagen alpha1(I) promoter and enhancer, the smooth muscle a actin promoter, or an NF-kappaB responsive element. These mice will be treated chronically with ethanol by the intragastric ethanol feeding model. By combining in vivo and in culture studies using these transgenic mice, our goal is to discover new insights into the molecular pathogenesis of alcoholic liver fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN RESISTANCE IN HCV INFECTION Principal Investigator & Institution: Khalili, Mandana; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 30-JUN-2007 Summary: (provided by applicant): The overall objective of this proposal is to support the principal investigator's development in a career focused on patient-oriented research. This application has both training and scientific components. The training component includes course work towards a Master's in Clinical Research as well as a solid sponsorship structure for career development. The scientific component integrates a multidisciplinary approach in order to assess the impact of hepatitis C (HCV) infection on insulin action in patients with chronic HCV infection. Epidemiological studies have shown that there is an association between HCV and type 2 diabetes mellitus (DM). Type 2 DM in turn, is characterized by insulin resistance. Thus, it is possible that HCV infection promotes tissue resistance to insulin-mediated glucose uptake. Insulin resistance is of importance to liver disease because it can lead to hepatic steatosis (fatty liver). HCV also causes hepatic steatosis, and is associated with accelerated hepatic fibrosis. Therefore, it is of great importance to determine whether insulin resistance represents a cause of steatosis in patients with chronic HCV infection that could worsen the outcome of liver disease. The specific aims of this study are: 1. To characterize the variability in insulin sensitivity and insulin secretion in non-diabetic patients with HCV infection. 2. To determine the correlation between severity of steatosis and the degree of insulin resistance in HCV-infected individuals. 3. To determine the effect of HCV eradication on insulin resistance and insulin secretion. 4. To correlate changes in insulin sensitivity with changes in hepatic steatosis after successful HCV eradication. A prospective cohort design will be used to assess an outpatient HCV population. Insulin resistance, insulin secretory function, lipid and lipoprotein profiles will be evaluated using specific methodologies. Parameters of insulin sensitivity/insulin resistance will be compared to host and viral factors associated with HCV, in an effort to identify specific factors that may be causal. Finally, because we believe that the connection between HCV

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and insulin resistance is causal, we anticipate that successful treatment of HCV will result in improved insulin sensitivity together with a reduction in hepatic steatosis. One of the important advantages of this study is that patients will be evaluated before and after HCV treatment. This will permit a direct evaluation of the causative role of HCV in promoting insulin resistance and hepatic steatosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERFERON-GAMMA TO TREAT CHRONIC HCV INFECTION Principal Investigator & Institution: Muir, Andrew J.; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2001; Project Start 21-SEP-2001; Project End 31-AUG-2003 Summary: (adapted from the application) Current treatment options for chronic hepatitis C infection remain limited and unsatisfactory. Treatment with interferon-alpha and ribavirin leads to a sustained response in the minority of patients, and many patients may not be eligible for treatment due to side effects associated with these medications. Other treatment options are clearly necessary for chronic hepatitis C infection. A major complication of chronic hepatitis C infection is fibrogenesis, ultimately leading to development of cirrhosis. Animal models have demonstrated that interferon-gamma reduces fibrogenesis through its effect on stellate cells. A recent report in patients with idiopathic pulmonary fibrosis found that interferon-gamma was well-tolerated and led to improved pulmonary function, ostensibly due to a reduction in fibrogenesis. Given these data, we postulate not only that interferon-gamma will be effective for treatment of hepatitis C mediated fibrogenesis, but also that it will be safe. We have therefore proposed a phase I study to assess the effectiveness of interferongamma in twenty patients with chronic hepatitis C infection. The patients will include those who have failed previous therapy with interferon-alpha or are not candidates for interferon-alpha therapy. Men or women 18 years of age or older are eligible. Other inclusion criteria are serum positive for hepatitis C virus by PCR; liver biopsy consistent with chronic hepatitis and with a fibrosis score of at least one on the Knodell scale; compensated liver disease; and informed, written consent obtained prior to entry. All patients will receive 200 micrograms of interferon-gamma three times a week for twelve months. Patients will undergo liver biopsy prior to treatment and at the end of treatment. Safety and tolerance will be evaluated at weeks 1, 2, 4, 8 and then every 4 weeks during treatment and at weeks 4 and 12 following the completion of therapy. Serum HCV-RNA will be evaluated prior to initiating therapy and at the end of therapy. The primary endpoint of this study will be the histological response of patients with chronic hepatitis C infection to treatment with interferon-gamma. Secondary endpoints include the biochemical response, inflammatory and regulatory cytokine levels, and quality of life during treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIVER PATHOBIOLOGY AND GENE THERAPY RESEARCH CORE CENTER Principal Investigator & Institution: Shafritz, David A.; Professor; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2001; Project Start 01-JUN-1989; Project End 31-MAY-2004 Summary: An interdisciplinary Liver Research Center was established at the Albert Einstein College of Medicine in 1974 with support from NIDDK. At present, 38 faculty investigators, 1 emeritus investigator, and 2 provisional investigators in 12 departments

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at the medical school, together with 17 Consultants/Collaborators and 4 Supporting Staff Faculty at AECOM, constitute the Liver Research Center. The major objective is to understand fundamental mechanisms of normal liver function, as well as alterations in these functions resulting from diseases caused by metabolic, drug, metal, inheritable and viral agents. Specific areas under study include transport processes, membrane receptor biology, and structural-functional relationships; molecular biology, somatic gene transfer and gene therapy, hepatic fibrosis and mechanisms of hepatic carcinogenesis; hepatic cell transplantation, liver cell metabolism, heavy metal metabolism, mechanisms of liver injury and organelle pathology. By bringing excellent basic scientists into disease-related research, together with hepatologists interested in fundamental mechanisms of hepatic dysfunction, we believe that imaginative approaches to basic cell biology, pathophysiology, diagnosis, treatment and prevention of liver disease will emerge. The Center is the focus of an active research-oriented education program (research seminars, visiting scientists, pathobiology sessions and work-in-progress discussion groups), and has extensive collaborative studies with investigators in other institutions. Core facilities, including Molecular Biology and Genetics, Cell Culture and Genetic Engineering, Imaging and Cell Structure, Special Animals and Administrative, efficiently facilitate interdisciplinary research projects. Facilities include 38 well-equipped laboratories for major investigators, 5 core facilities. Animal Institute, and all institutional support services (library, machine shop, engineering, computer center, etc.) The available clinical facilities include a 1100 bed general hospital (Bronx Municipal Hospital Center), Montefiore Hospital (729 beds) and the Jack D. Weiler Hospital of Albert Einstein College of Medicine (375 beds). A large and diverse patient population provides many individuals with viral, alcoholic and parasite liver disease, as well as varius inheritable disorders of the liver. The Center is directed by the Principal Investigator (Dr. David A. Sharfritz) and Associate Director (Dr. Allan W. Wolkoff), governed by an Executive Committee, advised and reviewed by a Scientific Advisory Committee and functions through several school-wide committees. The Center was officially chartered by the medical school in 1977 as a free standing, extra- and supra-departmental entity. The importance of the Liver Research Center to the College of Medicine has been reconfirmed by extensive renovation of existing facilities, updating of equipment, an endowment fund and recruitment of new faculty with resources provided by the Dean, Dominick P. Purpura, M.D. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIVER REGENERATION IN PEDIATRIC LIVER DISEASE Principal Investigator & Institution: Rudnick, David; Pediatrics; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: Liver regenration occurs after many types of injury, including metabolic, toxic, infectious, and traumatic injuries. It is thought to influence recovery from acute insults, but also to contribute to the development of cirrhosis and neoplasia when deranged during chronic disease. From studies of the response of experimental animals to partial hepatectomy (PH) it is known to be a highly regulated response that proceeds until the original hepatic mass is restored. Recent studies in knockout mice have provided new information about the specific molecules involved in initiation of regeneration. Still, relatively little information is known about downstream signals involved in initiation, or the signals that very precisely terminate regeneration. Furthermore, there is little known about how liver disease influences the signaling pathways that activate and terminate the regenerative response, how they may be

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deranged, or whether novel pathways are involved. The long term goal of this grant application is to determine whether the molecular signaling pathways involved in initiation and termination of liver regeneration after PH are also involved in the regenerative response in pediatric liver disease using genetically altered mouse models. Preliminary results using specific antagonists and knockout mice suggest that prostaglandin metabolism, specifically that involving COX-2, is critical for initiating regeneration after PH and may precede the action of the cytokine IL-6 in the regenerative response. Other preliminary results using a knockout mouse suggest that the prapoptotic protein Bid plays a role in terminating regeneration. Finally, the preliminary results provide evidence for the feasibility of generating a novel transgenic mouse model of alpha1-AT deficiency using liver specific, inducible expression of human alpha1-ATZ to study liver regeneration in pediatric liver disease. Further studies using genetically altered mice proposed in this application are designed to provide a basis for novel pharmacologic and cell transplantation strategies for treatment/prevention of pediatric liver diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MANAGEMENT/HEPATITIS C/HIV-INFECTED AND UNINFECTED IDU'S Principal Investigator & Institution: Sulkowski, Mark S.; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Injection drug use is the predominant mode of HCV transmission in the United States and most injection drug users have HCV infection. In East Baltimore, 80-90% of IDUs are infected with hepatitis C, which can cause progressive hepatic fibrosis (cirrhosis) over 20 or more years, leading, in some patients, to end-stage liver disease, hepatocellular carcinoma and death. Furthermore, coinfection with human immunodeficiency virus (HIV) is present in 30% of HCVinfected IDUs, and is associated with the more rapid progression of HCV-related liver disease. Treatment of hepatitis C with pegylated interferon/ribavirin (PEG/RBV) eradicates HCV infection in approximately one-half of patients. However, persons who use or have used injection drugs are typically excluded from these treatment protocols, as are persons with other comorbidities such as HIV infection and psychiatric disease. This research aims to address the reality that the persons most affected by HCV infection are the least studied and the least treated, a disparity that becomes even more compelling as the success of HCV therapy increases. However, the implementation of HCV care is hindered by the paucity of data regarding which HIV-infected and uninfected IDUs are eligible and need HCV treatment. To address these issue we propose to accomplish the following aims: 1) to determine proportion of HIV-infected and uninfected IDUs who are eligible for HCV therapy with PEG/RBV according to absolute and relative criteria; 2) To determine the medical necessity of HCV treatment among HIV-infected and uninfected persons who are eligible for the PEG/RBV (determined by liver histology and non-invasive markers); and 3) Given the experience of the investigative team and the extensive preliminary research, we anticipate providing data that will have important impact on the medical care HCV-infected IDUs with and without HIV coinfection as well as the development of policies for the management and delivery of hepatitis C care among IDUs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MATERNAL LIVER DISEASE AND FATTY ACID OXIDATION DEFECTS Principal Investigator & Institution: Ibdah, Jamal A.; Internal Medicine; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2001; Project Start 21-SEP-2001; Project End 31-AUG-2006 Summary: Mitochondrial trifunctional protein (TFP) catalyzes the last 3 steps in the beta-oxidation spiral of long chain fatty acids and consists of 4 alpha and 4 beta subunits. Long chain 3- hydroxyacyl Co-A dehydrogenase (LCHAD) resides in the alpha- subunit. Mutations in the alpha-subunit such as the prevalent G1528C mutation cause "isolated" LCHAD deficiency. Other mutations cause complete TFP deficiency (all the 3 enzymes are deficient). Recently, we have documented a fetal-maternal interaction that causes maternal liver disease in heterozygote women who carry fetuses with isolated LCHAD deficiency. This raises several questions. First, what is the mechanism of this fetal-maternal interaction? Second, what is the effect of environmental factors such as high fat diet and fasting on the development of maternal liver disease in the susceptible heterozygotes? Our hypothesis is that heterozygote women develop acute fatty liver of pregnancy (AFLP) or HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome due to accumulation of hepato-toxic fatty acid metabolites generated by either the affected fetus or the susceptible heterozygote under conditions of oxidative stress. To test this hypothesis we propose the following studies. 1) To use conventional and inducible Cre/lox P strategies to generate and characterize two knockout mice models for complete TFP deficiency (null mutation) and isolated LCHAD deficiency (G1528C mutation). Clinical, biochemical, histological, and molecular analyses will be performed. Tissue-specific and developmental stage-specific gene expression will also be characterized in these mice. Differences in the accumulated fatty acid metabolites will be correlated to the genotypes and phenotypes to elucidate the role of fatty acid metabolites in the genotype-phenotype correlations in these disorders. 2) To employ preimplantation genotyping and embryo transfer to independently study the effects of fetal and maternal genotypes on development of maternal liver disease in knockout mice. Pregnant dams will be monitored for evidence of liver disease. Fatty acid metabolites will be measured in fetal and maternal sera, fetal and maternal livers, and placentas, and will be correlated to the fetal/maternal genotypes and maternal phenotypes to identify the fatty acid metabolites that are potentially toxic to the maternal liver. 3) To conduct dietary studies in knockout mice to elucidate the effects of high fat diet and fasting on pregnant heterozygotes while carrying unaffected fetuses. Four different high fat diets will be studied to elucidate the effects of fat content, fatty acid configuration, and protein/carbohydrate contents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISM OF NOD.IDD3/10/17/18/9(LD) LIVER DISEASE Principal Investigator & Institution: Ridgway, William M.; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 30-JUN-2006 Summary: (provided by applicant): The goal of this proposal is to determine mechanisms of a novel autoimmune and biliary tract disease discovered in the NOD.ldd3/10/17/18/9(LD) mouse. The Nonobese diabetic (NOD) mouse is an animal model of spontaneous, genetically complex autoimmune diabetes. NOD mice develop lymphocytic infiltrates into the pancreatic islets (insulitis) progressing to diabetes. The NOD.ldd3/1 0/17/1 8/9(LD) congenic mouse, which has a 95% NOD genetic

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background and 5% "protective" B6/B10 genetic background, was bred from the NOD.ldd3/10/17/18 and NOD.ldd9 congenic mice, and is completely protected from autoimmune diabetes. However, we have discovered that it develops an entirely separate disease characterized by lymphocytic infiltrates into the portal tract, antipyruvate dehydrogenase complex (PDC) and other autoantibodies, and progressive polycystic liver leading to fatal biliary obstruction. In this grant, we will dissect the immunological, cellular, and genetic mechanisms of this novel disease. The central hypothesis of this grant is that the biliary disease in NOD.ldd3/10/17/18/9(LD) mice is an autoimmune disease arising via an interaction between the NOD background genes and B6/B10 loci, which are "protective" for autoimmune diabetes. This model provides a unique opportunity to dissect genetic and immunologic mechanisms resulting in 2 different organ specific autoimmune diseases in a genetically related pedigree. In specific aim one, we will define cellular and immunogenetic mechanisms of the liver disease in NOD.ldd3/10/17/18/9(LD) congenic mice by using transfer studies and related NOD congenic strains. In specific aim two, we will dissect cellular and immunogenetic mechanisms of immune subphenotypes in NOD.ldd3/10/17/18/9(LD) and related NOD congenic mice, including autoantibody production, T and B cell responses to PDC (Pyruvate dehydrogenase, specifically the E2 component), and mechanisms of lymphocytic liver infiltration in NOD.ldd3/10/17/18/9(LD) and related congenic mice. These studies are important for understanding the pathogenesis of autoimmune biliary diseases, autoimmune diabetes, and the genetics of autoimmunity in families. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF CHRONIC HEPATITIS B INFECTION Principal Investigator & Institution: Milich, David R.; President; Vaccine Research Institute of San Diego San Diego, Ca 92109 Timing: Fiscal Year 2001; Project Start 01-MAY-1984; Project End 31-MAR-2006 Summary: (Adapted from applicant's abstract): The hepatitis B virus (HBV) is a major cause of infectious liver disease throughout the world. There are 1.2 million carriers of HBV in the U.S. and approximately 300 million worldwide. Neonatal HBV infection is rarely cleared and as many as 90 percent of perinatally infected children become chronically infected. Therefore, in addition to worldwide vaccine programs to prevent new infections, methods for treating HBV chronic carriers will be necessary to eradicate this disease. This application is focused on understanding the mechanisms responsible for inducing and maintaining chronic HBV infection, and specifically the role of HBV nucleoprotein antigens, the nucleocapsid (HBcAg) and the secreted non-particulate HBeAg. The specific aims are addressed through the use of HBc/HBeAg-expressing and HBV replicating transgenic (Tg) mice, the eight recently developed HBc/HBeAg-specific T cell receptor (TCR)-Tg lineages and various combinations of "double and triple-Tg" hybrids. The specific aims are: (1) production and characterization of TCR-Tg lineages; (2) development of models to explore the relationship between chronicity and perinatal infection; (3) examine the potential of the secreted HBeAg to elicit and maintain immune tolerance and promote chronicity; (4) explore mechanisms that allow HBc/HBeAgspecific CD4+ T cells to escape tolerance induction and co-exist with viral antigens; (5) examine mechanisms by which residual (i.e., non-tolerized) HBc/HBeAg-specific CD4+ T cells cause liver injury; and (6) use the models of liver injury to screen HBc/HbeAgspecific immunotherapies potentially useful in the treatment of chronic infection. It is anticipated that the results of these studies will have diagnostic, therapeutic, and

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vaccine applications and will provide a better understanding of basic immune mechanisms responsible for viral persistence and clearance in chronic HBV infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF LIVER DISEASE IN A MOUSE MODEL OF AIH Principal Investigator & Institution: Gorham, James D.; Pathology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2003; Project Start 01-DEC-2002; Project End 30-NOV-2006 Summary: (provided by applicant): Autoimmune hepatitis (AIH) results from a dysfunction in normal immune homeostasis in the liver. Little is understood, however, about either the normal mechanisms that regulate the hepatic immune system, or about the pathogenesis of AIH. A new mouse model recapitulates the important features of AIH, and is characterized by (1) extensive liver inflammation (2) significant hepatocyte damage (3) spontaneous disease development (4) the strong influence of genetic background and (5) the involvement of T helper type 1 (Th1) cells. Additional features render the model particularly amenable to experimental manipulation, such as predictability of kinetics, genetic homogeneity, and intensity of disease. Balb/c mice with a knockout in the gene encoding the immunoregulatory cytokine transforming growth factor-beta1(TGF-b1) predictably and uniformly develop a lethal Th1-mediated fulminant hepatitis, that is under strict genetic control. Experiments are proposed using this mouse model to understand the mechanisms that regulate the initiation, progression, and effector phases of autoimmune liver disease in BALB/c-TGF-b1 (-/)mice. The first aim of this project is to determine whether cell compartment-specific expression of TGF-b1 dictates the development of liver disease. The second aim is to determine whether the development of immune mediated hepatocellular damage in BALB/c-TGF-b1 (-/-) mice is antigen-specific or antigen nonspecific. The final aim is to analyze the genetics, mechanisms, and specificity of hepatic BALB/c-TGF-b1(-/-) effector cytotoxic T lymphocytes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF LIVER INJURY BY HEPATITIS C AND ALCOHOL Principal Investigator & Institution: Weinman, Steven A.; Professor of Internal Medicine and Physi; Physiology and Biophysics; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2001; Project Start 27-SEP-2000; Project End 31-AUG-2005 Summary: Hepatitis C is the most common form of chronic liver disease in the U.S. with an estimated 4-5 million people infected. The disease is characterized by hepatic inflammation and progressive fibrosis leading to eventual development of cirrhosis and/or hepatocellular carcinoma in as many as 20-30% of individuals. Alcohol consumption greatly increases the severity and rapidity of disease progression but the mechanism of alcohol/HCV synergy is unknown. Development of new therapeutic approaches has been hampered by the limited experimental models systems available and a lack of understanding of the pathogenic mechanisms involved. The long-term objective of this study is to characterize a transgenic mouse model which expresses HCV proteins in the liver and to use this model to determine the role of oxidative stress and mitochondrial dysfunction in producing the increased liver toxicity of alcohol in chronic hepatitis C. The specific aims are 1. To examine the mechanisms and consequences of HCV protein-induced stimulation of ROS production. These experiments will use cell culture expression systems to determine the effects of HCV core protein on basal and

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TNF-induced ROS production and examine the source of abnormal ROS. The consequences of core-induced ROS changes to cell survival and its modification by antioxidants and NF-XB activation will be determined. Changes in gene expression induced by HCV protein expression in cell lines will be measured using RNase protection assays. 2. To determine the effects of HCV protein expression on ethanolinduced liver injury. Chronic alcohol feeding of normal and a-ansgenic mice will be performed and liver histology and oxidant injury compared. Alcohol induced changes in liver gene expression will be measured using DNA microarrays. 3. To evaluate antioxidant based approaches to modify HCV/alcohol-induced cell and liver injury. Ethanol-fed transgenic animals and cell culture systems will be used to determine the potential to modify HCV/alcohol -induced liver injury with antioxidants and anti-TNF antibodies. Successful completion of these studies will result in the development of a new model for the study of HCV-induced liver injury, new insight into the role of oxidative stress in HCV/alcohol induced liver injury, and a preliminary evaluation of potential therapeutic modalities for this disease. 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

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portal hypertensive and biliary cirrhotic animals. Our long-term goal is to use an 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: MESENCHYMAL STEM CELL THERAPY: A1 ANTITRYPSIN DEFICIENCY Principal Investigator & Institution: Verfaillie, Catherine M.; Professor; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Alpha-l-antitrypsin (alpha1AT) is a plasma protein, produced in the liver that inhibits elastase, alpha1AT-deficiency is an autosomal recessive disorder that affects approximately 105 individuals in the US. Liver injury in alpha1AT-deficiency is caused by the hepatotoxic effects of mutant alpha1AT retained within the endoplasmic reticulum (ER) of hepatocytes, and emphysema by uninhibited proteolytic damage to elastic tissue in the lung parenchyma. Orthoptic liver transplantation is the only curative therapy for alpha1AT-mediated liver disease. If a reliable source of hepatocytes were available, they could conceivably be used to replace 20-25% of the host liver, elevating plasma levels of alpha1AT to greater than 10 muM, and preventing pulmonary toxicity due to alpha1AT-deficiency. We have identified multipotent adult progenitor cells, or MAPC, that can be cultured from human, mouse and rat bone marrow (BM). Single MAPC differentiate into mesodermal, neuroectoderm-like cells and functioning hepatocyte-like cells in vitro. MAPC do not form tumors when infused IV, IM or SQ, but differentiate in response to local cues into hematopoietic cells and epithelium of lung, intestine and liver. For MAPC derived hepatocytes to be suitable for therapy of alpha1AT, or other liver disorders, better characterization of the in vitro differentiation process will be needed. In addition, we will need to demonstrate that MAPC-derived cells function like hepatocytes in vivo. We propose three aims to determine whether MAPC-derived hepatocytes may be a source of cells to treat alpha1AT-deficiency mediated pulmonary and/or liver disease. Studies in SA1 will further demonstrate that hepatocyte like cells can be generated from bone marrow derived MAPC, and develop methods to select progenitors/precursors for hepatocytes generated during culture. Selection of such progenitors will serve two purposes: characterization of differentiation from pluripotent adult stem cells to hepatocytes, and generation of a potential source of cells for effective transplantation in liver disease. Studies described in SA2 that will assess all functions of mature hepatocytes in spheroid cultures should help confirm that hepatocytes generated from BM MAPC are similar to hepatocytes derived from primary liver. Studies in SA3 will establish whether MAPC themselves, MAPC-derived hepatocyte progenitors or mature hepatocytes can restore liver function in vivo, in the setting of hepatocyte cell death and in the setting of abnormal liver function but without liver cell death. This should lay the groundwork for future studies testing whether MAPC or MAPC-derived hepatocyte progenitors/hepatocytes can serve as a suitable source of cells for therapy of alpha1AT, a single gene defect associated with lung damage and/or liver failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MODELS FOR OPTIMAL LIVER TRANSPLANT OUTCOMES Principal Investigator & Institution: Dickson, E R.; Mary Lowell Leary Professor of Medicine; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905

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Timing: Fiscal Year 2002; Project Start 15-JAN-1986; Project End 30-NOV-2006 Summary: Orthotopic liver transplantation (OLT) is now a well- established means of restoring health in patients with end stage liver disease. Our long-term objective is to provide evidence- based information to help optimize the outcome of OLT, which is relevant not only at the individual physician and patient level, but also at the health policy level. Building on our achievements from the previous program period and data collaboration from a network of academic transplant centers, we propose to study the three most important issues that face liver transplantation in the United States today. In specific aim 1, we will prospectively validate the Model for End-stage Liver Disease (MELD) in current OLT candidates. The MELD scale, a liver disease severity index developed by this program, has recently been adopted by the United Network for Organ Sharing (UNOS) as the national liver allocation system for OLT. Our central hypothesis is that the addition of further variables to the model will not materially improve the model, except in patients with hepatocellular carcinoma, in whom the risk of tumor progression needs to be considered in addition to the severity of underlying liver disease. In specific aim 2, we will identify determinants of the outcome of recurrent hepatitis C following OLT. OLT recipients with hepatitis C, the most common indication for the procedure today, have shorter survival and poorer quality of life. Our hypothesis is that pretransplant alcohol consumption and post-transplant obesity affect the rate of progression of recurrent hepatitis C and thus, the outcome. In specific aim 3, we will study the cardiovascular morbidity in long-term survivors following OLT. Based on the number of patients and length of follow-up available in our database, we will identify traditional (e.g., diabetes, hypertension, and hyperlipidemia) and transplant-specific (e.g., cytomegalovirus infection and liver disease diagnosis) risk factors that are associated with cardiovascular complications. The results of these studies will provide relevant information not only to clinicians in practice, but also transplantation policy makers. The feasibility of the proposed projects is supported by the extensive experience and track record of this program in creating and maintaining a large, multicenter, liver transplant database and strong statistical expertise. 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-

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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 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 HCV INFECTION IN DRUG USERS Principal Investigator & Institution: Klein, Robert S.; Professor; Montefiore Medical Center (Bronx, Ny) Bronx, Ny 104672490 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality. Injection drug users have the highest prevalence of HCV infection among all populations in the U.S. at risk. We will study prospectively the natural history of HCV infection among all populations in the U.S. at risk. We will study prospectively the natural history of HCV infection in a cohort of drug users with or at risk for HIV infection. Subjects will be recruited from among participants already enrolled in a large longitudinal study of the natural history of HIV infection in drug users. We will, therefore, be able to take advantage of the large and complex sets of data being collected in that study, and we will be able to link new data that will be collecting on the natural history of HCV infection with those data. Participants will have detailed standardized interviews on demographics, medical history, sexual and drug use behaviors, HIV and immunological testing, and testing for HCV infection, including quantitative HCV RNA levels, including quantitative HCV RNA levels, HCV genotyping, anti-HCV antibodies and, in a subset of participants, HCV sequencing. Persons found to have HCV infection will be referred to the study hepatologist to be evaluated for liver disease and they will be offered standard medical therapy for their HCV infection. Our aims are to determine 1) the effects of HIV infection and its associated immunodeficiency, HCV genotype, and drug use behaviors on HCV viral load and progression of liver disease, 2) the effects of HIV infection and immunodeficiency on response to therapy for HCV infection, 3) the effects of highly active anti-retroviral therapy and control of HIV viral load on the natural history of HCV infection, and 4) whether genetic diversity of HCV is facilitated by immunodeficiency. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NATURAL HISTORY OF HEPATITIS C INFECTION IN HIV DISEASE Principal Investigator & Institution: Craven, Donald E.; Professor; Boston Medical Center Gambro Bldg, 2Nd Fl, 660 Harrison Ave, Ste a Boston, Ma 02118

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Timing: Fiscal Year 2001; 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 •

Project Title: NOVEL APPLICATION

ALT

ISOENZYMES

AND

THEIR

DIAGNOSITC

Principal Investigator & Institution: Gong, Da-Wei; Assistant Professor; Medicine; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): For nearly fifty years, alanine transaminase (ALT) has been a widely used clinical diagnostic marker of acute and chronic hepatic injury. Although elevated serum ALT is a common feature of liver damage, it is also observed in other diseases such as obesity, muscle disease, and in apparently healthy people. The cellular mechanisms leading to ALT changes in the above situations are poorly understood, which often renders the interpretation of ALT data problematic. The work proposed in this application is based upon our recent discovery of a novel homologue of human ALT, which we have designated ALT2. ALT2 has significant homology to ALT1 (the only previously known ALT) with 69% identity and 78% similarity at the peptide level. Importantly, the two isoenzymes are encoded by distinct genes and differ significantly in tissue distribution; ALT2 is highly expressed in muscle, kidney and adipose tissue, whereas ALT1 is mainly expressed in liver, kidney and heart. Since

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current assays to measure serum ALT levels are enzymatic, they do not differentiate between ALT1 and ALT2. Measurement of an isoenzyme in serum may have more diagnostic value than total enzyme activity, as exemplified by creatine kinase-MB for cardiac infarction and bone-specific alkaline phosphatase for bone disease. We hypothesize that ALT2 circulates in serum and contributes variably (depending on disease etiology) to total ALT activity measured in currently available clinical assays. Furthermore, we hypothesize that ALT2 will be particularly elevated in patients with fatty liver and/or obesity, since ALT2, but not ALT1, is abundantly expressed in adipose tissue. To examine these hypotheses, we propose to develop an ALT isoenzyme-specific immunoassay. This assay will be used to measure serum levels of ALT isoenzymes in a host of disease states including liver disease and obesity (stable and during weight loss). We predict that serum ALT2 will be higher in patients with fatty liver or obesity and may be a clinically useful marker for this and other disease states. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ONTOGENY OF HEPATIC ION TRANSPORT Principal Investigator & Institution: Suchy, Frederick J.; Professor of Pediatrics; Pediatrics; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2001; Project Start 01-SEP-1985; Project End 31-MAR-2003 Summary: This is a renewal application to further define the ontogeny of hepatic ion transport as well as define the mechanisms by which transporters are modified under conditions of cholestasis. The overall objective of this competing renewal application is further defined by the mechanisms underlying the expression of basolateral and canalicular transporters for bile acids and other organic anions during development and cholestatic liver disease. Since transcriptional activation of the liver Na+ /bile acid cotransporter gene (Ntcp) is largely responsible for the abrupt expression of transport activity in the perinatal period, the investigators propose that a change in chromating structure, reflected in an increase in DNASE I hypersensitivity and a decrease in gene methylation precedes the onset of transcription during development. Transgenic mice expressing various portions of the 5' untranslated region linked to the luciferase reporter gene will be used to define sequences that direct tissue- and developmental stagespecific expression of Ntcp. Transgenic animals will be used to show that the rapid postnatal increase in Ntcp transcription could in part be mediated by prolactin. To demonstrate the importance of the Na+/bile acid cotransporter to hepatobiliary function, the Ntcp gene will be rendered nonfunctional in mice by targeted disruption. The phenotypes of the mice with null mutations will be defined including whether liver disease (cholestasis) is induced and how the mutation alters hepatobiliary function and enterohepatic cycling of bile acids. The signaling mediating the targeting of the liver and ileal Na+/bile acid cotransporters to the plasma membrane will be determined through transfection and analysis of native transporters, truncated mutants lacking cytoplasmic tails, and chimeric transporters comprised of portions of the liver and ileal transporters. Finally, the development of the canalicular multi specific organic anion transporter (cMOAT/Mrp1) will be defined including a correlation of transport activity in canalicular membrane vesicles with levels of Mrp2 mRNA and protein. The investigators will determine the mechanisms underlying the effects of bile acids and the inflammatory cytokines TNF-alpha and IL-beta on expression of Ntcp and Mrp2 through transfection of chimeric promoter/reporter gene constructs into primary hepatocytes. DNA foot printing and gel mobility shift assays will determine the importance of known or novel cis-acting elements and trans-activating factors in

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regulating gene expression. These studies should provide insights into the biology and pathobiology of hepatic anion transporters and help explain the susceptibility of the infant to develop cholestatic liver disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OXIDANT HEPATIC INJURY IN CHOLESTASIS Principal Investigator & Institution: Sokol, Ronald J.; Professor; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 10-MAY-1987; Project End 31-MAR-2006 Summary: (Adapted from the Applicant's Abstract): The pathogenesis of liver injury in human cholestatic diseases is poorly understood. Current therapies for these disorders are inadequate, thus progression to end-stage liver disease is common. Developing novel treatment approaches will require an expanded understanding of the fundamental mechanisms causing hepatocyte necrosis and apoptosis in this condition. The overall objective of this proposal is to test the hypothesis that oxidative stress and hepatic mitochondrial dysfunction are key elements involved in the pathogenesis of liver injury in cholestasis. In this grant renewal, we will expand our previous investigations to now examine mechanisms involved in hepatocellular apoptosis and necrosis induced by toxic bile acids that accumulate in the liver during cholestasis. We will test the following interrelated hypotheses, using freshly isolated rat and human hepatocytes, hepatic mitochondria, an intravenous bile acid toxicity model developed in our laboratory, the bile duct-ligated model of cholestasis and transgenic mice. To determine if generation of reactive oxygen species (ROS) are a proximate event in bile acid-induced hepatocyte necrosis and apoptosis, the time-sequence of related intracellular events will be carefully assessed during these two forms of cell death in isolated hepatocytes and, by using various inhibitors of critical processes involved, the role of ROS generation will be evaluated. Digitized confocal fluorescent microscopy will also be used to better define the role of mitochondria in these processes. To determine the role played by the hepatic mitochondrion in bile acid-induced liver injury, we will investigate the role of the mitochondrial permeability transition, cytochrome c release, ROS generation, activation of caspases, translocation of Bcl-2 family proteins, ATP concentrations and mitochondrial iron in bile acid-induced necrosis and apoptosis. To determine the role played by nitric oxide (NO) in this injury, generation of NO and its metabolites and their effect on cellular steps of apoptosis and necrosis will be studied in isolated hepatocytes and mitochondria undergoing bile acid-induced injury. To explore oxidative mechanisms to explain the increased susceptibility of the neonatal liver to cholestatic injury, we will investigate developmental differences of mitochondrial processes involved in necrosis and apoptosis in hepatic mitochondria isolated from the developing rat. The results from these investigations will improve our fundamental understanding of the mechanisms of hepatocellular necrosis and apoptosis in cholestasis, and may form the basis for the development and application of new therapies for these disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATHOGENESIS OF LIVER DISEASE IN HEPATITIS Principal Investigator & Institution: Chisari, Francis V.; Professor & Head; Scripps Research Institute Tpc7 La Jolla, Ca 92037 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

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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 •

Project Title: PILOT--ALCOHOL AND HEPATITIS C HOST RESPONSE AND DISEASE ACTIVITY Principal Investigator & Institution: Fried, Michael W.; Associate Professor of Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 27-DEC-2002; Project End 30-NOV-2007 Summary: The clinical spectrum of chronic hepatitis C is variable and the factors responsible for these divergent outcomes remain unknown. Alcohol consumption has been identified as a co-factor in accelerating the progression of liver disease in patients with chronic hepatitis C. Studies of this issue are difficult because there is no animal model of hepatitis C-induced fibrosis. We propose to prospectively study a cohort of patients infected with hepatitis C who also consume alcohol to define the effects of alcohol consumption on hepatic fibrogenesis, oxidant stress, and expression of mediators of inflammation and fibrogenesis in liver tissue and peripheral blood mononuclear cells. The hypothesis to be tested is that alcohol consumption will increase markers of hepatic inflammation, fibrogenesis and oxidant stress, and ultimately reflect an increase in the progression of liver disease. Subjects with concurrent hepatitis C infection on ongoing alcohol use/abuse will undergo a detailed clinical evaluation, including liver biopsy and blood sampling. A control group of non-drinking subjects with chronic hepatitis C will be matched for gender, estimated duration of HCV infection, and mode of HCV acquisition. We will study the effects of alcohol use on hepatic fibrogenesis using standard histologic techniques and novel immunohistochemical markers of stellate cell activation (alpha-smooth muscle actin, collagen II propeptide) in liver biopsy specimens from alcohol consuming and nondrinking patients with chronic hepatitis C. We will also evaluate lipid peroxidation production products using immunohistochemical techniques with antibodies to 4nonalal and malondealdehyde. In addition, using specimens obtained from these two cohorts, we will identify mRNAs in liver tissue and peripheral blood mononuclear cells encoding host mediators of inflammation and fibrogenesis that are up-regulated in

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patients with hepatitis C who consume alcohol. This information will provide key information for developing additional hypotheses to be tested in a larger clinical trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PORPHYRIN BIOSYNTHESIS IN NORMAL AND DISEASE STATES Principal Investigator & Institution: Kushner, James P.; Professor of Medicine; Internal Medicine; University of Utah 200 S University St Salt Lake City, Ut 84112 Timing: Fiscal Year 2002; Project Start 01-SEP-1977; Project End 30-JUN-2007 Summary: (provided by applicant): Porphyria cutanea tarda (PCT), the most common form of porphyria in humans, is due to sub-normal activity of uroporphyrinogen decarboxylase (URO-D), a cytosolic enzyme in the heme biosynthetic pathway. Our preliminary data indicate that diminished activity of URO-D in the livers of rodents with experimentally induced porphyria and in humans with PCT is due to the generation of a low-molecular-weight inhibitor. Generation of the inhibitor can be initiated by both environmental and genetic factors, and involves an iron-catalyzed reaction. We hypothesize that the inhibitor is generated from oxidized hydroxymethyl bilane, an early intermediate in the heme biosynthetic pathway. We propose to chemically synthesize this inhibitor and to establish that an identical compound is generated in vivo in rats and mice with experimental porphyria. We have identified the presence of a URO-D inhibitor in liver biopsy samples from subjects with PCT. We plan to confirm this finding in additional subjects and to establish that the inhibitor occurs only in patients with PCT by attempting to detect inhibitor in liver biopsy samples from patients with hepatitis C, alcoholic liver disease, and hemochromatosis. Murine models of PCT will be developed in carefully characterized genetic backgrounds by intercrossing a strain we have generated by disrupting one allele of the URO-D gene (URO-D+/- mice). These animals have been intercrossed with homozygous hemochromatosis knockout animals (HFE-/-) and the resultant animals develop PCT without the need for any exogenous agents. We plan introduce null alleles of cytochrome P4501A2 (CYP1A2) and null alleles of peroxisome proliferator activated receptor (PPARa) onto the URO-D+/-:HFE-/- background to define the genetic components required for the development of experimental PCT. Our findings in PCT could serve as a paradigm for other dominantly transmitted porphyrias where clinical expression cannot be simply explained by half-normal activity of non-rate-limiting heme biosynthetic enzymes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PREDICTING LIVER DISEASE IN HIV-HCV-INFECTED WOMEN Principal Investigator & Institution: Taylor, Jill; Wadsworth Center Empire State Plaza Albany, Ny 12237 Timing: Fiscal Year 2002; Project Start 27-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): The purpose of this retrospective pilot study is to identify adaptive mutations that are selected in nonstructural coding regions of the hepatitis C virus (HCV) genome. The dominant virus population that was present in women co-infected with Human Immunodeficiency virus (HIV) and HCV, when clinical signs of progressive liver disease were apparent, will be analyzed. The long-term goal is to understand the viral genomic characteristics of HCV that result in enhanced viral replication, and lead, in conjunction with host immunity and environmental factors, to liver damage. The central hypothesis is that efficient replication of specific HCV variants with enhanced growth properties contributes to liver damage. It is postulated that the

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enhancement of viral replication is due to the selection of adaptive mutations in the nonstructural coding regions of the genome. This viral population can then become dominant over time in a hepatic environment in which control of viral replication has been weakened by HIV-induced immunosuppression, alcohol and substance abuse. To test this hypothesis we will sequence the NS3/NS4A and NS5B nonstructural coding regions of the HCV genome in virus from HIV-HCV co-infected women with and without clinical signs of progressive liver disease. The rationale for the proposed research is that once specific mutations are identified as markers of advanced disease, a prognostic assay can be developed to identify patients at higher risk of progression. The study population is 100 HlV-HCV co-infected women, with the additional risk factors of alcohol and substance abuse, enrolled in the Women's Interagency HIV Study (WIHS) at SUNY Downstate in Brooklyn, NY. The experienced investigators collaborating on this proposal represent the cross-disciplinary fields of molecular virology, HIV-HCV primary care and clinical research, and biostatistics. The WIHS cohort at SUNY Downstate has been selected, not only because of the availability of robust demographic and clinical information and stored plasma samples collected since 1994, but also because of the potential for expansion to include the entire WIHS cohort of >2,000 women. HIV-HCV co-infected individuals have been specifically chosen because of the mounting evidence that HIV infection exacerbates HCV disease. Liver failure has become a leading cause of death in the HIV-HCV co-infected population, emphasizing the urgent public health need for earlier treatment intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RACE & VIRAL RESISTANCE IN CHRONIC HEPATITIS C (VIRAHEP* Principal Investigator & Institution: Brown, Robert S.; Associate Professor; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 30-JUN-2006 Summary: (provided by applicant): The pathogenesis of hepatitis C (HCV) associated liver injury is poorly understood. Studies of HCV pathogenesis have been impeded by the lack of an animal model, the inability to maintain HCV in cell culture systems, and the slow progression of disease, which hinders natural history studies. However, though host and viral factors likely play a role in liver injury, neither has been rigorously analyzed. Early studies suggest that viral clearance with acute infection as well as with treatment is markedly decreased iin patients of African American heritage. The reasons for this poor response are not understood, but possibly relate to differences in demographics (e.g socioeconomic status), comorbid conditions (e.g., obesity), genotype distribution or virulence, viral kinetics, immune response, and compliance with therapy. Previous studies have been limited by small sample size and referral bias. Over the last 2 years, The Columbia-Cornell Liver Clinical Trials Network has established an extended network of care that has performed clinical trials including a large number of African Americans. This Network includes the Columbia Presbyterian and Harlem Hospital Centers both within the Harlem section of Manhattan and The New York-Cornell Center in central Manhattan. Within this ethnically diverse population, we will answer several questions. The primary hypothesis is that treatment response to PEGylated interferon and ribavirin is decreased in African Americans. However, we postulate that most of this decrease can be explained by differences in baseline characteristics and non-biologic parameters, including body mass index, comorbid medical conditions, socioeconomic status and the ability to complete therapy. Additionally we will search for clinical predictors of response to therapy including

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differences in immunogenetics and early viral kinetics. The secondary hypothesis is that the progression of liver disease in African Americans is comparable to that in a Caucasian American population after controlling for potential confounders including the variables mentioned above and alcohol consumption. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF HBV REPLICATION BY THE IMMUNE SYSTEM Principal Investigator & Institution: Guidotti, Luca G.; Associate Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 01-JAN-1997; Project End 31-DEC-2006 Summary: (provided by applicant): The hepatitis B virus (HBV) causes acute and chronic necroinflammatory liver disease and hepatocellular carcinoma. Over 350 million people worldwide are persistently infected by HBV, representing an enormous reservoir for horizontal and vertical spread of this virus to others. The long term objective of this application is to elucidate the molecular basis for liver disease, viral clearance and viral persistence in the pathogenesis of HBV infection with the ultimate hope that this knowledge will lead to the development of new therapeutic strategies to terminate persistent infection and its attendant costs and complications. Using transgenic mice that replicate HBV at high levels in the liver as recipients of HBVspecific CTLs, we have shown that the antiviral potential of the CTLs is primarily mediated by noricytolytic mechanisms that involve the intrahepatic production of type I inflammatory cytokines by these cells. This occurs after the CTLs specifically recognize viral antigens on the surface of the hepatocyte. Following antigen recognition, the CTLs also trigger the death of a small number of hepatocytes and this process leads to the recruitment of many host-derived lymphomononuclear and polymorphonuclear cells into the liver that contribute to the formation of necroinflaminatory foci histologically identical to classical viral hepatitis in man. The recruited inflammatory cells are likely to be responsible for antigen-nonspecific amplification mechanisms that greatly enhance the liver damage initiated by the CTLs. The recruitment of these cells is probably mediated by secretion of chemokines by either the antigen-activated CTLs or other cellular components of the liver. In support of this, we have performed preliminary experiments showing that a large variety of chemokines are rapidly and strongly induced in the liver of HBV transgenic mice after CTL transfer and their expression is regulated by type 1 inflammatory cytokines. Chemokines are likely to play a role in viral pathogenesis by regulating the trafficking of inflammatory cells to tissue sites of infection and, perhaps, by directly inhibiting viral replication. Whether this is the case during HBV infection is not known. To explore these hypotheses, we will use in vivo (HBV-replicating transgenic mice) and in vitro (HBV-replicating hepatocytes) systems to determine the function of chemokines and chemokine receptors on the recruitment, antiviral and pathogenic effector functions of CTLs and other inflammatory cells. We will also define the role that type 1 inflammatory cytokines may play in these processes. The results of these experiments will provide insight into the basic immunological processes that may determine liver disease, viral clearance and viral persistence in the pathogenesis of HBV infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RESEARCH NETWORK FOR DRUG-INDUCED LIVER DISEASE Principal Investigator & Institution: Bonkovsky, Herbert L.; Professor of Medicine; Clinical Research Center; University of Connecticut Sch of Med/Dnt Bb20, Mc 2806 Farmington, Ct 060302806

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Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2006 Summary: (provided by applicant): Drugs and other chemicals have numerous salutary effects on humans, but they may also cause toxicity. Because of the central role played by the liver in metabolism, the liver is the most frequent and important site of drug- or chemical-induced tissue injury. As more drugs have been developed and used and more so-called complementary medicines (CAM) and herbal remedies are used, drug-induced liver disease (DILD) has become a problem of major and growing importance, and there is a growing need for better systems for early detection, characterization, and reporting of instances of DILD. Such systems should be applied both to drugs still under development and to drugs, CAM, and herbal remedies already on the market. The longterm aim of this research program is to develop a regional consortium and network in the Northeastern U.S.A. for the detection and clinico-pathological and molecular (genomic, proteomic) characterization of DILD. A key aspect of this work will be to develop a clinical, laboratory, and histopathological data base of "phenotypic" information on subjects with known or suspected DILD, and also to establish DNA, RNA, serum, and tissue banks on these same subjects. This will facilitate the development of "genotypic" (DNA), gene expression (RNA), and protein expression (proteomic) profiling of the same subjects, eventually permitting the detailed phenotypic-genotypic-proteomic correlations that will be possible as candidate genes and gene products involved in DILD are identified and characterized. Indeed, the regional and national data bases that will be established as a result of this program will aid us in discovering and identifying such genes and gene products, thereby bringing to fruition the enormous potential implicit in the successful sequencing of the human genome. The specific aims of this proposal are to: (1.) establish one of the national interactive Clinical Centers of the Hepatotoxicity Clinical Research Network, based at the University of Connecticut Health Center (UCHC). Our Center will serve as the coordinating center for a consortium of academic and practicing hepatologists and groups in the Northeastern U.S.A. We will take advantage of the strong research infrastructure of the UCHC Office of Clinical Research and the NIH-supported GCRC at UCHC; (2.) work with other members of the Network nationwide to develop consistent, standardized approaches and instruments to identify and fully characterize bona fide cases of drug-, CAM-, and toxin-induced liver injury, identified retrospectively. We will also obtain data from suitable control subjects thereby allowing for case-control studies, which will facilitate studies of the epidemiology and clinical spectrum of such hepatotoxicity; (3.) do prospective studies of selected, commonly used hepatotoxic drugs (HAART for HIV, INH for tuberculosis, methotrexate (MTX) for psoriasis); and (4.) obtain biological samples (blood, liver, plasma, serum) for study of the pathogenesis of DILD, using biochemical, serological, genetic, and proteomic techniques. The clinicopathological database and the tissue and DNA repositories will permit us to create and test numerous hypotheses relating to the pathogenesis and pharmacogenomics of DILD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RETROVIRUS ISOLATION FROM PRIMARY BILIARY CIRRHOSIS Principal Investigator & Institution: Mason, Andrew; University of Alberta Edmonton T6g 2E1, Canada Edmonton, Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Approximately 1 in 2,000 women above the age of 50 develop primary biliary cirrhosis (PBC). There is no cure for this progressive hepatobiliary disease, which is one of the major indications for liver transplantation in the US. About 95% of patients develop anti-mitochondrial antibodies (AMA) reactive to

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pyruvate dehydrogenase complex E2 component (PDC-E2), which is aberrantly expressed on cell surface of biliary epithelial cells of patients with PBC. This abnormal distribution of PDC-E2 is only observed in patients with PBC and considered a phenotypic manifestation of the disease. We have cloned an exogenous retrovirus from a PBC biliary epithelium cDNA library with homology to betaretroviruses. Most PBC patients have specific antibody reactivity to the virus by Western blot and evidence for infection in lymph nodes using RT-PCR and immunohistochemistry. Also, we have found that affinity purified AMA from PBC patient's serum react with the virus. To study the viral infection in vitro, we have developed a model for PBC by co-culturing normal biliary epithelium cells with perihilar lymph nodes from patients with chronic liver disease. The biliary epithelium cells incubated with PBC lymph node extracts express increased levels of PDC-E2 autoantigen after 5 days, which is a finding specific for the PBC co-cultures. The supernatants from the PBC co-cultures also induce PDC-E2 expression in fresh biliary epithelial cells, which can be abrogated by gamma irradiation. We have also demonstrated that the development of the PBC phenotype corresponds with betaretrovirus infection in the biliary epithelium cells and supernatants. In a pilot study of anti-retroviral therapy with Combivir, 40% of patients completely normalized their liver function tests and there was a significant reversal of ductopenia on liver biopsy. In order to test the hypothesis that a retrovirus is associated with PBC, we plan to isolate the retrovirus and use our in vitro model of PBC to demonstrate that the specific isolate induces the phenotypic manifestation of disease in normal biliary epithelial cells. We will then assess whether patients with PBC have serologic evidence for infection. We anticipate that our studies will help to further our knowledge of how viral infections can promote autoimmune disorders and provide alternative strategies to help manage PBC patients with anti-viral therapy or vaccination for susceptible individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SCRATCH-INDUCING CAPACITY OF CHOLESTATIC EXTRACTS Principal Investigator & Institution: Bergasa, Nora V.; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 21-SEP-2001; Project End 31-JUL-2003 Summary: (provided by applicant) The etiology of the pruritus of cholestasis is unknown and its treatment unsatisfactory. The pruritus of cholestasis has a negative impact on the quality of life of patients and it can be so severe that it alone can be an indication for liver transplantation in children and adults, even in the face of good hepatic function. Accordingly, the provision of satisfactory treatment for this symptom is needed. The spontaneous disappearance of pruritus in patients with cholestasis heralds liver failure. In addition, replacement of the diseased liver in a patient who has cholestasis and pruritus is followed by the cessation of this symptom. These two clinical observations suggest that a certain degree of hepatic function is necessary for the pruritus of cholestasis to be perceived and that the cholestatic liver participates in the production of the pruritogenic substance. The measurement of substances that are found in plasma as a method of research in the field of pruritus has not led to progress in the elucidation of the pathogenesis of the pruritus of cholestasis. Because pruritus is a perception, it cannot be objectively quantitated. Recently however, clinical studies that have incorporated quantitative methodology to measure scratching behavior, have suggested that the pruritus of cholestasis is in part, mediated by endogenous opioids. In these studies, the administration of opiate antagonist drugs ameliorated the perception of pruritus and the scratching activity index, which is the behavioral manifestation of

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the pruritus of cholestasis. An animal model of scratching behavior in animals has been developed recently. The use of animal models in the study of the pruritus of cholestasis offers the opportunity to discover the substance, or group of substances, which mediate this form of pruritus. The aim of this proposal is to adapt an assay of centrally mediated scratching behavior in rats. This assay will be used to study the scratch-inducing capacity of cholestatic extracts from patients with liver disease and itch and from rats after their central administration. The long term objective of these studies is to identify that substances that mediate the pruritus of cholestasis and to develop effective specific therapies for this complication of liver disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SOLID ORGAN TRANSPLANTATION IN HIV: MULTI-SITE STUDY Principal Investigator & Institution: Stock, Peter G.; Surgery; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The primary aim of this study is to evaluate the safety and efficacy of solid organ transplantation in people with HIV disease by conducting a prospective, multi-center cohort of HIV-positive (+) patients who undergo kidney o liver transplantation. Our long-range goals are: (1) to provide patients and clinicians with information regarding the HIV-specific risks of transplantation, (2) to provide clinicians with information necessary to manage immunosuppressive and antiretroviral (ARV) medications together, and (3) to understand underlying basic science mechanisms that explain patient outcomes so that clinical management can be adjusted to maximize the outcomes. Patients with HIV infection are at significant risk for end stage organ disease. Prior to the advent of highly active antiretroviral therapy (HAART), such patients were often not considered as transplant candidates based on poor prognosis. However, with the use of HAART, HIV positive patients have experienced significant improvements in morbidity and mortality. Thus, increasing numbers of HIV+ patients with end stage kidney and liver disease are potential candidates for transplantation. Despite increasing referrals, patients and clinicians lack the necessary data to determine the safety and efficacy of transplantation and immunosuppression in this group. This lack of conclusive data has led to continued denial of care by many transplant centers and third party payers, resulting in frustration and confusion for both patients and their health care providers. Therefore, the primary clinical focus of this proposal is the design of a multi-center study that is powered to test the hypothesis that HIV+ liver and kidney transplant recipients will have patient and graft survival rates equivalent to other patient groups without HIV infection currently considered acceptable transplant candidates. In addition to providing the numbers required for a sufficiently powered study, the multicenter study provides access to 16 transplant centers for HIV+ patients facing end stage organ disease, facilitating regional access to avoid the logistic difficulties associated with limited access to distant sites. Of equal importance, the research plan establishes a prospective cohort that provides an ideal opportunity to explore mechanisms underlying disease progression in HIV+ transplant recipients and key issues in their medical management. The multi-center approach will capitalize on access to experts in the fields of virology and immunology. These investigators will explore the effects of immunosuppression (IS) on progression of HIV and viral co-pathogens known to be important in both transplant recipients and people with HIV infection. Progression of HIV and viral co-pathogens will be correlated with changes in the host immune response to HIV, viral co-pathogens, and allografts. These data will provide an essential contribution to an understanding of the factors that

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may be responsible for variations in graft and patient survival rates. This cohort will also provide the basis for describing the pharmacokinetic interactions between IS and the hepatically-metabolized ARVs, data that will greatly benefit health care workers managing HIV+ patients following transplantation, as maintaining appropriate levels of both of these classes of drugs will be essential for success. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STUDIES OF MECHANISMS AND TREATMENT OF LIVER DISEASE Principal Investigator & Institution: Sanyal, Arun J.; Associate Professor; Internal Medicine; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 31-AUG-2004 Summary: This candidate is an Associate Professor of Gastroenterology and Hepatology at the Medical College of Virginia (MCV). He has played a key role in the growth of the Hepatology program at MCV and has won national recognition for his research on the role of transjugular intrahepatic portasystemic shunts (TIPS) in the treatment of portal hypertension. His career goals are: (1) to be an outstanding clinician, (2) to be a leading scientist in patient- oriented research in liver disease, and (3) to train junior clinicians as bio-medical scientists. This application has been written to mainly consolidate his status as a clinical scientist and teacher. During the period of the proposed studies, the candidate will perform research and serve as a mentor to junior colleagues. Two specific research projects will be performed: (1) a randomized prospective multi-center trial of total paracenteses (TP) vs TP + TIPS for refractory ascites of which he is the principal investigator. (2): studies on the pathogenesis of nonalcoholic steatohepatitis (NASH), a common yet poorly understood disease. It is hypothesized that susceptibility to NASH results from spontaneous mutations of mitochondrial DNA (mtDNA) which cause defective expression of electron-transport chain enzymes in a fraction of hepatocyte mitochondria. Functionally, this results in abnormal oxidation/phosphorylation. when such individuals develop insulin-resistance e.g. from obesity or diabetes, increased lipolysis provides more fatty acid for hepatic uptake and beta oxidation. The resultant oxidative stress in hepatocytes with abnormal mitochondria generates free radicals which cause lipid peroxidation and cell injury. This will be tested by (1) comparison of insulin sensitivity and lipolysis in patients with NASH to three control groups( nonalcoholic fatty liver, matched normal controls, and non-fatty liver disease) using an euglycemic clamp, (2) comparison of hepatocyte mitochondrial structure and function across these four groups by electron microscopy and histochemical assessment of cytochrome oxidase and succinate dehydrogenase, (3) comparison of lipid peroxides in liver biopsy homogenates across these four groups, and (4) comparison of the prevalence and types of mtDNA mutations across these four groups. The latter studies will be done by Dr. Vantuyle (Dept. Biochem, MCV). The institutional and departmental environment as well as the facilities and resources are excellent for career development in academic medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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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

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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 •

Project Title: THE EFFECT OF A PROBIOTIC ON HEPATIC STEATOSIS Principal Investigator & Institution: Diehl, Anna M.; Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 15-JUL-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States. NAFLD includes a spectrum of hepatic pathology that ranges from fatty liver (steatosis) at the most clinically indolent extreme, to cirrhosis at the opposite extreme where most liver specific morbidity and mortality occurs. Indeed, NAFLD is now thought to be responsible for most of what was once classified as 'cryptogenic cirrhosis'. Cryptogenic cirrhosis accounts for half of the annual liver-related deaths. The study of NAFLD has been hindered by the lack of an easily measurable, clinically relevant outcome measure. Safe, inexpensive, well-tolerated treatments for NAFLD are greatly needed. Recent breakthroughs using animal models have advanced understanding of the pathogenesis of NAFLD and provide hope for the development of effective treatments. Based on extensive work in our own laboratory, our OVERALL HYPOTHESIS is that alcohol and lipopolysacchride (LPS) production by intestinal bacterial overgrowth (IBO) cause inflammatory signaling in the liver that leads to hepatic insulin resistance and NAFLD.

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To evaluate this possibility, we treated a murine model of NAFLD with probiotics or anti-tumor necrosis factor a (TNF) antibodies. Indeed, both treatments decreased activation of well-defined molecular inflammatory pathways and improved steatosis by biopsy. This exciting preliminary data provides rationale for studying probiotics in humans. Therefore, this project has a single SPECIFIC AIM: to determine if probiotic therapy can decrease hepatic steatosis in humans with NAFLD. We propose a doubleblinded, randomized, placebo-controlled four month pilot study of 30 patients with NAFLD. The main outcome measure will be grade of hepatic steatosis evaluated by biopsy. We will also measure steatosis by magnetic resonance spectroscopy (MRS). The possibility that probiotics, which are safe, well-tolerated and natural therapies, might improve NAFLD is exciting because liver-related morbidity and mortality are late complications of most chronic liver diseases, including NAFLD. Thus, the safety profile of probiotics makes them an attractive treatment option for a disease that will likely require chronic therapy. If the efficacy of probiotics is established one type of chronic liver disease, the possibility that similar biological therapies might benefit other chronic inflammatory states would merit further evaluation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE EPIDEMIOLOGY OF HEPATITIS C INFECTION IN THAILAND Principal Investigator & Institution: Nelson, Kenrad E.; Professor; Epidemiology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 20-SEP-1999; Project End 31-AUG-2004 Summary: The proposed research program will involve integrated collaborative studies of the epidemiology, biology and natural history of hepatitis C virus (HCV) infections in Northern Thailand. Infections with HCV are a worldwide health problem and are a major cause of chronic liver disease, liver cancer and cirrhosis. It is estimated that 4 million persons in the United States and 180 million persons worldwide are infected with HCV. After infection 80 percent of individuals will become chronic carriers and 20 percent of them will progress to chronic liver disease or cancer in the next 15-20 years. Epidemiologic studies in some populations have found high rates of HCV in injection drug users and lower but elevated rates from sexual and perinatal transmission. However, infections in many individuals are cryptogenic. The reasons for the persistence of HCV infection in such a high proportion of infected individuals is not clear. However, the virus is genetically quite diverse and viral variation with the emergence of new quasispecies usually occurs in chronically infected people. Furthermore the epidemiology and transmission of HCV is intertwined with HIV, so many persons who are infected with both viruses may be immunosuppressed. The studies we have planned will involve comprehensive investigations of the epidemiology, virology and natural history of HCV infections in various populations in Northern Thailand, most of whom are being evaluated for HIV infection. Liver cancer is one of the leading causes of cancer in Thailand and HCV prevalence in blood donors is 8-10 fold greater than in the U.S. The study populations will include injection drug users, sex workers, STD patients, military recruits, blood donors and their spouses and general community populations. Through the transfer of technology for HCV research to our collaborators, we hope to focus on understanding the biology and epidemiology of HCV and the development of more effective prevention of HCV. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE GENETIC BASIS OF HEREDITARY LIVER DISEASE Principal Investigator & Institution: Bull, Laura N.; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (Investigator's abstract): The goals of this project are to identify and characterize the molecular bases for two forms of inherited liver disease, cholestasislymphedema syndrome (CLS) and familial hyperbileacidemia (FHB). We will work toward this goal through the following three specific aims: 1) identify the gene mutated in CLS, and further genetically characterize this disorder; 2) characterize the expression pattern of the CLS gene and protein; and 3) identify the gene mutated in FHB, and further genetically characterize this disorder. These genes will be genetically localized through use of recently developed, highly efficient genetic mapping techniques, and then candidate genes identified through analysis of available sequence databases, and use of laboratory-based gene identification techniques. Mutations causing CLS and FHB will be identified, and clinical data examined to identify any correlations between the type of mutation present in a patient, and the characteristics of that patient's disease. The types of cells in which the CLS gene is expressed will be identified using in situ hybridization approaches, and the cellular and subcellular localization of the CLS protein will be characterized, using immunohistochemical techniques. The identification of genes mutated in hereditary disorders, and the subsequent characterization of their protein products, has become a valuable tool for increasing our understanding of the pathophysiology of diseases, including disorders of the hepatobiliary system, which affect millions of people in the U.S. Identification of the genetic cause of a disease assists in diagnosis, and also aids further study that may lead to better treatment and prevention. Most importantly, the identification of a disease gene provides specific insight into the biological pathways that are deranged in the illness, and tools for further study of these pathways. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE ROLE OF GDF-15 IN ORGAN INJURY Principal Investigator & Institution: Koniaris, Leonidas G.; Surgery; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): This proposal seeks funding for the scientific development of Leonidas Koniaris, M.D., an Assistant Professor of Surgery at the University of Rochester School of Medicine. The candidate, a gastrointestinal and trauma surgeon with over four years of basic science research training in the function and signaling of cytokines and growth factors, seeks funding for a mentored research program to examine the role of a novel secreted factor, GDF-15, in shock and organ injury. Shock and organ injury are common cytokine-dependent pathophysiologic processes that lead to the morbidity and mortality seen in virtually all serious disease states. We and others have cloned the new Transforming Growth Factor-B (TGF-B) superfamily members GDF-15, and its human homologue GDF-l 4. GDF- 15 expression is potently induced in mouse models of liver, bile duct, kidney and lung injury and shock. Likewise, GDF-14 is highly expressed in acute and chronic human liver disease. Macrophages from GDF-15 null mice hyper-express inflammatory cytokines and chemokines both in the unstimuiated state and after treatment with phorbol ester. Others report that GDF-14 can signal through the TGF-B receptor and exert TGF-B-like anti-proliferative effects. Taken together these data suggest that GDF- 14/15 is an early

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signal or mediator of shock and organ injury, that GDF- 14/15 may limit the inflammatory response by regulating cytokine production by macrophages, and that GDF 14/15 may regulate parenchymal cell proliferation after tissue injury. This proposal seeks to determine the function of GDF- 15 by describing its expression pattern, by evaluating the response of GDF-15 null mice to organ injury and shock, and by examining the effect of recombinant GDF-15 in vitro on macrophages and parenchymal cells and in vivo in over-expressing mice. The candidate will be sponsored by the Chairman of Surgery, James V. Silzmann, M.D., and Professor of Immunology I. Nickolas Crispe, Ph.D., who will provide expertise and training in the areas of murine surgery and shock and macrophage methodology respectively. The completion of this mentored research training will further the candidate?s goal of applying bench-derived scientific discovery to the treatment of surgical disease as an independent investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INFECTION

TREATMENT

DISPARITIES/OUTCOMES

OF

HCV-HIV

CO-

Principal Investigator & Institution: Butt, Adeel A.; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2008 Summary: (provided by applicant): About 4 million Americans, and 170 million persons worldwide are infected with the Hepatitis C virus (HCV). Each year, 8,000-10,000 Americans die of HCV. End stage liver disease due to HCV is one of the leading cause for liver transplantation in the United States. Co-infection with HCV and human immunodeficiency virus (HIV) is common with over one-third of the HIV infected patients in the US being co-infected with HCV. Despite high prevalence and mortality, very few patients with HCV and even fewer with HCV-HIV co-infection receive treatment for HCV. Additionally, the long term outcomes after HCV treatment in HCVHIV co-infected patients are unknown. The goal of this application is to study the treatment patterns of HCV in patients with and without HIV co-infection, and the clinical outcomes after treatment and to prepare the applicant for an independent research career in the field of HCV-HIV co-infection. The specific research aims are to determine i) whether HCV-HIV co-infected patients are less likely to receive treatment for HCV than those infected with HCV alone, and whether this disparity could be explained by HIV co-infection itself, age, race, gender, history of psychiatric illness, and drug and alcohol use ii) whether HCV-HIV infected patients who do receive treatment for HCV are less likely to complete the course of treatment when compared with HCV alone infected patients, and to understand the factors associated with failure to complete treatment, and iii) whether patients who complete the treatment have improved outcomes as measured by survival, emergency department visits, liver disease related hospitalization and incidence of hepatocellular carcinoma. The study population will be all HCV infected Veterans who have been entered in the national VA administrative database between 1999 and 2002. The total number of patients newly diagnosed to be HCV antibody positive in the VA Healthcare System during 1999-2001 was 109,700. Demographic and social variables, prescription and completion of HCV treatment, clinical outcomes including survival, liver disease related hospitalizations, utilization of emergency care for liver disease related conditions and development of hepatocellular carcinoma will be studied. This information will be retrieved from the national VA administrative database using ICD 9 codes, and from the Pharmacy Benefits Management database. To attain the educational goals of this application, the applicant will enroll in University of Pittsburgh Clinical Research Training Program, to complete

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course work for a Masters of Science degree in Clinical Effectiveness and Outcomes Research, and participate actively in the School of Medicine's continuing educational activities. The long term objective of the applicant is to make a clinically relevant impact on the HCV treatment patterns and outcomes, especially in the HCV-HIV co-infected patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TUMOR NECROSIS FACTOR AND ALCOHOLIC LIVER DISEASE Principal Investigator & Institution: Mcclain, Craig J.; Professor of Internal Medicine; Medicine; University of Louisville University of Louisville Louisville, Ky 40292 Timing: Fiscal Year 2001; Project Start 01-MAR-1996; Project End 31-JUL-2006 Summary: (Applicant's Abstract): Alcoholic liver disease (ALD) is a major cause of liver disease and liver related morbidity/mortality in the United States. One major difficulty in devising specific therapies for ALD has been our limited understanding of the mechanism(s) for the development and progression of this liver injury. Cytokines are low molecular weight mediators of cellular communication that are produced and released by numerous cell types such as monocytes, macrophages, and of particular relevance to liver disease, Kupffer cells. Pro-inflammatory cytokines, such as tumor necrosis factor a (TNF), and chemokines, such as interleukin-8, have been postulated to play a role in modulating many of the systemic manifestations of ALD and certain aspects of the liver injury in ALD. Many factors stimulate cytokine production, including endotoxin (lipopolysaccharide or LPS) and reactive oxygen intermediates (ROIs), both of which are of direct relevance to this proposal. Endotoxin stimulates cytokine production via interaction with LPS binding protein (LBP); membrane bound CD 14, and ultimately the recently described LPS receptor, Toll-like receptor TLR4. TLR4 then causes activation of the redox sensitive transcription factor, NFkB, with subsequent production of cytokines such as TNF. NFKB also has been identified as a survival factor against TNF induced apoptosis in multiple cell types. Thus, NFKB not only serves as a transcription factor for several inflammatory cytokines such as TNF and IL-8, but also for several potentially protective factors such as inhibitors of apoptosis (lAPs). Inhibition of NFkB can initiate fulminant liver injury and hepatocyte apoptosis, at least in part, by allowing unregulated signaling via the TNF "death domain." We postulate that in ALD there is: 1) increased NFkB activation and TNF production in the major cytokine producing cell in the liver (Kupffer cell); and 2) decreased NFkB activation and decreased "protective signaling" in conjunction with increased TNF death signaling in the target cell (hepatocyte). In this proposal, we will use in vitro systems, in vivo animal models of ALD and ultimately will perform translational human studies to further define mechanisms of liver injury in ALD and potential pathways for intervention. The specific aims of this proposal are to: 1) Evaluate mechanisms for increased NFkB activation and TNF production by monocyte/Kupffer cells in ALD (priming), 2) Evaluate mechanisms of increased susceptibility to TNF/cytokine hepatotoxicity in ALD (sensitization). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

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 Timing: Fiscal Year 2001; Project Start 01-APR-1993; Project End 31-MAR-2004

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Liver Disease

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: VARIATION IN THE EFFECTS OF ALCOHOL ON LIVER FUNCTION Principal Investigator & Institution: Whitfield, John B.; Queensland Institute of Medical Research Bramston Terr, Herston Brisbane, Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): This resubmission is one of a group of Interactive Research Project Grant applications, which have the broad objective of clarifying the role of genes in alcohol dependence and related disorders. Alcohol dependence is a common condition with a substantial genetic component. This application focuses on pre-clinical alcoholic liver disease in a community-based sample and will complement published studies on patients with more advanced disease. The objective is to identify risk factors able to predict which hazardous drinkers are at risk of eventual progression to liver disease. Successful identification of risk factors for alcoholic liver disease may lead to improvements in early identification of people at risk from their drinking, and early intervention to prevent progression to clinical disease. Known risk factors include lifetime quantity of alcohol consumed, and gender (women are more susceptible to alcoholic liver disease than men). The postulated risk factors to be studied are based on a small number of published studies on patients, and on our preliminary work with

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community samples. They include obesity and related metabolic disorders; iron overload; and allelic variation in a range of candidate genes concerned with alcohol metabolism, inflammatory response within the liver, fatty liver and fibrosis. The specific aims are to test whether the postulated risk factors affect the probability of liver dysfunction in hazardous drinkers, using biochemical liver function tests to detect preclinical liver damage. The enzyme liver function tests are abnormal in a substantial proportion (approximately 30-40%) of hazardous drinkers and offer an opportunity for noninvasive testing in large numbers of subjects. Subjects will be drawn from twins and their families who have participated in previous studies of alcohol use and dependence. They will have met DSM-IV criteria for alcohol dependence and/or have reported hazardous levels of alcohol intake in the previous studies. They will provide information on recent alcohol intake, and blood samples will be taken for biochemical testing and as a source of DNA for genotyping. Data will be analyzed using standard methods for twin studies and tests will be included for the effects of postulated phenotypic risk factors, for heritability of liver abnormality conditional on hazardous drinking, and for allelic association at candidate genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VASCULAR HYPRTENSION

RESPONSE

TO

HEMMORHAGE

IN

PORTAL

Principal Investigator & Institution: Sitzmann, James V.; Chairman & Robert J. Coffey Professor; Surgery; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-SEP-1993; Project End 30-NOV-2006 Summary: (Provided by Applicant): The protean manifestations of portal hypertension (PHT) lead to the deaths of over 100,000 Americans each year, and disproportionately target minorities and women due to their greater susceptibility to liver disease. Hemorrhagic shock is the most common lethal complication of portal hypertension where patients tolerate massive hemorrhage poorly. Current treatment modalities may actually aggravate the underlying cause of bleeding, due to the poor understanding of the pathogenesis of the abnormal physiology. Our lab has been instrumental in elucidating the factors critical to the development of PHT, including the identification of the putative mediators of increased splanchnic blood flow (NO, PGI2, angiotensin [ANGII], endothelin [ET), and an altered transmembrane signaling in PHT that underlies the altered vascular response to hemorrhage. This proposal seeks to determine the relationship between the mechanical forces (increased flow, pressure and strain), and the putative mediators of increased splanchnic blood flow (NO, PGI2, ANGII, ET), and the abnormal vascular response to hemorrhage in PHT. Our central hypothesis is that changes in intraluminal mechanical forces (pressure and shear stress) increase endothelial expression of vasodilatory substances that chronically regulate pressor hormone receptor transmembrane signaling and vessel structural changes in PHT that determines the abnormal responsiveness of the hyperemic vasculature to hemorrhage and resuscitation. We will use in vivo models of PHT with and without cirrhosis (bile duct ligated [BDL] and partial portal vein ligated [PVL]) in wild type and iNOS, eNOS, COX 1, COX 2 knockout mice, in conjunction with in vitro models of perfused transcapillary endothelial cell (EC) and vascular smooth muscle cell (VSMC) co-culture system, and the Flexercell Strain System (mimicking the in vivo vascular architecture and mechanical forces of flow, pressure and strain). We will evaluate the effect of mechanical force upon EC nitric oxide synthase (NOS) and cyclooxygenase (COX) expression/activity and VSMC pressor hormone receptor (ANGII, ET) expression and transmembrane signaling and VSMC proliferation and migration. We will determine: 1)

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Liver Disease

changes in endothelial expression of NOS and COX in response to changes in flow, pressure, or strain; 2) changes in VSMC receptor and transmembrane signal transduction as well as alterations in proliferation and migration; 3) if shear, pressure, or strain induced alterations are modulated by the presence or absence of liver disease (cirrhosis); and 4) if mechanical force induced changes in EC vasoactive substance expression or VSMC changes result in abnormal vascular response to hemorrhage and shock. In summary, we will determine the role of obstruction to portal flow and the influence of mechanical forces and cirrhosis upon the abnormal vascular response to hemorrhage and resuscitation. These experiments will provide significant new information central to our understanding of PHT, and lead directly to effective treatment programs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VIRAHEP-C CLINICAL CENTER Principal Investigator & Institution: Conjeevaram, Hari S.; Assistant Professor of Medicine; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 30-JUN-2006 Summary: (provided by applicant): Chronic hepatitis C is the leading cause of chronic liver disease and cirrhosis in the United States and is now the leading cause for liver transplantation due to end-stage liver disease. Approximately 1.8% of population (4 million) in the United States have antibody to hepatitis C virus (anti-HCV) and approximately 2.7 million Americans have evidence of chronic infection. The prevalence of antibody to HCV is higher among African Americans (3.2%) than among the nonHispanic whites (1.8%). Treatment of chronic hepatitis C remains problematical and unsatisfactory. Interferon (IFN) monotherapy given as three times weekly injections has been shown to have biochemical, virological and histological beneficial effects. However, sustained virological response (SVR) is seen in only a minority of patients (616%). Treatment with combination of IFN + and ribavirin for 24 or 48 weeks results in SVR rates of up to 35 to 43% respectively. Very limited published data is currently available on the impact of race on response to antiviral therapy in patients with chronic hepatitis C. Most available reports show that African Americans have a significantly lower SVR when compared to non-Hispanic whites with all treatment regimens. We are proposing a multicenter, controlled clinical trial of combination therapy of pegylated interferon + ribavirin for African Americans and non-Hispanic whites chronically infected with HCV genotype 1 virus. Treatment will be administered for a total duration of 48 weeks with a 48-week follow-up post completion of therapy. A total of 400 patients with equal numbers of Caucasians and African Americans (200 in each group) will be enrolled into this study. The primary end-point of this trial is to determine rate of SVR among African Americans and non-Hispanic whites. In addition, factors predictive for a favorable response and patterns of virological response will also be assessed in the two racial groups. The objectives of this trial are to evaluate: (a) the rates of SVR among African Americans and non-Hispanic Whites with chronic hepatitis C after treatment with combination therapy using pegylated interferon and ribavirin for 48 weeks; (b) the factors that are predictive of a SVR to combination therapy in each of the two racial groups and factors associated with poorer response in African Americans and (c) the patterns of virological response (including viral kinetics) early during treatment and determine if different responses predict the ultimate outcome (sustained response, relapse or a lack of response) in each of the two racial groups. The findings of this study will allow us to develop specific algorithms to predict rates of SVR to therapy among

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African Americans based on their pre-treatment characteristics and patterns of virological response during therapy. 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 “liver disease” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for liver disease in the PubMed Central database: •

Diagnosis of Hepatitis C Virus (HCV) Infection Using an Immunodominant Chimeric Polyprotein to Capture Circulating Antibodies: Reevaluation of the Role of HCV in Liver Disease. by Chien DY, Choo Q, Tabrizi A, Kuo C, McFarland J, Berger K, Lee C, Shuster JR, Nguyen T, Moyer DL, Tong M, Furuta S, Omata M, Tegtmeier G, Alter H, Schiff E, Jeffers L, Houghton M, Kuo G.; 1992 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50267

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Granulocyte Colony-Stimulating Factor Improves Deficient In Vitro Neutrophil Transendothelial Migration in Patients with Advanced Liver Disease. by Fiuza C, Salcedo M, Clemente G, Tellado JM.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=119958

•

High Prevalence of TT Virus Infection in Healthy Children and Adults and in Patients with Liver Disease in Taiwan. by Hsieh SY, Wu YH, Ho YP, Tsao KC, Yeh CT, Liaw YF.; 1999 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84962

•

In Situ Distribution of Hepatitis C Virus Replicative-Intermediate RNA in Hepatic Tissue and Its Correlation with Liver Disease. by Chang M, Marquardt AP, Wood BL, Williams O, Cotler SJ, Taylor SL, Carithers RL Jr, Gretch DR.; 2000 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111615

•

Keratin 8 and 18 mutations are risk factors for developing liver disease of multiple etiologies. by Ku NO, Darling JM, Krams SM, Esquivel CO, Keeffe EB, Sibley RK, Lee YM, Wright TL, Omary MB.; 2003 May 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156326

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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•

Mechanisms for virus-induced liver disease: tumor necrosis factor-mediated pathology independent of natural killer and T cells during murine cytomegalovirus infection. by Orange JS, Salazar-Mather TP, Opal SM, Biron CA.; 1997 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230227

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Mortality from liver disease in the West Midlands, 1993-2000: observational study. by Fisher NC, Hanson J, Phillips A, Rao JN, Swarbrick ET.; 2002 Aug 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117772

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Prevalence of hepatitis G viremia among healthy subjects, individuals with liver disease, and persons at risk for parenteral transmission. by Feucht HH, Zollner B, Polywka S, Knodler B, Schroter M, Nolte H, Laufs R.; 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229669

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The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. by Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ.; 2003 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=162288

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Type, prevalence, and significance of core promoter/enhancer II mutations in hepatitis B viruses from immunosuppressed patients with severe liver disease. by Gunther S, Piwon N, Iwanska A, Schilling R, Meisel H, Will H.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190919

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Uneven Distribution of Hepatitis C Virus Quasispecies in Tissues from Subjects with End-Stage Liver Disease: Confounding Effect of Viral Adsorption and Mounting Evidence for the Presence of Low-Level Extrahepatic Replication. by Laskus T, Radkowski M, Wang LF, Nowicki M, Rakela J.; 2000 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111624

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Unusual skin findings in a patient with liver disease. by Fisman D.; 2002 Jun 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113805

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Utility of the Mayo End-Stage Liver Disease (MELD) score in assessing prognosis of patients with alcoholic hepatitis. by Sheth M, Riggs M, Patel T.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=65516

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Weak Association between SEN Virus Viremia and Liver Disease. by Yoshida H, Kato N, Shiratori Y, Shao R, Wang Y, Shiina S, Omata M.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130791

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 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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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 liver disease, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “liver disease” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for liver disease (hyperlinks lead to article summaries): •

A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease. Author(s): Muhlbauer M, Bosserhoff AK, Hartmann A, Thasler WE, Weiss TS, Herfarth H, Lock G, Scholmerich J, Hellerbrand C. Source: Gastroenterology. 2003 October; 125(4): 1085-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14517792&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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Abnormal brain energy metabolism shown by in vivo phosphorus magnetic resonance spectroscopy in patients with chronic liver disease. Author(s): Barbiroli B, Gaiani S, Lodi R, Iotti S, Tonon C, Clementi V, Donati G, Bolondi L. Source: Brain Research Bulletin. 2002 October 15; 59(1): 75-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12372552&dopt=Abstract

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Acute autoimmune hepatitis presenting with centrizonal liver disease: case report and review of the literature. Author(s): Singh R, Nair S, Farr G, Mason A, Perrillo R. Source: The American Journal of Gastroenterology. 2002 October; 97(10): 2670-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12385459&dopt=Abstract

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Acute hepatic failure in alcoholic liver disease. Author(s): Kryczka W, Dutkiewicz E, Pabjan P. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2001 May; 7 Suppl 1: 252-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12211730&dopt=Abstract

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AGA technical review on nonalcoholic fatty liver disease. Author(s): Sanyal AJ; American Gastroenterological Association. Source: Gastroenterology. 2002 November; 123(5): 1705-25. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12404245&dopt=Abstract

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Alcoholic liver disease (ALD): a new domain for prevention efforts. Author(s): Sussman S, Dent CW, Skara S, de Calice P, Tsukamoto H. Source: Substance Use & Misuse. 2002; 37(14): 1887-904. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12511057&dopt=Abstract

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Alcoholic liver disease and transplantation. Author(s): Jain AB, Fung JJ. Source: Transplantation Proceedings. 2003 February; 35(1): 358-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591439&dopt=Abstract

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Alcohol-related liver disease. Author(s): James M, Ryder S. Source: The Practitioner. 2003 May; 247(1646): 414-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12760130&dopt=Abstract

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Alpha(1)-antitrypsin deficiency, liver disease and emphysema. Author(s): Parfrey H, Mahadeva R, Lomas DA. Source: The International Journal of Biochemistry & Cell Biology. 2003 July; 35(7): 100914. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12672469&dopt=Abstract

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Altered modulation of soluble guanylate cyclase by nitric oxide in patients with liver disease. Author(s): Corbalan R, Montoliu C, Minana MD, Del Olmo JA, Serra MA, Aparisi L, Rodrigo JM, Felipo V. Source: Metabolic Brain Disease. 2002 December; 17(4): 295-301. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12602506&dopt=Abstract

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American Gastroenterological Association medical position statement: nonalcoholic fatty liver disease. Author(s): American Gastroenterological Association. Source: Gastroenterology. 2002 November; 123(5): 1702-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12404244&dopt=Abstract

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Anabolic-androgenic steroids for alcoholic liver disease. Author(s): Rambaldi A, Iaquinto G, Gluud C. Source: Cochrane Database Syst Rev. 2003; (1): Cd003045. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12535450&dopt=Abstract

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•

Anesthesia care for living-related liver transplantation for infants and children with end-stage liver disease: report of our initial experience. Author(s): Djurberg H, Pothmann Facharzt W, Joseph D, Tjan D, Zuleika M, Ferns S, Rasheed A, Evans DA, Bassas A. Source: Journal of Clinical Anesthesia. 2002 December; 14(8): 564-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12565113&dopt=Abstract

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Antikeratin antibodies in sera of patients with connective tissue disease and liver disease. Author(s): Takeda I, Iwadate H, Sugisaki K, Kanno T, Shinzawa J, Kasukawa R. Source: Fukushima J Med Sci. 2002 December; 48(2): 85-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12680612&dopt=Abstract

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Are cultured liver cells the right tool to investigate mechanisms of liver disease or hepatotoxicity? Author(s): Jaeschke H. Source: Hepatology (Baltimore, Md.). 2003 October; 38(4): 1053-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14567386&dopt=Abstract

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Assessment of blood coagulation in severe liver disease using thromboelastography: use of citrate storage versus native blood. Author(s): Mancuso A, Fung K, Cox D, Mela M, Patch D, Burroughs AK. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. 2003 February; 14(2): 211-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12632034&dopt=Abstract

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Assessment of prognosis in alcoholic liver disease: can serum hyaluronate replace liver biopsy? Author(s): Phillips MG, Preedy VR, Hughes RD. Source: European Journal of Gastroenterology & Hepatology. 2003 September; 15(9): 941-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12923364&dopt=Abstract

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Autoimmune liver disease in children. Author(s): Mieli-Vergani G, Vergani D. Source: Ann Acad Med Singapore. 2003 March; 32(2): 239-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12772529&dopt=Abstract

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Autologous blood storage before hepatectomy for hepatocellular carcinoma with underlying liver disease. Author(s): Itamoto T, Katayama K, Nakahara H, Tashiro H, Asahara T. Source: The British Journal of Surgery. 2003 January; 90(1): 23-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12520570&dopt=Abstract

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Basal and post-methionine serum homocysteine and lipoprotein abnormalities in patients with chronic liver disease. Author(s): Ben-Ari Z, Tur-Kaspa R, Schafer Z, Baruch Y, Sulkes J, Atzmon O, Greenberg A, Levi N, Fainaru M. Source: Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research. 2001 July; 49(4): 325-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11478408&dopt=Abstract

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Basement membrane peptides as markers of liver disease in chronic hepatitis C. Author(s): Walsh KM, Fletcher A, MacSween RN, Morris AJ. Source: Journal of Hepatology. 2000 February; 32(2): 325-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10707874&dopt=Abstract

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Beating the odds in liver disease. Author(s): Johnson J. Source: Nurs Times. 1998 December 2-8; 94(48): 63-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9934180&dopt=Abstract

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Beneficial effect of salmon roe phosphatidylcholine in chronic liver disease. Author(s): Hayashi H, Tanaka Y, Hibino H, Umeda Y, Kawamitsu H, Fujimoto H, Amakawa T. Source: Current Medical Research and Opinion. 1999; 15(3): 177-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10621924&dopt=Abstract

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Beneficial influence of an indigenous low-iron diet on serum indicators of iron status in patients with chronic liver disease. Author(s): Tandon N, Thakur V, Guptan RK, Sarin SK. Source: The British Journal of Nutrition. 2000 March; 83(3): 235-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10884711&dopt=Abstract

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Beyond hepatorenal syndrome: glomerulonephritis in patients with liver disease. Author(s): Lhotta K. Source: Semin Nephrol. 2002 July; 22(4): 302-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12118395&dopt=Abstract

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Bile acid synthetic defects and liver disease. Author(s): Bove KE, Daugherty CC, Tyson W, Mierau G, Heubi JE, Balistreri WF, Setchell KD. Source: Pediatric and Developmental Pathology : the Official Journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. 2000 January-February; 3(1): 1-16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10594127&dopt=Abstract

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Bile acid-mediated hepatocyte apoptosis and cholestatic liver disease. Author(s): Guicciardi ME, Gores GJ. Source: Dig Liver Dis. 2002 June; 34(6): 387-92. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12132783&dopt=Abstract

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Bleeding problems in patients with liver disease. Ways to manage the many hepatic effects on coagulation. Author(s): Sallah S, Bobzien W. Source: Postgraduate Medicine. 1999 October 1; 106(4): 187-90, 193-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10533518&dopt=Abstract

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Blood antioxidant levels in patients with alcoholic liver disease correlate with the degree of liver impairment and are not specific to alcoholic liver injury itself. Author(s): Van de Casteele M, Zaman Z, Zeegers M, Servaes R, Fevery J, Nevens F. Source: Alimentary Pharmacology & Therapeutics. 2002 May; 16(5): 985-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11966508&dopt=Abstract

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Body composition and components of energy expenditure in children with end-stage liver disease. Author(s): Greer R, Lehnert M, Lewindon P, Cleghorn GJ, Shepherd RW. Source: Journal of Pediatric Gastroenterology and Nutrition. 2003 March; 36(3): 358-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604974&dopt=Abstract

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Body composition and hepatic steatosis as precursors for fibrotic liver disease. Author(s): McCullough AJ, Falck-Ytter Y. Source: Hepatology (Baltimore, Md.). 1999 April; 29(4): 1328-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10094983&dopt=Abstract

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Bolus somatostatin but not octreotide reduces hepatic sinusoidal pressure by a NOindependent mechanism in chronic liver disease. Author(s): Matrella E, Valatas V, Notas G, Roumpaki H, Xidakis C, Hadzidakis A, Mouzas I, Kouroumalis E. Source: Alimentary Pharmacology & Therapeutics. 2001 June; 15(6): 857-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11380324&dopt=Abstract

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Bone density, vitamin D status, and disordered bone remodeling in end-stage chronic liver disease. Author(s): Crosbie OM, Freaney R, McKenna MJ, Hegarty JE. Source: Calcified Tissue International. 1999 April; 64(4): 295-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10089221&dopt=Abstract

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Bone loss in primary biliary cirrhosis: absence of association with severity of liver disease. Author(s): Le Gars L, Grandpierre C, Chazouilleres O, Berenbaum F, Poupon R. Source: Joint, Bone, Spine : Revue Du Rhumatisme. 2002 March; 69(2): 195-200. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12027312&dopt=Abstract

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Bone metabolism in advanced cholestatic liver disease: analysis by bone histomorphometry. Author(s): Guichelaar MM, Malinchoc M, Sibonga J, Clarke BL, Hay JE. Source: Hepatology (Baltimore, Md.). 2002 October; 36(4 Pt 1): 895-903. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12297836&dopt=Abstract

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Bone mineral density and height gain in children with chronic cholestatic liver disease undergoing transplantation. Author(s): D'Antiga L, Moniz C, Buxton-Thomas M, Cheeseman P, Gray B, Abraha H, Baker AJ, Heaton ND, Rela M, Mieli-Vergani G, Dhawan A. Source: Transplantation. 2002 June 15; 73(11): 1788-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12085002&dopt=Abstract

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Brain electrical activity mapping of EEG for the diagnosis of (sub)clinical hepatic encephalopathy in chronic liver disease. Author(s): Kullmann F, Hollerbach S, Lock G, Holstege A, Dierks T, Scholmerich J. Source: European Journal of Gastroenterology & Hepatology. 2001 May; 13(5): 513-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11396530&dopt=Abstract

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Branched-chain amino acid-enriched supplements as therapy for liver disease: Rasputin lives. Author(s): Charlton M. Source: Gastroenterology. 2003 June; 124(7): 1980-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12806634&dopt=Abstract

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Burden of liver disease in the United States: summary of a workshop. Author(s): Kim WR, Brown RS Jr, Terrault NA, El-Serag H. Source: Hepatology (Baltimore, Md.). 2002 July; 36(1): 227-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12085369&dopt=Abstract

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Calciphylaxis in a patient with alcoholic liver disease in the absence of renal failure. Author(s): Lim SP, Batta K, Tan BB. Source: Clinical and Experimental Dermatology. 2003 January; 28(1): 34-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12558626&dopt=Abstract

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Chemokines in the pathogenesis of liver disease: so many players with poorly defined roles. Author(s): Simpson KJ, Henderson NC, Bone-Larson CL, Lukacs NW, Hogaboam CM, Kunkel SL. Source: Clinical Science (London, England : 1979). 2003 January; 104(1): 47-63. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12519087&dopt=Abstract

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Cholestatic liver disease: pathophysiology and therapeutic options. Author(s): Hofmann AF. Source: Liver. 2002; 22 Suppl 2: 14-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12220297&dopt=Abstract

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Cholestatic liver disease: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. Author(s): Suchy FJ, Burdelski M, Tomar BS, Sokol RJ. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002; 35 Suppl 2: S89-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12192176&dopt=Abstract

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Chronic liver disease in kidney recipients with hepatitis C virus infection. Author(s): Giordano HM, Franca AV, Meirelles L, Escanhoela CA, Nishimura NF, Santos RL, Quadros KR, Mazzali M, Alves-Filho G, Soares EC. Source: Clinical Transplantation. 2003 June; 17(3): 195-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12780667&dopt=Abstract

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Chronic liver disease in the primary care practices of Waterbury, Connecticut. Author(s): Navarro VJ, St Louis T, Bell BZ, Sofair AN. Source: Hepatology (Baltimore, Md.). 2003 October; 38(4): 1062. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14512898&dopt=Abstract

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Circulating soluble cytochrome c in liver disease as a marker of apoptosis. Author(s): Ben-Ari Z, Schmilovotz-Weiss H, Belinki A, Pappo O, Sulkes J, Neuman MG, Kaganovsky E, Kfir B, Tur-Kaspa R, Klein T. Source: Journal of Internal Medicine. 2003 August; 254(2): 168-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12859698&dopt=Abstract

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Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Author(s): Mofrad P, Contos MJ, Haque M, Sargeant C, Fisher RA, Luketic VA, Sterling RK, Shiffman ML, Stravitz RT, Sanyal AJ. Source: Hepatology (Baltimore, Md.). 2003 June; 37(6): 1286-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12774006&dopt=Abstract

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Clinical implications of viral activity in dual infection with hepatitis B and C in chronic liver disease. Author(s): Guptan RC, Thakur V, Malhotra V, Sarin SK. Source: J Assoc Physicians India. 2002 May; 50(5): 651-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12186118&dopt=Abstract

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Clinical profile of autosomal dominant polycystic liver disease. Author(s): Qian Q, Li A, King BF, Kamath PS, Lager DJ, Huston J 3rd, Shub C, Davila S, Somlo S, Torres VE. Source: Hepatology (Baltimore, Md.). 2003 January; 37(1): 164-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12500201&dopt=Abstract

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Color Doppler and laser velocimetry studies in the assessment of portal hemodynamics and severity of chronic liver disease. Author(s): De BK, Das TK. Source: Indian J Gastroenterol. 2002 September-October; 21(5): 173-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12416744&dopt=Abstract

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Comparative rates of nucleotide sequence variation in the hypervariable region of E1/E2 and the NS5b region of hepatitis C virus in patients with a spectrum of liver disease resulting from a common source of infection. Author(s): Duffy M, Salemi M, Sheehy N, Vandamme AM, Hegarty J, Curry M, Nolan N, Kelleher D, McKiernan S, Hall WW. Source: Virology. 2002 September 30; 301(2): 354-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12359437&dopt=Abstract

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Concurrence of histologic features of steatohepatitis with other forms of chronic liver disease. Author(s): Brunt EM, Ramrakhiani S, Cordes BG, Neuschwander-Tetri BA, Janney CG, Bacon BR, Di Bisceglie AM. Source: Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. 2003 January; 16(1): 49-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12527713&dopt=Abstract

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Copper-associated liver disease in Dalmatians: a review of 10 dogs (1998-2001). Author(s): Webb CB, Twedt DC, Meyer DJ. Source: J Vet Intern Med. 2002 November-December; 16(6): 665-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12465762&dopt=Abstract

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Current best treatment for non-alcoholic fatty liver disease. Author(s): Angulo P. Source: Expert Opinion on Pharmacotherapy. 2003 May; 4(5): 611-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12739988&dopt=Abstract

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Current biochemical studies of non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) suggest a new therapeutic approach. Author(s): Hookman P, Barkin JS. Source: The American Journal of Gastroenterology. 2003 February; 98(2): 495-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591075&dopt=Abstract

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Current biochemical studies of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis suggest a new therapeutic approach. Author(s): Hookman P, Barkin JS. Source: The American Journal of Gastroenterology. 2003 September; 98(9): 2093-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14499793&dopt=Abstract

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CYP enzyme polymorphisms and susceptibility to HCV-related chronic liver disease and liver cancer. Author(s): Silvestri L, Sonzogni L, De Silvestri A, Gritti C, Foti L, Zavaglia C, Leveri M, Cividini A, Mondelli MU, Civardi E, Silini EM. Source: International Journal of Cancer. Journal International Du Cancer. 2003 April 10; 104(3): 310-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12569554&dopt=Abstract

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CYP2E1 activity before and after weight loss in morbidly obese subjects with nonalcoholic fatty liver disease. Author(s): Emery MG, Fisher JM, Chien JY, Kharasch ED, Dellinger EP, Kowdley KV, Thummel KE. Source: Hepatology (Baltimore, Md.). 2003 August; 38(2): 428-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12883487&dopt=Abstract

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Cytochrome P4502D6(193-212): a new immunodominant epitope and target of virus/self cross-reactivity in liver kidney microsomal autoantibody type 1-positive liver disease. Author(s): Kerkar N, Choudhuri K, Ma Y, Mahmoud A, Bogdanos DP, Muratori L, Bianchi F, Williams R, Mieli-Vergani G, Vergani D. Source: Journal of Immunology (Baltimore, Md. : 1950). 2003 February 1; 170(3): 1481-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12538711&dopt=Abstract

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Decompensation of chronic stable alcoholic liver disease by severe exfoliative dermatitis. Author(s): Shawcross DL, Mookerjee RP, Jalan R. Source: European Journal of Gastroenterology & Hepatology. 2003 April; 15(4): 433-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12655267&dopt=Abstract

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Defining nonalcoholic fatty liver disease: implications for epidemiologic studies. Author(s): Clark JM, Diehl AM. Source: Gastroenterology. 2003 January; 124(1): 248-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12512048&dopt=Abstract

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De-novo humoral immune responses to cancer-associated autoantigens during transition from chronic liver disease to hepatocellular carcinoma. Author(s): Zhang JY, Zhu W, Imai H, Kiyosawa K, Chan EK, Tan EM. Source: Clinical and Experimental Immunology. 2001 July; 125(1): 3-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11472419&dopt=Abstract

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Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in american patients. Author(s): Marrero JA, Su GL, Wei W, Emick D, Conjeevaram HS, Fontana RJ, Lok AS. Source: Hepatology (Baltimore, Md.). 2003 May; 37(5): 1114-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12717392&dopt=Abstract

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Detection of acute cytotoxic changes in progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome) using diffusionweighted MRI and MR spectroscopy. Author(s): Ulmer S, Flemming K, Hahn A, Stephani U, Jansen O. Source: Journal of Computer Assisted Tomography. 2002 July-August; 26(4): 641-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12218835&dopt=Abstract

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Detection of hepatitis B virus in seropositive and seronegative patients with chronic liver disease using DNA amplification by PCR. Author(s): Balderas-Renteria I, Munoz-Espinosa LE, Dector-Carrillo MA, MartinezMartinez FJ, Barrera-Saldana HA. Source: Archives of Medical Research. 2002 November-December; 33(6): 566-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12505104&dopt=Abstract

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Detection of YMDD mutant using a novel sensitive method in chronic liver disease type B patients before and during lamivudine treatment. Author(s): Kirishima T, Okanoue T, Daimon Y, Itoh Y, Nakamura H, Morita A, Toyama T, Minami M. Source: Journal of Hepatology. 2002 August; 37(2): 259-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12127432&dopt=Abstract

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Determinants of hyperhomocysteinemia in patients with chronic liver disease and after orthotopic liver transplantation. Author(s): Bosy-Westphal A, Ruschmeyer M, Czech N, Oehler G, Hinrichsen H, Plauth M, Lotterer E, Fleig W, Muller MJ. Source: The American Journal of Clinical Nutrition. 2003 May; 77(5): 1269-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12716682&dopt=Abstract

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Development of a pediatric end-stage liver disease score to predict poor outcome in children awaiting liver transplantation. Author(s): McDiarmid SV, Anand R, Lindblad AS; Principal Investigators and Institutions of the Studies of Pediatric Liver Transplantation (SPLIT) Research Group. Source: Transplantation. 2002 July 27; 74(2): 173-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12151728&dopt=Abstract

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Diagnosis of fatty liver disease: is biopsy necessary? Author(s): Joy D, Thava VR, Scott BB. Source: European Journal of Gastroenterology & Hepatology. 2003 May; 15(5): 539-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12702913&dopt=Abstract

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Diagnosis of nonalcoholic fatty liver disease. Author(s): Mascitelli L, Pezzetta F. Source: Jama : the Journal of the American Medical Association. 2003 September 24; 290(12): 1577; Author Reply 1578. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14506112&dopt=Abstract

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Diagnosis of nonalcoholic fatty liver disease. Author(s): Yanai H, Morimoto M. Source: Jama : the Journal of the American Medical Association. 2003 September 24; 290(12): 1577; Author Reply 1578. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14506111&dopt=Abstract

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Discussion on celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure. Author(s): Ratziu V, Nourani M, Poynard T. Source: Gastroenterology. 2002 December; 123(6): 2158-9; Author Reply 2159-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12454882&dopt=Abstract

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Distribution of alpha-1 -antitrypsin phenotypes in Serbian newborns and children with liver disease. Author(s): Topic A, Jelic-Ivanovic Z, Spasojevic-Kalimanovska V, Spasic S, Stankovic I. Source: Acta Paediatrica (Oslo, Norway : 1992). 2002; 91(6): 726-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12162614&dopt=Abstract

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Do autoantibodies predict autoimmune liver disease in primary Sjogren's syndrome? Data of 180 patients upon a 5 year follow-up. Author(s): Csepregi A, Szodoray P, Zeher M. Source: Scandinavian Journal of Immunology. 2002 December; 56(6): 623-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12472675&dopt=Abstract

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Does hepatitis C virus cause severe liver disease only in people who drink alcohol? Author(s): Vento S, Cainelli F. Source: The Lancet Infectious Diseases. 2002 May; 2(5): 303-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12062996&dopt=Abstract

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Doppler ultrasonography in the assessment of renal hemodynamics in patients with chronic liver disease. Author(s): Rendon Unceta P, Rojas Mangas A, Macias Rodriguez MA, Martinez Sierra MC, Tejada Cabrera M, Martin Herrera L. Source: Rev Esp Enferm Dig. 2000 December; 92(12): 799-805. English, Spanish. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11468788&dopt=Abstract

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Dosimetric analysis and comparison of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy for patients with hepatocellular carcinoma and radiation-induced liver disease. Author(s): Cheng JC, Wu JK, Huang CM, Liu HS, Huang DY, Tsai SY, Cheng SH, Jian JJ, Huang AT. Source: International Journal of Radiation Oncology, Biology, Physics. 2003 May 1; 56(1): 229-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12694843&dopt=Abstract

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DRB1 alleles in relation to severity of liver disease in patients with chronic hepatitis C. Author(s): Kryczka W, Brojer E, Kalinska A, Urbaniak A, Zarebska-Michaluk D. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2001 May; 7 Suppl 1: 217-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12211723&dopt=Abstract

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Drug-induced liver disease during continuous epidural block with bupivacaine. Author(s): Yokoyama M, Ohashi I, Nakatsuka H, Mizobuchi S, Toda Y, Matsumi M, Morita K, Hirakawa M. Source: Anesthesiology. 2001 July; 95(1): 259-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11465567&dopt=Abstract

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Early-onset liver disease complicated with acute liver failure in Alstrom syndrome. Author(s): Quiros-Tejeira RE, Vargas J, Ament ME. Source: American Journal of Medical Genetics. 2001 June 1; 101(1): 9-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11343329&dopt=Abstract

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Economic impact of hospitalization for end-stage liver disease. Author(s): Talwalkar JA. Source: The American Journal of Gastroenterology. 2002 June; 97(6): 1562; Author Reply 1562-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12094888&dopt=Abstract

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Editorial comment: liver disease in the HIV-infected patient--the courage to treat. Author(s): Dieterich DT. Source: Aids Read. 2003 October; 13(10): 500-1. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14596228&dopt=Abstract

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Effect of iron depletion in carbohydrate-intolerant patients with clinical evidence of nonalcoholic fatty liver disease. Author(s): Facchini FS, Hua NW, Stoohs RA. Source: Gastroenterology. 2002 April; 122(4): 931-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11910345&dopt=Abstract

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Effect of iron depletion in patients with nonalcoholic fatty liver disease without carbohydrate intolerance. Author(s): Valenti L, Fracanzani AL, Fargion S. Source: Gastroenterology. 2003 March; 124(3): 866; Author Reply 866-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12612935&dopt=Abstract

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Effect of liver disease and transplantation on urea synthesis in humans: relationship to acid-base status. Author(s): Shangraw RE, Jahoor F. Source: The American Journal of Physiology. 1999 May; 276(5 Pt 1): G1145-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10330005&dopt=Abstract

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Efficacy of granulocyte-macrophage colony-stimulating factor or lamivudine combination with recombinant interferon in non-responders to interferon in hepatitis B virus-related chronic liver disease patients. Author(s): Guptan RC, Thakur V, Kazim SN, Sarin SK. Source: Journal of Gastroenterology and Hepatology. 2002 July; 17(7): 765-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12121506&dopt=Abstract

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Efficacy of lamivudine therapy for advanced liver disease in patients with precore mutant hepatitis B virus infection awaiting liver transplantation. Author(s): Andreone P, Biselli M, Gramenzi A, Cursaro C, Morelli MC, Sama C, Lorenzini S, Spinucci G, Porzio F, Felline F, Di Giammarino L, Bernardi M. Source: Transplantation. 2002 October 27; 74(8): 1119-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12438957&dopt=Abstract

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Elevated AST or ALT to nonalcoholic fatty liver disease: accurate predictor of disease prevalence? Author(s): Yu AS, Keeffe EB. Source: The American Journal of Gastroenterology. 2003 May; 98(5): 955-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12809814&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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Elevated plasma and urine levels of ADMA and 15(S)-8-iso-PGF2alpha in end-stage liver disease. Author(s): Tsikas D, Rode I, Becker T, Nashan B, Klempnauer J, Frolich JC. Source: Hepatology (Baltimore, Md.). 2003 October; 38(4): 1063-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14512899&dopt=Abstract

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Elevation of serum cystatin C concentrations in patients with chronic liver disease. Author(s): Takeuchi M, Fukuda Y, Nakano I, Katano Y, Hayakawa T. Source: European Journal of Gastroenterology & Hepatology. 2001 August; 13(8): 951-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11507361&dopt=Abstract

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Endotoxin and its binding proteins in chronic liver disease: the effect of transjugular intrahepatic portosystemic shunting. Author(s): Kaser A, Ludwiczek O, Waldenberger P, Jaschke W, Vogel W, Tilg H. Source: Liver. 2002 October; 22(5): 380-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12390473&dopt=Abstract

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End-stage liver disease in HIV. Author(s): Wallace MR. Source: Current Gastroenterology Reports. 2001 August; 3(4): 284. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12953708&dopt=Abstract

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End-stage liver disease in persons with hemophilia and transfusion-associated infections. Author(s): Goedert JJ, Eyster ME, Lederman MM, Mandalaki T, De Moerloose P, White GC 2nd, Angiolillo AL, Luban NL, Sherman KE, Manco-Johnson M, Preiss L, Leissinger C, Kessler CM, Cohen AR, DiMichele D, Hilgartner MW, Aledort LM, Kroner BL, Rosenberg PS, Hatzakis A. Source: Blood. 2002 September 1; 100(5): 1584-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12176875&dopt=Abstract

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Enhanced immunogenicity of recombinant hepatitis B vaccine in exposed family contacts of chronic liver disease patients. Author(s): Thakur V, Guptan RC, Basir SF, Parvez MK, Sarin SK. Source: Scandinavian Journal of Infectious Diseases. 2001; 33(8): 618-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11525358&dopt=Abstract

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Enterococcus faecalis causing empyema in a patient with liver disease. Author(s): Behnia M, Clay AS, Hart CM. Source: Southern Medical Journal. 2002 October; 95(10): 1201-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12425509&dopt=Abstract

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Excess mortality from liver disease and other non-AIDS-related diseases among HIVinfected individuals in Italy. Author(s): Conti S, Masocco M, Pezzotti P, Toccaceli V, Vichi M, Crialesi R, Frova L, Rezza G. Source: Journal of Acquired Immune Deficiency Syndromes (1999). 2002 January 1; 29(1): 105-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11782600&dopt=Abstract

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Expression of GP73, a resident Golgi membrane protein, in viral and nonviral liver disease. Author(s): Kladney RD, Cui X, Bulla GA, Brunt EM, Fimmel CJ. Source: Hepatology (Baltimore, Md.). 2002 June; 35(6): 1431-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12029628&dopt=Abstract

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Expression of interferon alfa signaling components in human alcoholic liver disease. Author(s): Nguyen VA, Gao B. Source: Hepatology (Baltimore, Md.). 2002 February; 35(2): 425-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11826419&dopt=Abstract

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Factors influencing the prevalence of gallstones in liver disease: the beneficial and harmful influences of alcohol. Author(s): Buchner AM, Sonnenberg A. Source: The American Journal of Gastroenterology. 2002 April; 97(4): 905-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12003426&dopt=Abstract

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Famciclovir treatment in transplant recipients with HBV-related liver disease: disappointing results. Author(s): Berenguer M, Prieto M, Rayon M, Bustamante M, Carrasco D, Moya A, Pastor MA, Gobernado M, Mir J, Berenguer J. Source: The American Journal of Gastroenterology. 2001 February; 96(2): 526-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11232701&dopt=Abstract

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Familial association in autoimmune liver disease. Author(s): Findor JA, Sorda JA, Daruich JR, Manero EF. Source: Medicina (B Aires). 2002; 62(3): 241-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12150007&dopt=Abstract

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Fasting insulin and uric acid levels but not indices of iron metabolism are independent predictors of non-alcoholic fatty liver disease. A case-control study. Author(s): Lonardo A, Loria P, Leonardi F, Borsatti A, Neri P, Pulvirenti M, Verrone AM, Bagni A, Bertolotti M, Ganazzi D, Carulli N; POLI.ST.E.N.A. Study Group. Policentrica Steatosi Epatica Non Alcolica. Source: Dig Liver Dis. 2002 March; 34(3): 204-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11990393&dopt=Abstract

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Fatigue in cholestatic liver disease--a perplexing symptom. Author(s): Kumar D, Tandon RK. Source: Postgraduate Medical Journal. 2002 July; 78(921): 404-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12151655&dopt=Abstract

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Features of cell death in brain and liver, the target tissues of progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher disease). Author(s): Simonati A, Filosto M, Savio C, Tomelleri G, Tonin P, Dalla Bernardina B, Rizzuto N. Source: Acta Neuropathologica. 2003 July; 106(1): 57-65. Epub 2003 April 30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12721699&dopt=Abstract

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February 2000: Dementia with motor dysfunction in a patient with liver disease. Author(s): Spencer DC, Forno LS. Source: Brain Pathology (Zurich, Switzerland). 2000 April; 10(2): 315-6, 319. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10764052&dopt=Abstract

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Ferrochelatase gene mutations in erythropoietic protoporphyria: focus on liver disease. Author(s): Chen FP, Risheg H, Liu Y, Bloomer J. Source: Cell Mol Biol (Noisy-Le-Grand). 2002 February; 48(1): 83-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11929052&dopt=Abstract

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FIC1, a P-type ATPase linked to cholestatic liver disease, has homologues (ATP8B2 and ATP8B3) expressed throughout the body. Author(s): Harris MJ, Arias IM. Source: Biochimica Et Biophysica Acta. 2003 July 21; 1633(2): 127-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12880872&dopt=Abstract

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Financial burden of alcohol abuse in patients with alcoholic liver disease. Author(s): Singh H, Masih B, Satpathy SK, Duseja A, Chawla Y. Source: Trop Gastroenterol. 2001 July-September; 22(3): 172. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11681117&dopt=Abstract

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First report of a psychosocial intervention for patients with alcohol-related liver disease undergoing liver transplantation. Author(s): Georgiou G, Webb K, Griggs K, Copello A, Neuberger J, Day E. 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): 772-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12827568&dopt=Abstract

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Folate deficiency, methionine metabolism, and alcoholic liver disease. Author(s): Halsted CH, Villanueva JA, Devlin AM. Source: Alcohol (Fayetteville, N.Y.). 2002 July; 27(3): 169-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12163145&dopt=Abstract

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Foreword: the impact of liver disease in children. Author(s): Berk PD, Brownstein AP. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002; 35 Suppl 1: S1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12151811&dopt=Abstract

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Free radical mechanisms in immune reactions associated with alcoholic liver disease. Author(s): Albano E. Source: Free Radical Biology & Medicine. 2002 January 15; 32(2): 110-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11796198&dopt=Abstract

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Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease. Author(s): Charlton M, Kasparova P, Weston S, Lindor K, Maor-Kendler Y, Wiesner RH, Rosen CB, Batts KP. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2001 July; 7(7): 608-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11460228&dopt=Abstract

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Fulminant hepatic failure caused by diffuse intrasinusoidal metastatic liver disease: a case report. Author(s): Martelli O, Coppola L, De Quarto AL, Palma M, Sarmiento R, Foggi CM. Source: Tumori. 2000 September-October; 86(5): 424-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11130575&dopt=Abstract

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Fulminant hepatitis A in patients with chronic liver disease. Author(s): Lefilliatre P, Villeneuve JP. Source: Canadian Journal of Public Health. Revue Canadienne De Sante Publique. 2000 May-June; 91(3): 168-70. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10927841&dopt=Abstract

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Fulminant hepatitis in patients with chronic liver disease. Author(s): O'Grady JG. Source: Journal of Viral Hepatitis. 2000 May; 7 Suppl 1: 9-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10866838&dopt=Abstract

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Fulminant liver disease. Author(s): Schiodt FV, Lee WM. Source: Clinics in Liver Disease. 2003 May; 7(2): 331-49, Vi. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879987&dopt=Abstract

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Fungal colonization of the esophagus in alcoholic liver disease. Author(s): Peter Z, Zala J, Szabo O, Telegdy L, Horvath Z, Makara M, Schuller J. Source: Zeitschrift Fur Gastroenterologie. 2000 October; 38(10): 821-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11089265&dopt=Abstract

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GB virus C in patients with liver disease of unknown etiology. Author(s): Quiros E, Piedrola G, Maroto C. Source: Journal of Clinical Laboratory Analysis. 2000; 14(2): 70-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10683617&dopt=Abstract

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GB virus C/hepatitis G virus infection in patients investigated for chronic liver disease and in the general population in southern Sweden. Author(s): Bjorkman P, Widell A, Veress B, Verbaan H, Hoffmann G, Elmstahl S, Lindgren S. Source: Scandinavian Journal of Infectious Diseases. 2001; 33(8): 611-7. Erratum In: Scand J Infect Dis 2001; 33(10): 798. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11525357&dopt=Abstract

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Gene expression profiling of preneoplastic liver disease and liver cancer: a new era for improved early detection and treatment of these deadly diseases? Author(s): Kim JW, Wang XW. Source: Carcinogenesis. 2003 March; 24(3): 363-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12663493&dopt=Abstract

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Gene therapy and pediatric liver disease. Author(s): Soriano HE, Grompe M. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002; 35 Suppl 1: S51-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12151822&dopt=Abstract

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Gene therapy for malignant liver disease. Author(s): Mohr L, Geissler M, Blum HE. Source: Expert Opinion on Biological Therapy. 2002 February; 2(2): 163-75. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11849116&dopt=Abstract

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General medicine and surgery for dental practitioners. Part 5: liver disease. Author(s): Greenwood M, Meechan JG. Source: British Dental Journal. 2003 July 26; 195(2): 71-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12881742&dopt=Abstract

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Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease. Author(s): Vidali M, Stewart SF, Rolla R, Daly AK, Chen Y, Mottaran E, Jones DE, Leathart JB, Day CP, Albano E. Source: Hepatology (Baltimore, Md.). 2003 February; 37(2): 410-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12540792&dopt=Abstract

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Genetic and immunological characterization of fibrinogen inclusion bodies in patients with hepatic fibrinogen storage and liver disease. Author(s): Medicina D, Fabbretti G, Brennan SO, George PM, Kudryk B, Callea F. Source: Annals of the New York Academy of Sciences. 2001; 936: 522-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11460509&dopt=Abstract

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Genetic disorders and molecular mechanisms in cholestatic liver disease--a clinical approach. Author(s): Trauner M, Fickert P, Zollner G. Source: Semin Gastrointest Dis. 2001 April; 12(2): 66-88. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11352122&dopt=Abstract

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Genetic evaluation of the dysplasia-carcinoma sequence in chronic viral liver disease: a detailed analysis of two cases and a review of the literature. Author(s): van Dekken H, Wink J, Alers JC, de Man RA, IJzermans JN, Zondervan PE. Source: Acta Histochemica. 2003; 105(1): 29-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12666986&dopt=Abstract

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Genetic liver disease in adults. Early recognition of the three most common causes. Author(s): Morrison ED, Kowdley KV. Source: Postgraduate Medicine. 2000 February; 107(2): 147-52, 155, 158-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10689414&dopt=Abstract

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Genetic polymorphisms of cytochrome p4502E1 and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a white population: a study and literature review, including meta-analysis. Author(s): Wong NA, Rae F, Simpson KJ, Murray GD, Harrison DJ. Source: Molecular Pathology : Mp. 2000 April; 53(2): 88-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10889908&dopt=Abstract

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Genetic polymorphisms of interleukin-1beta in association with the development of alcoholic liver disease in Japanese patients. Author(s): Takamatsu M, Yamauchi M, Maezawa Y, Saito S, Maeyama S, Uchikoshi T. Source: The American Journal of Gastroenterology. 2000 May; 95(5): 1305-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10811344&dopt=Abstract

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Genotype of ethanol metabolizing enzyme genes by oligonucleotide microarray in alcoholic liver disease in Chinese people. Author(s): Yu C, Li Y, Chen W, Yue M. Source: Chinese Medical Journal. 2002 July; 115(7): 1085-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12173598&dopt=Abstract

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Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease. Author(s): Drenth JP, te Morsche RH, Smink R, Bonifacino JS, Jansen JB. Source: Nature Genetics. 2003 March; 33(3): 345-7. Epub 2003 February 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12577059&dopt=Abstract

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GH treatment in adults with chronic liver disease: a randomized, double-blind, placebo-controlled, cross-over study. Author(s): Wallace JD, Abbott-Johnson WJ, Crawford DH, Barnard R, Potter JM, Cuneo RC. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 June; 87(6): 2751-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12050245&dopt=Abstract

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Granulocyte colony-stimulating factor improves deficient in vitro neutrophil transendothelial migration in patients with advanced liver disease. Author(s): Fiuza C, Salcedo M, Clemente G, Tellado JM. Source: Clinical and Diagnostic Laboratory Immunology. 2002 March; 9(2): 433-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11874890&dopt=Abstract

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Growth hormone plasma levels in nonalcoholic fatty liver disease. Author(s): Lonardo A, Loria P, Leonardi F, Ganazzi D, Carulli N. Source: The American Journal of Gastroenterology. 2002 April; 97(4): 1071-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12003400&dopt=Abstract

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Guidelines on the management of osteoporosis associated with chronic liver disease. Author(s): Collier JD, Ninkovic M, Compston JE. Source: Gut. 2002 February; 50 Suppl 1: I1-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11788576&dopt=Abstract

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Guinea pig transglutaminase immunolinked assay does not predict coeliac disease in patients with chronic liver disease. Author(s): Carroccio A, Giannitrapani L, Soresi M, Not T, Iacono G, Di Rosa C, Panfili E, Notarbartolo A, Montalto G. Source: Gut. 2001 October; 49(4): 506-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11559647&dopt=Abstract

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H MR spectroscopy in the evaluation of the severity of chronic liver disease. Author(s): Lim AK, Hamilton G, Patel N, Bell JD, Taylor-Robinson SD. Source: Radiology. 2003 January; 226(1): 288-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12511705&dopt=Abstract

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Haemostatic abnormalities in patients with liver disease. Author(s): Lisman T, Leebeek FW, de Groot PG. Source: Journal of Hepatology. 2002 August; 37(2): 280-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12127437&dopt=Abstract

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HBV related chronic liver disease. Author(s): Poddar U, Thappa BR. Source: Indian Pediatrics. 2003 March; 40(3): 278; Author Reply 279-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12657775&dopt=Abstract

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Hemostatic modulation with the liver dialysis device in humans with advanced liver disease. Author(s): George MM, Van Thiel DH, Tarasuk G, Chejfec G, McClatchey KD, Hamdani R, Fareed J. Source: Hepatogastroenterology. 2002 September-October; 49(47): 1333-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12239938&dopt=Abstract

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Hepatic metallothionein in patients with chronic hepatitis C: relationship with severity of liver disease and response to treatment. Author(s): Carrera G, Paternain JL, Carrere N, Folch J, Courtade-Saidi M, Orfila C, Vinel JP, Alric L, Pipy B. Source: The American Journal of Gastroenterology. 2003 May; 98(5): 1142-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12809840&dopt=Abstract

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Hepatitis A vaccination in patients with chronic liver disease: to screen or not to screen? Author(s): Rothstein KD. Source: The American Journal of Gastroenterology. 2002 July; 97(7): 1590-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12135006&dopt=Abstract

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Hepatitis B and C single and co-infection in chronic liver disease and their effect on the disease pattern. Author(s): Bukhtiari N, Hussain T, Iqbal M, Malik AM, Qureshi AH, Hussain A. Source: J Pak Med Assoc. 2003 April; 53(4): 136-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12776896&dopt=Abstract

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Hepatitis c and cirrhotic liver disease in the Nile delta of Egypt: a community-based study. Author(s): Darwish MA, Faris R, Darwish N, Shouman A, Gadallah M, El-Sharkawy MS, Edelman R, Grumbach K, Rao MR, Clemens JD. Source: The American Journal of Tropical Medicine and Hygiene. 2001 March-April; 64(3-4): 147-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11442209&dopt=Abstract

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Hepatitis C seropositivity among chronic liver disease patients in Hazara, Pakistan. Author(s): Khan TS, Rizvi F, Rashid A. Source: J Ayub Med Coll Abbottabad. 2003 April-June; 15(2): 53-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14552251&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 E virus superinfection in patients with chronic liver disease. Author(s): Hamid SS, Atiq M, Shehzad F, Yasmeen A, Nissa T, Salam A, Siddiqui A, Jafri W. Source: Hepatology (Baltimore, Md.). 2002 August; 36(2): 474-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12143058&dopt=Abstract

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Herpes simplex esophagitis in patients with liver disease. Author(s): Pauwels A, Carbonell N, Galula G, Mohand-Mamar D, Maury E, de LajartheThirouard AS, Levy VG, Poupon R. Source: Digestive Diseases and Sciences. 2002 October; 47(10): 2189-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12395891&dopt=Abstract

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High expression of MDR1, MRP1, and MRP3 in the hepatic progenitor cell compartment and hepatocytes in severe human liver disease. Author(s): Ros JE, Libbrecht L, Geuken M, Jansen PL, Roskams TA. Source: The Journal of Pathology. 2003 August; 200(5): 553-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12898590&dopt=Abstract

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High rate of positive anti-tissue transglutaminase antibodies in chronic liver disease. Role of liver decompensation and of the antigen source. Author(s): Vecchi M, Folli C, Donato MF, Formenti S, Arosio E, de Franchis R. Source: Scandinavian Journal of Gastroenterology. 2003 January; 38(1): 50-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12608464&dopt=Abstract

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High TT virus load as an independent factor associated with the occurrence of hepatocellular carcinoma among patients with hepatitis C virus-related chronic liver disease. Author(s): Tokita H, Murai S, Kamitsukasa H, Yagura M, Harada H, Takahashi M, Okamoto H. Source: Journal of Medical Virology. 2002 August; 67(4): 501-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12115995&dopt=Abstract

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Histological improvement of chronic liver disease after spontaneous serum hepatitis C virus clearance. Author(s): Sugiyasu Y, Yuki N, Nagaoka T, Yamashiro M, Kawahara K, Iyoda K, Kakiuchi Y, Kaneko A, Yamamoto K, Hikiji K, Kato M. Source: Journal of Medical Virology. 2003 January; 69(1): 41-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12436476&dopt=Abstract

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History of hepatitis and liver disease in Indonesia. Author(s): Noer HM. Source: Journal of Gastroenterology and Hepatology. 2002 December; 17 Suppl: S508-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12534790&dopt=Abstract

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Human herpesvirus-6 has no apparent influence on course of HCV hepatitis, but may complicate HBV hepatitis and alcoholic liver disease. A pilot study. Author(s): Rojo J, Simoes P, Krueger GR, Humberto CO, Ramon AM. Source: In Vivo. 2003 January-February; 17(1): 29-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12655786&dopt=Abstract

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Hyperamylasemia after hepatectomy in chronic liver disease patients. Author(s): Hotta T, Kobayashi Y, Taniguchi K, Johata K, Sahara M, Watanabe T, Tanimura H. Source: Hepatogastroenterology. 2003 July-August; 50(52): 1060-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12845982&dopt=Abstract

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Hypercarcinogenic state in chronic liver disease. Author(s): Umeda T, Hino O. Source: Intern Med. 2001 July; 40(7): 555-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11506289&dopt=Abstract

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Imaging of diffuse liver disease. Author(s): Mortele KJ, Ros PR. Source: Seminars in Liver Disease. 2001 May; 21(2): 195-212. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11436572&dopt=Abstract

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Immune-mediated drug-induced liver disease. Author(s): Liu ZX, Kaplowitz N. Source: Clinics in Liver Disease. 2002 August; 6(3): 467-86. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12362579&dopt=Abstract

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Immunohistochemical evidence of lactoferrin in hepatic biopsies of patients with viral or cryptogenetic chronic liver disease. Author(s): Tuccari G, Villari D, Giuffre G, Simone A, Squadrito G, Raimondo G, Barresi G. Source: Histology and Histopathology. 2002 October; 17(4): 1077-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12371135&dopt=Abstract

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Impact of oestrogens on the progression of liver disease. Author(s): Shimizu I. Source: Liver International : Official Journal of the International Association for the Study of the Liver. 2003 February; 23(1): 63-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640729&dopt=Abstract

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Improvement of alanine aminotransferase by administration of suplatast tosilate plus ursodeoxycholic acid in patients with resistance to ursodeoxycholic acid monotherapy on hepatitis C virus-related chronic liver disease. Author(s): Matsuda Y, Inada M, Maeda H, Matsuyama T. Source: Intern Med. 2002 October; 41(10): 774-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12412994&dopt=Abstract

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Inappropriate ileal conservation of bile acids in cholestatic liver disease: homeostasis gone awry. Author(s): Hofmann AF. Source: Gut. 2003 September; 52(9): 1239-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12912852&dopt=Abstract

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Incidence and prevalence of coccidioidomycosis in patients with end-stage liver disease. Author(s): Blair JE, Balan V, Douglas DD, Hentz JG. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2003 August; 9(8): 843-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12884198&dopt=Abstract

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Increased expression of T cell chemokines and their receptors in chronic hepatitis C: relationship with the histological activity of liver disease. Author(s): Apolinario A, Majano PL, Alvarez-Perez E, Saez A, Lozano C, Vargas J, Garcia-Monzon C. Source: The American Journal of Gastroenterology. 2002 November; 97(11): 2861-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12425561&dopt=Abstract

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Increased susceptibility to nonalcoholic fatty liver disease in heterozygotes for the mutation responsible for hereditary hemochromatosis. Author(s): Valenti L, Dongiovanni P, Fracanzani AL, Santorelli G, Fatta E, Bertelli C, Taioli E, Fiorelli G, Fargion S. Source: Dig Liver Dis. 2003 March; 35(3): 172-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12779071&dopt=Abstract

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Influence of age and autoimmunity on liver disease in HCV-associated type II mixed cryoglobulinemia. Author(s): De Rosa FG, Pucillo LP, Coviello R, Pirro MR, Fiaschetti P, Candela M, Gabrielli A, Lagana B, Fiorilli M, Casato M. Source: Human Immunology. 2002 September; 63(9): 751-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12175729&dopt=Abstract

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Influence of hepatitis B virus genotypes on the development of preS deletions and advanced liver disease. Author(s): Sugauchi F, Ohno T, Orito E, Sakugawa H, Ichida T, Komatsu M, Kuramitsu T, Ueda R, Miyakawa Y, Mizokami M. Source: Journal of Medical Virology. 2003 August; 70(4): 537-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12794715&dopt=Abstract

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Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Author(s): Sumi H, Yokosuka O, Seki N, Arai M, Imazeki F, Kurihara T, Kanda T, Fukai K, Kato M, Saisho H. Source: Hepatology (Baltimore, Md.). 2003 January; 37(1): 19-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12500184&dopt=Abstract

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Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for end-stage alcoholic liver disease. Author(s): Tome S, Martinez-Rey C, Gonzalez-Quintela A, Gude F, Brage A, Otero E, Abdulkader I, Forteza J, Bustamante M, Varo E. Source: Journal of Hepatology. 2002 June; 36(6): 793-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12044530&dopt=Abstract

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Influence of the spleen on portal haemodynamics: a non-invasive study with Doppler ultrasound in chronic liver disease and haematological disorders. Author(s): Piscaglia F, Donati G, Cecilioni L, Celli N, Stagni B, Pini P, Gaiani S, Gherlinzoni F, Bolondi L. Source: Scandinavian Journal of Gastroenterology. 2002 October; 37(10): 1220-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12408529&dopt=Abstract

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Influence of TNF gene polymorphism and HLA-DRB1 haplotype in Japanese patients with chronic liver disease caused by HCV. Author(s): Tokushige K, Tsuchiya N, Hasegawa K, Hashimoto E, Yamauchi K, Komatsu T, Hayashi N. Source: The American Journal of Gastroenterology. 2003 January; 98(1): 160-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12526952&dopt=Abstract

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Insights into SEN virus prevalence, transmission, and treatment in community-based persons and patients with liver disease referred to a liver disease unit. Author(s): Wong SG, Primi D, Kojima H, Sottini A, Giulivi A, Zhang M, Uhanova J, Minuk GY. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2002 October 1; 35(7): 789-95. Epub 2002 September 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12228814&dopt=Abstract

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Interaction of non-alcoholic fatty liver disease with other liver diseases. Author(s): Clouston AD, Powell EE. Source: Best Practice & Research. Clinical Gastroenterology. 2002 October; 16(5): 767-81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12406444&dopt=Abstract

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Interactions of ethanol and folate deficiency in development of alcoholic liver disease in the micropig. Author(s): Halsted CH, Villanueva JA, Devlin AM, James SJ. Source: Trans Am Clin Climatol Assoc. 2002; 113: 151-62; Discussion 162-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12053707&dopt=Abstract

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Investigational pharmacologic treatment for liver disease. Author(s): Siatkosky LL, Shermock KM, Younossi ZM. Source: Expert Opinion on Investigational Drugs. 2002 September; 11(9): 1281-93. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12225249&dopt=Abstract

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Is liver disease an octreotide side effect? Author(s): Uygur-Bayramicli O, Gemici C. Source: Journal of Clinical Gastroenterology. 2003 July; 37(1): 86-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12811219&dopt=Abstract

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Jeune syndrome and liver disease: report of three cases treated with ursodeoxycholic acid. Author(s): Labrune P, Fabre M, Trioche P, Estournet-Mathiaud B, Grangeponte MC, Rambaud C, Maurage C, Bernard O. Source: American Journal of Medical Genetics. 1999 December 3; 87(4): 324-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10588838&dopt=Abstract

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Kayser-Fleischer like rings in alcoholic liver disease: a case report. Author(s): Williams EJ, Gleeson D, Burton JL, Stephenson TJ. Source: European Journal of Gastroenterology & Hepatology. 2003 January; 15(1): 91-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544701&dopt=Abstract

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Keratin 8 and 18 mutations are risk factors for developing liver disease of multiple etiologies. Author(s): Ku NO, Darling JM, Krams SM, Esquivel CO, Keeffe EB, Sibley RK, Lee YM, Wright TL, Omary MB. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 May 13; 100(10): 6063-8. Epub 2003 April 30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12724528&dopt=Abstract

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Keratin 8 mutations in patients with cryptogenic liver disease. Author(s): Ku NO, Gish R, Wright TL, Omary MB. Source: The New England Journal of Medicine. 2001 May 24; 344(21): 1580-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11372009&dopt=Abstract

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Laparoscopic liver resection for subcapsular hepatocellular carcinoma complicating chronic liver disease. Author(s): Laurent A, Cherqui D, Lesurtel M, Brunetti F, Tayar C, Fagniez PL. Source: Archives of Surgery (Chicago, Ill. : 1960). 2003 July; 138(7): 763-9; Discussion 769. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12860758&dopt=Abstract

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Laparoscopic treatment of simple hepatic cysts and polycystic liver disease. Author(s): Fiamingo P, Tedeschi U, Veroux M, Cillo U, Brolese A, Da Rold A, Madia C, Zanus G, D'Amico DF. Source: Surgical Endoscopy. 2003 April; 17(4): 623-6. Epub 2003 February 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12574922&dopt=Abstract

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Liv.52 in alcoholic liver disease: a prospective, controlled trial. Author(s): de Silva HA, Saparamadu PA, Thabrew MI, Pathmeswaran A, Fonseka MM, de Silva HJ. Source: Journal of Ethnopharmacology. 2003 January; 84(1): 47-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12499076&dopt=Abstract

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Liver abscesses due to Fusobacterium spp that mimick malignant metastatic liver disease. Author(s): Athavale NV, Leitch DG, Cowling P. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2002 December; 21(12): 884-6. Epub 2002 December 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12525925&dopt=Abstract

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Liver disease and HIV. Hepatitis is an ongoing threat. Author(s): Johnson D, Cohen S, Bonacini M. Source: Adv Nurse Pract. 2003 June; 11(6): 63-6, 68, 70. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807059&dopt=Abstract

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Liver disease caused by failure to racemize trihydroxycholestanoic acid: gene mutation and effect of bile acid therapy. Author(s): Setchell KD, Heubi JE, Bove KE, O'Connell NC, Brewsaugh T, Steinberg SJ, Moser A, Squires RH Jr. Source: Gastroenterology. 2003 January; 124(1): 217-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12512044&dopt=Abstract

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Liver disease history in India. Author(s): Tandon BN. Source: Journal of Gastroenterology and Hepatology. 2002 December; 17 Suppl: S504-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12534788&dopt=Abstract

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Liver disease in hereditary hemorrhagic telangiectasia. Author(s): Larson AM. Source: Journal of Clinical Gastroenterology. 2003 February; 36(2): 149-58. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544200&dopt=Abstract

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Liver microbubble transit time compared with histology and Child-Pugh score in diffuse liver disease: a cross sectional study. Author(s): Blomley MJ, Lim AK, Harvey CJ, Patel N, Eckersley RJ, Basilico R, Heckemann R, Urbank A, Cosgrove DO, Taylor-Robinson SD. Source: Gut. 2003 August; 52(8): 1188-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865280&dopt=Abstract

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Liver transplantation for polycystic liver disease--indications and outcome. Author(s): Gustafsson BI, Friman S, Mjornstedt L, Olausson M, Backman L. Source: Transplantation Proceedings. 2003 March; 35(2): 813-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12644149&dopt=Abstract

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Living related liver transplantation for polycystic liver disease. Author(s): Koyama I, Fuchinoue S, Urashima Y, Kato Y, Tsuji K, Kawase T, Murakami T, Tojimbara T, Nakajima I, Teraoka S. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 2002 November; 15(11): 578-80. Epub 2002 September 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12461664&dopt=Abstract

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Management of umbilical hernia in patients with advanced liver disease. Author(s): McAlister V. 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): 623-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783406&dopt=Abstract

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Managing antiretroviral-associated liver disease. Author(s): Dieterich D. Source: Journal of Acquired Immune Deficiency Syndromes (1999). 2003 September; 34 Suppl 1: S34-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14562856&dopt=Abstract

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Metabolic liver disease in the young adult. Author(s): Mailliard ME, Gollan JL. Source: Best Practice & Research. Clinical Gastroenterology. 2003 April; 17(2): 307-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12676121&dopt=Abstract

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Metformin-associated lactic acidosis in a patient with liver disease. Author(s): Edwards CM, Barton MA, Snook J, David M, Mak VH, Chowdhury TA. Source: Qjm : Monthly Journal of the Association of Physicians. 2003 April; 96(4): 315-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12651978&dopt=Abstract

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Model for End-Stage Liver Disease score does not predict patient or graft survival in living donor liver transplant recipients. Author(s): Hayashi PH, Forman L, Steinberg T, Bak T, Wachs M, Kugelmas M, Everson GT, Kam I, Trotter JF. 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): 737-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12827562&dopt=Abstract

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Modifier genes and cystic fibrosis liver disease. Author(s): Pirzada O, Taylor C. Source: Hepatology (Baltimore, Md.). 2003 March; 37(3): 714; Author Reply 714. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12601371&dopt=Abstract

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Molecular epidemiology and transmission of hepatitis B virus in close family contacts of HBV-related chronic liver disease patients. Author(s): Thakur V, Kazim SN, Guptan RC, Malhotra V, Sarin SK. Source: Journal of Medical Virology. 2003 August; 70(4): 520-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12794713&dopt=Abstract

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Molecular genetics of 3beta-hydroxy-Delta5-C27-steroid oxidoreductase deficiency in 16 patients with loss of bile acid synthesis and liver disease. Author(s): Cheng JB, Jacquemin E, Gerhardt M, Nazer H, Cresteil D, Heubi JE, Setchell KD, Russell DW. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 April; 88(4): 183341. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12679481&dopt=Abstract

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Mortality due to hepatitis C-related liver disease in HIV-infected patients in France (Mortavic 2001 study). Author(s): Rosenthal E, Poiree M, Pradier C, Perronne C, Salmon-Ceron D, Geffray L, Myers RP, Morlat P, Pialoux G, Pol S, Cacoub P; GERMIVIC Joint Study Group. Source: Aids (London, England). 2003 August 15; 17(12): 1803-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891066&dopt=Abstract

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MR imaging of diffuse liver disease. Author(s): Danet IM, Semelka RC, Braga L. Source: Radiologic Clinics of North America. 2003 January; 41(1): 67-87. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12630686&dopt=Abstract

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Neonatal liver disease associated with placental transfer of anti-mitochondrial antibodies. Author(s): Hannam S, Bogdanos DP, Davies ET, Hussain MJ, Portmann BC, MieliVergani G, Vergani D. Source: Autoimmunity. 2002 December; 35(8): 545-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765481&dopt=Abstract

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New North American research network focuses on biliary atresia and neonatal liver disease. Author(s): Sokol RJ. Source: Journal of Pediatric Gastroenterology and Nutrition. 2003 January; 36(1): 1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12537011&dopt=Abstract

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Nonalcoholic fatty liver disease (NAFLD)--two decades later: are we smarter about its natural history? Author(s): Ong JP, Younossi ZM. Source: The American Journal of Gastroenterology. 2003 September; 98(9): 1915-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14499766&dopt=Abstract

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Nonalcoholic fatty liver disease in patients investigated for elevated liver enzymes. Author(s): Kichian K, McLean R, Gramlich LM, Bailey RJ, Bain VG. Source: Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. 2003 January; 17(1): 38-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12560853&dopt=Abstract

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Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome. Author(s): Sanyal AJ, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Stravitz RT, Mills AS. Source: The American Journal of Gastroenterology. 2003 September; 98(9): 2064-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14499789&dopt=Abstract

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Nonalcoholic Fatty liver disease. Author(s): Jorgensen RA. Source: Gastroenterology Nursing : the Official Journal of the Society of Gastroenterology Nurses and Associates. 2003 July-August; 26(4): 150-4; Quiz 154-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12920429&dopt=Abstract

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Non-alcoholic fatty liver disease: an overview. Author(s): Mulhall BP, Ong JP, Younossi ZM. Source: Journal of Gastroenterology and Hepatology. 2002 November; 17(11): 1136-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453271&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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Non-alcoholic fatty liver disease: treatment options based on pathogenic considerations. Author(s): Oneta CM, Dufour JF. Source: Swiss Medical Weekly : Official Journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology. 2002 September 7; 132(35-36): 493-505. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12506331&dopt=Abstract

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Nutritional deficiencies in German middle-class male alcohol consumers: relation to dietary intake and severity of liver disease. Author(s): Bergheim I, Parlesak A, Dierks C, Bode JC, Bode C. Source: European Journal of Clinical Nutrition. 2003 March; 57(3): 431-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12627180&dopt=Abstract

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Obesity and liver disease. Author(s): Scheen AJ, Luyckx FH. Source: Best Practice & Research. Clinical Endocrinology & Metabolism. 2002 December; 16(4): 703-16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12468416&dopt=Abstract

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Organ allocation: model for end-stage liver disease, Child-Turcotte-Pugh, Mayo risk score, or something else. Author(s): Botero RC, Lucey MR. Source: Clinics in Liver Disease. 2003 August; 7(3): 715-27, Ix. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14509535&dopt=Abstract

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Organ and non-organ specific autoantibody titres and IgG levels as markers of disease activity: a longitudinal study in childhood autoimmune liver disease. Author(s): Gregorio GV, McFarlane B, Bracken P, Vergani D, Mieli-Vergani G. Source: Autoimmunity. 2002 December; 35(8): 515-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765477&dopt=Abstract

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Orthotopic liver transplantation in patients with human immunodeficiency virus and end-stage liver disease. Author(s): Neff GW, Bonham A, Tzakis AG, Ragni M, Jayaweera D, Schiff ER, Shakil O, Fung JJ. 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): 239-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12619020&dopt=Abstract

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Osteoporosis and liver disease: additional reasons for coeliac disease screening. Author(s): Marignani M, Angeletti S, Morini S. Source: Gut. 2003 March; 52(3): 452. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12584234&dopt=Abstract

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Other disease associations with non-alcoholic fatty liver disease (NAFLD). Author(s): Allard JP. Source: Best Practice & Research. Clinical Gastroenterology. 2002 October; 16(5): 783-95. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12406445&dopt=Abstract

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Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Author(s): MacBride Emerick K. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002 July; 35(1): 103-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12152623&dopt=Abstract

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Outcome of pregnancy with severe liver disease. Author(s): Shah S. Source: Indian J Gastroenterol. 2002 July-August; 21(4): 170. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12385564&dopt=Abstract

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Oxidants and antioxidants in alcohol-induced liver disease. Author(s): Arteel GE. Source: Gastroenterology. 2003 March; 124(3): 778-90. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12612915&dopt=Abstract

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Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Author(s): Roskams T, Yang SQ, Koteish A, Durnez A, DeVos R, Huang X, Achten R, Verslype C, Diehl AM. Source: American Journal of Pathology. 2003 October; 163(4): 1301-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14507639&dopt=Abstract

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Pathologic spectrum and prognostic significance of underlying liver disease in hepatocellular carcinoma. Author(s): Mino M, Lauwers GY. Source: Surg Oncol Clin N Am. 2003 January; 12(1): 13-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12735126&dopt=Abstract

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Pathological significance of oxidative cellular damage in human alcoholic liver disease. Author(s): Seki S, Kitada T, Sakaguchi H, Nakatani K, Wakasa K. Source: Histopathology. 2003 April; 42(4): 365-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12653948&dopt=Abstract

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Phagocytosis and production of reactive oxygen species by peripheral blood phagocytes in patients with different stages of alcohol-induced liver disease: effect of acute exposure to low ethanol concentrations. Author(s): Parlesak A, Schafer C, Paulus SB, Hammes S, Diedrich JP, Bode C. Source: Alcoholism, Clinical and Experimental Research. 2003 March; 27(3): 503-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12658117&dopt=Abstract

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Plasma P-selectin levels are elevated in patients with chronic liver disease. Author(s): Tacke F, Schoffski P, Trautwein C, Luedde T, Ganser A, Manns MP, von Depka M. Source: Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis. 2003 June; 14(4): 319-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12945872&dopt=Abstract

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Portal lymphocytic infiltrate in alcoholic liver disease. Author(s): Colombat M, Charlotte F, Ratziu V, Poynard T. Source: Human Pathology. 2002 December; 33(12): 1170-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12514784&dopt=Abstract

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Pregnancy and liver disease. Author(s): Sandhu BS, Sanyal AJ. Source: Gastroenterology Clinics of North America. 2003 March; 32(1): 407-36, Ix. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12635424&dopt=Abstract

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Preoperative right portal vein embolization in patients with metastatic liver disease. Metastatic liver volumes after RPVE. Author(s): Barbaro B, Di Stasi C, Nuzzo G, Vellone M, Giuliante F, Marano P. Source: Acta Radiologica (Stockholm, Sweden : 1987). 2003 January; 44(1): 98-102. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12631007&dopt=Abstract

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Prevalence and genomic variability of transfusion transmitted virus in Italian cryptogenic chronic liver disease and healthy blood donors. Author(s): Artini M, Cariani E, Almerighi C, Fulco M, Rossini A, Pietropaolo L, Stivali G, Montalto G, Caratozzolo M, Girelli G, Grimali E, Costanzo A, Levrero M, Balsano C. Source: Dig Liver Dis. 2002 August; 34(8): 570-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12502213&dopt=Abstract

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Prevalence of hepatitis B infection within family contacts of chronic liver disease patients--does HBeAg positivity really matter? Author(s): Thakur V, Guptan RC, Malhotra V, Basir SF, Sarin SK. Source: J Assoc Physicians India. 2002 November; 50: 1386-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12583467&dopt=Abstract

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Prolylhydroxylase and procollagen type III in long-term survivors of acute lymphoblastic leukemia (ALL): a biochemical approach to HCV-related liver disease. Author(s): Leonardi S, La Spina M, La Rosa M, Schiliro G. Source: Medical and Pediatric Oncology. 2003 July; 41(1): 17-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12764737&dopt=Abstract

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Quality of life after liver transplantation for alcoholic liver disease. Author(s): Pereira SP, Howard LM, Muiesan P, Rela M, Heaton N, Williams R. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2000 November; 6(6): 762-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11084065&dopt=Abstract

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Quality of life assessment in chronic liver disease. Author(s): Cirrincione R, Taliani G, Caporaso N, Mele A. Source: Hepatogastroenterology. 2002 May-June; 49(45): 813-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12063997&dopt=Abstract

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Quality of life before and after liver transplantation for cholestatic liver disease. Author(s): Gross CR, Malinchoc M, Kim WR, Evans RW, Wiesner RH, Petz JL, Crippin JS, Klintmalm GB, Levy MF, Ricci P, Therneau TM, Dickson ER. Source: Hepatology (Baltimore, Md.). 1999 February; 29(2): 356-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9918910&dopt=Abstract

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Quantitative analysis and in situ localization of human telomerase RNA in chronic liver disease and hepatocellular carcinoma. Author(s): Ogami M, Ikura Y, Nishiguchi S, Kuroki T, Ueda M, Sakurai M. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 1999 January; 79(1): 15-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9952107&dopt=Abstract

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Quantitative analysis of transforming growth factor beta 1 mRNA in patients with alcoholic liver disease. Author(s): Chen WX, Li YM, Yu CH, Cai WM, Zheng M, Chen F. Source: World Journal of Gastroenterology : Wjg. 2002 April; 8(2): 379-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11925630&dopt=Abstract

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Quantitative estimation of attenuation in ultrasound video images: correlation with histology in diffuse liver disease. Author(s): Graif M, Yanuka M, Baraz M, Blank A, Moshkovitz M, Kessler A, Gilat T, Weiss J, Walach E, Amazeen P, Irving CS. Source: Investigative Radiology. 2000 May; 35(5): 319-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10803673&dopt=Abstract

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Radiation-induced liver disease after three-dimensional conformal radiotherapy for patients with hepatocellular carcinoma: dosimetric analysis and implication. Author(s): Cheng JC, Wu JK, Huang CM, Liu HS, Huang DY, Cheng SH, Tsai SY, Jian JJ, Lin YM, Cheng TI, Horng CF, Huang AT. Source: International Journal of Radiation Oncology, Biology, Physics. 2002 September 1; 54(1): 156-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12182986&dopt=Abstract

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Relations between oxidative stress, hepatocyte growth factor, and liver disease in hemodialysis patients. Author(s): Borawski J, Pawlak K, Naumnik B, Mysliwiec M. Source: Renal Failure. 2002 November; 24(6): 825-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12472204&dopt=Abstract

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Relationship of the model for end-stage liver disease (MELD) scale to hepatic encephalopathy, as defined by electroencephalography and neuropsychometric testing, and ascites. Author(s): Yoo HY, Edwin D, Thuluvath PJ. Source: The American Journal of Gastroenterology. 2003 June; 98(6): 1395-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818287&dopt=Abstract

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Respective roles of porto-septal fibrosis and centrilobular fibrosis in alcoholic liver disease. Author(s): Michalak S, Rousselet MC, Bedossa P, Pilette C, Chappard D, Oberti F, Gallois Y, Cales P. Source: The Journal of Pathology. 2003 September; 201(1): 55-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12950017&dopt=Abstract

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Review article: Non-alcoholic fatty liver disease. Author(s): Alba LM, Lindor K. Source: Alimentary Pharmacology & Therapeutics. 2003 Apr15; 17(8): 977-86. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12694079&dopt=Abstract

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Review article: Nutritional therapy in alcoholic liver disease. Author(s): Stickel F, Hoehn B, Schuppan D, Seitz HK. Source: Alimentary Pharmacology & Therapeutics. 2003 August 15; 18(4): 357-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12940921&dopt=Abstract

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Risk factors for the development of cystic fibrosis related liver disease. Author(s): Slieker MG, Deckers-Kocken JM, Uiterwaal CS, van der Ent CK, Houwen RH. Source: Hepatology (Baltimore, Md.). 2003 September; 38(3): 775-6; Author Reply 776-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12939606&dopt=Abstract

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Role of fresh frozen plasma infusion in correction of coagulopathy of chronic liver disease: a dual phase study. Author(s): Youssef WI, Salazar F, Dasarathy S, Beddow T, Mullen KD. Source: The American Journal of Gastroenterology. 2003 June; 98(6): 1391-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818286&dopt=Abstract

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Role of hepatitis C infection in chronic liver disease in Egypt. Author(s): Strickland GT, Elhefni H, Salman T, Waked I, Abdel-Hamid M, Mikhail NN, Esmat G, Fix A. Source: The American Journal of Tropical Medicine and Hygiene. 2002 October; 67(4): 436-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12452500&dopt=Abstract

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Role of S-adenosyl-L-methionine in the treatment of alcoholic liver disease: introduction and summary of the symposium. Author(s): Purohit V, Russo D. Source: Alcohol (Fayetteville, N.Y.). 2002 July; 27(3): 151-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12163142&dopt=Abstract

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Screening for celiac disease in patients with chronic liver disease. Author(s): Carroccio A, Soresi M, Di Prima L, Montalto G. Source: Gastroenterology. 2003 October; 125(4): 1289; Author Reply 1289-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14552324&dopt=Abstract

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Secondary osteoporosis in liver transplant recipients: a longitudinal study in patients with and without cholestatic liver disease. Author(s): Bjoro K, Brandsaeter B, Wiencke K, Bjoro T, Godang K, Bollerslev J, Schrumpf E. Source: Scandinavian Journal of Gastroenterology. 2003 March; 38(3): 320-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12737449&dopt=Abstract

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Selective approach to major hepatic resection for hepatocellular carcinoma in chronic liver disease. Author(s): Kianmanesh R, Regimbeau JM, Belghiti J. Source: Surg Oncol Clin N Am. 2003 January; 12(1): 51-63. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12735129&dopt=Abstract

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SEN virus infection in patients with chronic liver disease and hepatocellular carcinoma in Thailand. Author(s): Tangkijvanich P, Theamboonlers A, Sriponthong M, Thong-Ngam D, Kullavanijaya P, Poovorawan Y. Source: Journal of Gastroenterology. 2003; 38(2): 142-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12640527&dopt=Abstract

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Seroprevalence of hepatitis A virus antibody in patients with chronic liver disease-experience from a tertiary care hospital in north India. Author(s): Dhotial A, Kapoor D, Kumar N. Source: Trop Gastroenterol. 2002 October-December; 23(4): 170-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12833702&dopt=Abstract

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Serum hyaluronate correlates with histological progression in alcoholic liver disease. Author(s): Stickel F, Poeschl G, Schuppan D, Conradt C, Strenge-Hesse A, Fuchs FS, Hofmann WJ, Seitz HK. Source: European Journal of Gastroenterology & Hepatology. 2003 September; 15(9): 945-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12923365&dopt=Abstract

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Significance of thymidine phosphorylase in HCC with chronic liver disease for longterm postoperative recurrence. Author(s): Ezaki T, Ikegami T, Ishida T, Aimitsu S, Mori M, Fujihara M. Source: Journal of Surgical Oncology. 2003 July; 83(3): 173-9; Discussion 179. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12827687&dopt=Abstract

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SMART amplification maintains representation of relative gene expression: quantitative validation by real time PCR and application to studies of alcoholic liver disease in primates. Author(s): Seth D, Gorrell MD, McGuinness PH, Leo MA, Lieber CS, McCaughan GW, Haber PS. Source: Journal of Biochemical and Biophysical Methods. 2003 January 31; 55(1): 53-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559588&dopt=Abstract

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Split-liver transplantation eliminates the need for living-donor liver transplantation in children with end-stage cholestatic liver disease. Author(s): Gridelli B, Spada M, Petz W, Bertani A, Lucianetti A, Colledan M, Altobelli M, Alberti D, Guizzetti M, Riva S, Melzi ML, Stroppa P, Torre G. Source: Transplantation. 2003 April 27; 75(8): 1197-203. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12717203&dopt=Abstract

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Surgery in the patient with liver disease. Author(s): Rizvon MK, Chou CL. Source: The Medical Clinics of North America. 2003 January; 87(1): 211-27. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12575891&dopt=Abstract

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The 1-year and 3-month prognostic utility of the AST/ALT ratio and model for endstage liver disease score in patients with viral liver cirrhosis. Author(s): Giannini E, Botta F, Testa E, Romagnoli P, Polegato S, Malfatti F, Fumagalli A, Chiarbonello B, Risso D, Testa R. Source: The American Journal of Gastroenterology. 2002 November; 97(11): 2855-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12425560&dopt=Abstract

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The choice of inhalation anaesthetic for major abdominal surgery in children with liver disease. Author(s): Green DW, Ashley EM. Source: Paediatric Anaesthesia. 2002 October; 12(8): 665-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12472701&dopt=Abstract

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The epidemiology of liver disease in Tayside database: a population-based recordlinkage study. Author(s): Steinke DT, Weston TL, Morris AD, MacDonald TM, Dillon JF. Source: Journal of Biomedical Informatics. 2002 June; 35(3): 186-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669982&dopt=Abstract

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The management of alcoholic liver disease. Author(s): Stewart SF, Day CP. Source: Journal of Hepatology. 2003; 38 Suppl 1: S2-13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591182&dopt=Abstract

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The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Author(s): Harrison SA, Torgerson S, Hayashi PH. Source: The American Journal of Gastroenterology. 2003 September; 98(9): 2042-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14499785&dopt=Abstract

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The rational use of potentially hepatotoxic medications in patients with underlying liver disease. Author(s): Lewis JH. Source: Expert Opinion on Drug Safety. 2002 July; 1(2): 159-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904150&dopt=Abstract

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The role of HBeAg seroconversion in acute exacerbation of liver disease with termination of hepatitis B and D virus infection in a chronic hepatitis D patient during alpha-interferon therapy. Author(s): Yalcin K, Degertekin H, Yurdaydin C, Bozdayi M, Bozkaya H. Source: European Journal of Gastroenterology & Hepatology. 2003 July; 15(7): 819-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12811314&dopt=Abstract

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The role of polymorphism in manganese superoxide dismutase in susceptibility to alcoholic liver disease. Author(s): Brind A, Fryer A, Hurlstone A, Fisher N, Pirmohamed M. Source: Gastroenterology. 2003 June; 124(7): 2000-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12812194&dopt=Abstract

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Tissue factor and thrombomodulin in hemodialysis patients: associations with endothelial injury, liver disease, and erythropoietin therapy. Author(s): Borawski J, Naumnik B, Mysliwiec M. Source: Clinical and Applied Thrombosis/Hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2002 October; 8(4): 359-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12516686&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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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

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Ultrasound of diffuse liver disease and portal hypertension. Author(s): Vilgrain V. Source: European Radiology. 2001; 11(9): 1563-77. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11511876&dopt=Abstract

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Uncommon causes of liver disease in juvenile systemic lupus erythematosus. Author(s): Ravelli A, Caria MC, Malattia C, Temporini F, Cavallero A, Silini EM, Martini A. Source: Clin Exp Rheumatol. 2001 July-August; 19(4): 474. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11491509&dopt=Abstract

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Unravelling complexity--the scientific basis of genetic predisposition in autoimmune liver disease. Author(s): Spengler U. Source: Journal of Hepatology. 2001 July; 35(1): 127-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11495030&dopt=Abstract

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Unusual skin findings in a patient with liver disease. Author(s): Fisman D. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2002 June 11; 166(12): 1567. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12074126&dopt=Abstract

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Up-regulation of transferrin receptor expression in hepatocytes by habitual alcohol drinking is implicated in hepatic iron overload in alcoholic liver disease. Author(s): Suzuki Y, Saito H, Suzuki M, Hosoki Y, Sakurai S, Fujimoto Y, Kohgo Y. Source: Alcoholism, Clinical and Experimental Research. 2002 August; 26(8 Suppl): 26S31S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12198371&dopt=Abstract

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Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Author(s): Paumgartner G, Beuers U. Source: Hepatology (Baltimore, Md.). 2002 September; 36(3): 525-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12198643&dopt=Abstract

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Use of complementary and alternative medicine in patients with liver disease. Author(s): Strader DB, Bacon BR, Lindsay KL, La Brecque DR, Morgan T, Wright EC, Allen J, Khokar MF, Hoofnagle JH, Seeff LB. Source: The American Journal of Gastroenterology. 2002 September; 97(9): 2391-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12358262&dopt=Abstract

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Use of recombinant factor vila to control bleeding in an adolescent male with severe hemophilia A, HIV thrombocytopenia, hepatitis C, and end-stage liver disease. Author(s): Puetz JJ, Bouhasin JD. Source: Am J Hosp Palliat Care. 2002 July-August; 19(4): 277-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12141793&dopt=Abstract

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Utility of the Mayo End-Stage Liver Disease (MELD) score in assessing prognosis of patients with alcoholic hepatitis. Author(s): Sheth M, Riggs M, Patel T. Source: Bmc Gastroenterology [electronic Resource]. 2002; 2(1): 2. Epub 2002 January 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11835693&dopt=Abstract

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Vaccination against hepatitis B in patients with chronic liver disease awaiting liver transplantation. Author(s): Horlander JC, Boyle N, Manam R, Schenk M, Herring S, Kwo PY, Lumeng L, Chalasani N. Source: The American Journal of the Medical Sciences. 1999 November; 318(5): 304-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10555092&dopt=Abstract

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Vaccination for hepatitis A virus is not required for patients with chronic liver disease in India. Author(s): Acharya SK, Batra Y, Saraya A, Hazari S, Dixit R, Kaur K, Bhatkal B, Ojha B, Panda SK. Source: Natl Med J India. 2002 September-October; 15(5): 267-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12502138&dopt=Abstract

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Validity and clinical utility of the aspartate aminotransferase-alanine aminotransferase ratio in assessing disease severity and prognosis in patients with hepatitis C virus-related chronic liver disease. Author(s): Giannini E, Risso D, Botta F, Chiarbonello B, Fasoli A, Malfatti F, Romagnoli P, Testa E, Ceppa P, Testa R. Source: Archives of Internal Medicine. 2003 January 27; 163(2): 218-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12546613&dopt=Abstract

•

Value of determining carbohydrate-deficient transferrin isoforms in the diagnosis of alcoholic liver disease. Author(s): Stadheim LM, O'Brien JF, Lindor KD, Gores GJ, McGill DB. Source: Mayo Clinic Proceedings. 2003 June; 78(6): 703-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12934779&dopt=Abstract

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•

Value of total body potassium in assessing the nutritional status of children with end-stage liver disease. Author(s): Trocki O, Wotton MJ, Cleghorn GJ, Shepherd RW. Source: Annals of the New York Academy of Sciences. 2000 May; 904: 400-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10865778&dopt=Abstract

•

Variant estrogen receptors and their role in liver disease. Author(s): Villa E, Colantoni A, Grottola A, Ferretti I, Buttafoco P, Bertani H, De Maria N, Manenti F. Source: Molecular and Cellular Endocrinology. 2002 July 31; 193(1-2): 65-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12161003&dopt=Abstract

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Venoocclusive liver disease (VOD) as a complication of Wilms' tumour management in the series of consecutive 206 patients. Author(s): Czauderna P, Katski K, Kowalczyk J, Kurylak A, Lopatka B, SkotnickaKlonowicz G, Sawicz-Birkowska K, Godzinski J. Source: European Journal of Pediatric Surgery : Official Journal of Austrian Association of Pediatric Surgery. [et Al] = Zeitschrift Fur Kinderchirurgie. 2000 October; 10(5): 300-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11194540&dopt=Abstract

•

Vibrio vulnificus infection in patients with liver disease: report of five autopsy cases. Author(s): Chen Y, Satoh T, Tokunaga O. Source: Virchows Archiv : an International Journal of Pathology. 2002 July; 441(1): 88-92. Epub 2002 February 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12111206&dopt=Abstract

•

Viral induction of type 2 diabetes and autoimmune liver disease. Author(s): Mason A. Source: The Journal of Nutrition. 2001 October; 131(10): 2805S-2808S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11584111&dopt=Abstract

•

Viral load in Indonesian patients with chronic liver disease and in blood donors infected with different subtypes of hepatitis C virus. Author(s): Lusida MI, Soetjipto, Handajani R, Nidom CA, Soemarto, Darmadi S, Adi P, Fujii M, Fujita T, Ishido S, Hotta H. Source: Japanese Journal of Infectious Diseases. 2000 April; 53(2): 67-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10871917&dopt=Abstract

•

Water retention and aquaporins in heart failure, liver disease and pregnancy. Author(s): Schrier RW, Cadnapaphornchai MA, Ohara M. Source: Journal of the Royal Society of Medicine. 2001 June; 94(6): 265-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11387413&dopt=Abstract

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Weak association between SEN virus viremia and liver disease. Author(s): Yoshida H, Kato N, Shiratori Y, Shao R, Wang Y, Shiina S, Omata M. Source: Journal of Clinical Microbiology. 2002 September; 40(9): 3140-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12202544&dopt=Abstract

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When and how to screen for liver disease. Author(s): Bach N, Koff RS, Maddrey W. Source: Mlo: Medical Laboratory Observer. 2000 June; 32(6): 58-64, 66; Quiz 67-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11066401&dopt=Abstract

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Who gets alcoholic liver disease: nature or nurture? Author(s): Day CP. Source: Journal of the Royal College of Physicians of London. 2000 NovemberDecember; 34(6): 557-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11191974&dopt=Abstract

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Why are patients with liver disease jaundiced? ATP-binding cassette transporter expression in human liver disease. Author(s): Jansen PL, Roskams T. Source: Journal of Hepatology. 2001 December; 35(6): 811-3. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11738110&dopt=Abstract

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Wilson's disease with neuropsychiatric manifestations and liver disease but no Kayser-Fleischer ring. Author(s): Makharia GK, Nandi B, Garg PK, Tandon RK. Source: Journal of Clinical Gastroenterology. 2002 July; 35(1): 101-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12080239&dopt=Abstract

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Wine: risk factors for liver disease and antifibrotic compounds. Author(s): Svegliati-Baroni G, Jezequel AM, Orlandi F. Source: Drugs Exp Clin Res. 1999; 25(2-3): 143-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10370877&dopt=Abstract

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Work outcomes for female liver transplant recipients with alcohol-related liver disease. Author(s): Newton SE. Source: Gastroenterology Nursing : the Official Journal of the Society of Gastroenterology Nurses and Associates. 2001 November-December; 24(6): 288-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11837214&dopt=Abstract

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•

Xanthine oxidoreductase activity in human liver disease. Author(s): Stirpe F, Ravaioli M, Battelli MG, Musiani S, Grazi GL. Source: The American Journal of Gastroenterology. 2002 August; 97(8): 2079-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12190180&dopt=Abstract

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CHAPTER 2. NUTRITION AND LIVER DISEASE Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and liver disease.

Finding Nutrition Studies on Liver Disease 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 “liver disease” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

7

Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

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

Antifibrotic properties of botanicals in chronic liver disease. Author(s): Department of Medicine I, Division of Hepatology, Division of Complementary Medicine, University of Erlangen-Nuremberg, Ulmenweg 18, D-91054 Erlangen, Germany. [email protected] Source: Stickel, F Brinkhaus, B Krahmer, N Seitz, H K Hahn, E G Schuppan, D Hepatogastroenterology. 2002 Jul-August; 49(46): 1102-8 0172-6390

•

Coagulation disorders in liver disease. Author(s): Gastroenterology Unit, A. Cardarelli Hospital, Via Morghen 92, 80129 Naples, Italy. [email protected] Source: Amitrano, Lucio Guardascione, Maria A Brancaccio, Vincenzo Balzano, Antonio Semin-Liver-Dis. 2002 February; 22(1): 83-96 0272-8087

•

Detection of acute cytotoxic changes in progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome) using diffusionweighted MRI and MR spectroscopy. Author(s): Section of Neuroradiology, Deparment of Neurosurgery, University Hospital, Kiel, Germany. [email protected] Source: Ulmer, S Flemming, K Hahn, A Stephani, U Jansen, O J-Comput-Assist-Tomogr. 2002 Jul-August; 26(4): 641-6 0363-8715

•

Hepatic encephalopathy associated with cobalt deficiency and white liver disease in lambs. Author(s): Large Animal Practice, Royal (Dick) School of Veterinary Studies, Easter Bush Veterinary Centre, Roslin. Source: Sargison, N D Scott, P R Wilson, D J Bell, G J Mauchline, S Rhind, S M Vet-Rec. 2001 December 22-29; 149(25): 770-2 0042-4900

•

Interactions of ethanol and folate deficiency in development of alcoholic liver disease in the micropig. Author(s): University of California, Davis, California and National Toxicological Research Center, Jefferson, Arkansas, USA. Source: Halsted, C H Villanueva, J A Devlin, A M James, S J Trans-Am-Clin-ClimatolAssoc. 2002; 113: 151-62; discussion 162-3 0065-7778

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Is intravenous iron safe in patients with liver disease? Source: Berns, Jeffrey S Semin-Dial. 2002 May-June; 15(3): 212-3 0894-0959

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Nf-kappab activation is associated with free radical generation and endotoxemia and precedes pathological liver injury in experimental alcoholic liver disease. Author(s): Department of Pathology, Harvard Medical School, Boston, MA, USA. Source: Jokelainen, K Reinke, L A Nanji, A A Cytokine. 2001 October 7; 16(1): 36-9 10434666

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Nutritional aspects of liver disease and transplantation. Author(s): Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain. Source: Cabre, E Gassull, M A Curr-Opin-Clin-Nutr-Metab-Care. 2001 November; 4(6): 581-9 1363-1950

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Nutritional management of acute and chronic liver disease. Author(s): Division of Digestive Diseases, University of Cincinnati, OH 45267-0595, USA.

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Source: Florez, D A Aranda Michel, J Semin-Gastrointest-Dis. 2002 July; 13(3): 169-78 1049-5118 •

Oxidative stress in the pathogenesis of nonalcoholic fatty liver disease, in rats fed with a choline-deficient diet. Author(s): Deptartment of Gastroenterology of the Medical School, University of Sao Paulo, Instituto Central, Sao Paulo, Brazil. [email protected] Source: Oliveira, C P da Costa Gayotto, L C Tatai, C Della Bina, B I Janiszewski, M Lima, E S Abdalla, D S Lopasso, F P Laurindo, F R Laudanna, A A J-Cell-Mol-Med. 2002 JulSeptember; 6(3): 399-406 1582-1838

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Silybin-beta-cyclodextrin in the treatment of patients with diabetes mellitus and alcoholic liver disease. Efficacy study of a new preparation of an anti-oxidant agent. Author(s): Department of Medical and Surgical Sciences, University of Padova, Italy. [email protected] Source: Lirussi, F Beccarello, A Zanette, G De Monte, A Donadon, V Velussi, M Crepaldi, G Diabetes-Nutr-Metab. 2002 August; 15(4): 222-31 0394-3402

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Use of dietary saturated fatty acids and vitamin E in the treatment of alcoholic liver disease. Author(s): Dept of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA Source: Nanji, A.A. Asia-Pacific-Journal-of-Clinical-Nutrition (United Kingdom). (1997). volume 6(1) page 46-48.

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

•

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/

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

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

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

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

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

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

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

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

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

The following is a specific Web list relating to liver disease; 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 Niacin Source: Integrative Medicine Communications; www.drkoop.com Niacin Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,892,00.html Vitamin A Source: Healthnotes, Inc.; www.healthnotes.com Vitamin A Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B3 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B3 (Niacin) Source: Integrative Medicine Communications; www.drkoop.com Vitamin K Alternative names: Menadione, Menaphthone, Menaquinone, Phylloquinone Source: Integrative Medicine Communications; www.drkoop.com

Nutrition

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Minerals Carnitine Source: Prima Communications, Inc.www.personalhealthzone.com Iron Source: Healthnotes, Inc.; www.healthnotes.com

•

Food and Diet Diabetes Source: Healthnotes, Inc.; www.healthnotes.com High Cholesterol Source: Healthnotes, Inc.; www.healthnotes.com Shiitake Mushrooms Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,308,00.html

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CHAPTER 3. ALTERNATIVE MEDICINE AND LIVER DISEASE Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to liver disease. 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 “liver disease” (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. •

S-Adenosyl-L-Methionine for Treatment of Depression, Osteoarthritis, and Liver Disease Source: Rockville, MD: Agency for Healthcare Research and Quality. 2002. 6 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: D175. Summary: This evidence report/technology assessment summary from the Agency for Healthcare Research and Quality (AHRQ) provides a review of the published literature on the use of S-adenosyl-L-methionine (SAMe) for the treatment of osteoarthritis, depression, and liver disease (cholestasis of pregnancy). The literature review is used to evaluate evidence for the efficacy of SAMe. The summary includes a description of the methodology, including the search strategy; selection criteria; and data collection and analysis. The findings are then discussed followed by an overview of future research on the topic. Information is also given on when and where the full report will be available. 1 reference.

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 liver disease 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 “liver disease” (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 liver disease: •

Advances in alcoholic liver disease. Author(s): Arteel G, Marsano L, Mendez C, Bentley F, McClain CJ. Source: Best Practice & Research. Clinical Gastroenterology. 2003 August; 17(4): 625-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828959&dopt=Abstract

•

Branched-chain amino acid-enriched supplements as therapy for liver disease: Rasputin lives. Author(s): Charlton M.

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Source: Gastroenterology. 2003 June; 124(7): 1980-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12806634&dopt=Abstract •

Gene therapy of neoplastic liver diseases. Author(s): Sangro B, Herraiz M, Prieto J. Source: The International Journal of Biochemistry & Cell Biology. 2003 February; 35(2): 135-48. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12479864&dopt=Abstract

•

Is liver disease an octreotide side effect? Author(s): Uygur-Bayramicli O, Gemici C. Source: Journal of Clinical Gastroenterology. 2003 July; 37(1): 86-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12811219&dopt=Abstract

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Is silymarin hepatoprotective in alcoholic liver disease? Author(s): Berger J, Kowdley KV. Source: Journal of Clinical Gastroenterology. 2003 October; 37(4): 278-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14506381&dopt=Abstract

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Liv.52 in alcoholic liver disease: a prospective, controlled trial. Author(s): de Silva HA, Saparamadu PA, Thabrew MI, Pathmeswaran A, Fonseka MM, de Silva HJ. Source: Journal of Ethnopharmacology. 2003 January; 84(1): 47-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12499076&dopt=Abstract

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Milk thistle for the treatment of liver disease: a systematic review and meta-analysis. Author(s): Jacobs BP, Dennehy C, Ramirez G, Sapp J, Lawrence VA. Source: The American Journal of Medicine. 2002 October 15; 113(6): 506-15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12427501&dopt=Abstract

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Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. Treatment approaches using vitamin E, magnesium, and betaine. Author(s): Patrick L. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 2002 August; 7(4): 276-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12197781&dopt=Abstract

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Phytoestrogens and liver disease. Author(s): Lei B, Roncaglia V, Vigano R, Cremonini C, De Maria N, Del Buono MG, Manenti F, Villa E.

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Source: Molecular and Cellular Endocrinology. 2002 July 31; 193(1-2): 81-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12161005&dopt=Abstract •

Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Author(s): Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, Desimone C, Song XY, Diehl AM. Source: Hepatology (Baltimore, Md.). 2003 February; 37(2): 343-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12540784&dopt=Abstract

•

Role of S-adenosyl-L-methionine in the treatment of alcoholic liver disease: introduction and summary of the symposium. Author(s): Purohit V, Russo D. Source: Alcohol (Fayetteville, N.Y.). 2002 July; 27(3): 151-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12163142&dopt=Abstract

•

Silybin-beta-cyclodextrin in the treatment of patients with diabetes mellitus and alcoholic liver disease. Efficacy study of a new preparation of an anti-oxidant agent. Author(s): Lirussi F, Beccarello A, Zanette G, De Monte A, Donadon V, Velussi M, Crepaldi G. Source: Diabetes Nutr Metab. 2002 August; 15(4): 222-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12416659&dopt=Abstract

•

Use of complementary and alternative medicine in patients with liver disease. Author(s): Strader DB, Bacon BR, Lindsay KL, La Brecque DR, Morgan T, Wright EC, Allen J, Khokar MF, Hoofnagle JH, Seeff LB. Source: The American Journal of Gastroenterology. 2002 September; 97(9): 2391-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12358262&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/

•

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

•

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

•

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/

•

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 liver disease; 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 Amenorrhea Source: Integrative Medicine Communications; www.drkoop.com Appendicitis Source: Integrative Medicine Communications; www.drkoop.com Asthma Source: Prima Communications, Inc.www.personalhealthzone.com Atherosclerosis and Heart Disease Prevention Source: Prima Communications, Inc.www.personalhealthzone.com Benign Prostatic Hyperplasia Alternative names: Prostate Enlargement Source: Prima Communications, Inc.www.personalhealthzone.com Bulimia Nervosa Source: Integrative Medicine Communications; www.drkoop.com Cataracts (Prevention) Source: Prima Communications, Inc.www.personalhealthzone.com Chickenpox and Shingles Source: Integrative Medicine Communications; www.drkoop.com Cirrhosis Source: Integrative Medicine Communications; www.drkoop.com

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Cold Sores Source: Integrative Medicine Communications; www.drkoop.com Colds and Flus Source: Prima Communications, Inc.www.personalhealthzone.com Congestive Heart Failure Source: Prima Communications, Inc.www.personalhealthzone.com Cyclic Mastalgia Alternative names: Cyclic Mastitis, Fibrocystic Breast Disease Source: Prima Communications, Inc.www.personalhealthzone.com Diabetes Source: Prima Communications, Inc.www.personalhealthzone.com Diverticular Disease Source: Integrative Medicine Communications; www.drkoop.com Gout Source: Prima Communications, Inc.www.personalhealthzone.com Heart Attack Source: Healthnotes, Inc.; www.healthnotes.com Hepatitis Source: Healthnotes, Inc.; www.healthnotes.com Herpes Simplex Virus Source: Integrative Medicine Communications; www.drkoop.com Herpes Zoster and Varicella Viruses Source: Integrative Medicine Communications; www.drkoop.com High Cholesterol Source: Integrative Medicine Communications; www.drkoop.com High Cholesterol Source: Prima Communications, Inc.www.personalhealthzone.com High Triglycerides Source: Healthnotes, Inc.; www.healthnotes.com Hypercholesterolemia Source: Integrative Medicine Communications; www.drkoop.com Hypoglycemia Source: Healthnotes, Inc.; www.healthnotes.com Inflammatory Bowel Disease Source: Integrative Medicine Communications; www.drkoop.com

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Liver Cirrhosis Source: Healthnotes, Inc.; www.healthnotes.com Liver Disease Source: Integrative Medicine Communications; www.drkoop.com Low Back Pain Source: Healthnotes, Inc.; www.healthnotes.com Malabsorption Source: Healthnotes, Inc.; www.healthnotes.com Menopause Source: Integrative Medicine Communications; www.drkoop.com Morning Sickness Source: Healthnotes, Inc.; www.healthnotes.com Osteoarthritis Source: Prima Communications, Inc.www.personalhealthzone.com Pancreatic Insufficiency Source: Healthnotes, Inc.; www.healthnotes.com Peritonitis Source: Integrative Medicine Communications; www.drkoop.com Radiation Damage Source: Integrative Medicine Communications; www.drkoop.com Sarcoidosis Source: Integrative Medicine Communications; www.drkoop.com Shingles and Chickenpox Source: Integrative Medicine Communications; www.drkoop.com Ulcerative Colitis Source: Integrative Medicine Communications; www.drkoop.com Varicella and Herpes Zoster Viruses Source: Integrative Medicine Communications; www.drkoop.com Varicose Veins Source: Prima Communications, Inc.www.personalhealthzone.com Viral Hepatitis Source: Prima Communications, Inc.www.personalhealthzone.com •

Alternative Therapy Chelation Therapy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com

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Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,679,00.html •

Herbs and Supplements 5-hydroxytryptophan Source: Healthnotes, Inc.; www.healthnotes.com Alanine Source: Healthnotes, Inc.; www.healthnotes.com Alpha-lipoic Acid Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10002,00.html Angkak Source: Integrative Medicine Communications; www.drkoop.com Arginine Source: Healthnotes, Inc.; www.healthnotes.com Australian Fevertree Source: Integrative Medicine Communications; www.drkoop.com Beni-koji Source: Integrative Medicine Communications; www.drkoop.com Betaine Alternative names: Trimethylglycine Source: Integrative Medicine Communications; www.drkoop.com Betaine (trimethylglycine) Source: Healthnotes, Inc.; www.healthnotes.com Boldo Alternative names: Peumus boldus Source: Healthnotes, Inc.; www.healthnotes.com Boneset Alternative names: Eupatorium perfoliatum Source: Healthnotes, Inc.; www.healthnotes.com Branched-chain Amino Acids Source: Healthnotes, Inc.; www.healthnotes.com Camellia Sinensis Source: Integrative Medicine Communications; www.drkoop.com Carotenoids Source: Healthnotes, Inc.; www.healthnotes.com

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Chaparral Alternative names: Larrea tridentata Source: Healthnotes, Inc.; www.healthnotes.com Coltsfoot Alternative names: Tussilago farfara Source: Healthnotes, Inc.; www.healthnotes.com Comfrey Alternative names: Symphytum officinale Source: Healthnotes, Inc.; www.healthnotes.com Eucalyptus Alternative names: Eucalyptus globulus Source: Healthnotes, Inc.; www.healthnotes.com Eucalyptus Alternative names: Eucalyptus globulus, Eucalyptus fructicetorum, polybractea, smithii, Australian Fevertree Source: Integrative Medicine Communications; www.drkoop.com Eucalyptus Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,778,00.html Eucalyptus Globulus Source: Integrative Medicine Communications; www.drkoop.com Feverfew Source: Prima Communications, Inc.www.personalhealthzone.com Glutamic Acid Source: Healthnotes, Inc.; www.healthnotes.com Glutathione Source: Healthnotes, Inc.; www.healthnotes.com Glycine Source: Healthnotes, Inc.; www.healthnotes.com Glycyrrhiza1 Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Goldenseal Source: Prima Communications, Inc.www.personalhealthzone.com Greater Celandine Alternative names: Chelidonium majus Source: Healthnotes, Inc.; www.healthnotes.com

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Green Tea Alternative names: Camellia sinensis Source: Healthnotes, Inc.; www.healthnotes.com Green Tea Alternative names: Camellia sinensis Source: Integrative Medicine Communications; www.drkoop.com Green Tea Source: Prima Communications, Inc.www.personalhealthzone.com Guggul Alternative names: Commiphora mukul Source: Healthnotes, Inc.; www.healthnotes.com Gugulipid Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10033,00.html Gymnema Alternative names: Gymnema sylvestre Source: Healthnotes, Inc.; www.healthnotes.com Gymnema Source: Prima Communications, Inc.www.personalhealthzone.com He Shou Wu Source: Prima Communications, Inc.www.personalhealthzone.com Histidine Source: Healthnotes, Inc.; www.healthnotes.com Hong Qu Source: Integrative Medicine Communications; www.drkoop.com Horse Chestnut Alternative names: Aesculus hippocastanum Source: Healthnotes, Inc.; www.healthnotes.com Horsetail Source: Prima Communications, Inc.www.personalhealthzone.com Hung-chu Source: Integrative Medicine Communications; www.drkoop.com Juniper Berry Source: Prima Communications, Inc.www.personalhealthzone.com Kudzu Source: Prima Communications, Inc.www.personalhealthzone.com

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Lecithin Source: Prima Communications, Inc.www.personalhealthzone.com Lipoic Acid Source: Prima Communications, Inc.www.personalhealthzone.com Liver Extracts Source: Healthnotes, Inc.; www.healthnotes.com Medium-chain Triglycerides Source: Prima Communications, Inc.www.personalhealthzone.com Menadione Source: Integrative Medicine Communications; www.drkoop.com Menaphthone Source: Integrative Medicine Communications; www.drkoop.com Menaquinone Source: Integrative Medicine Communications; www.drkoop.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: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10044,00.html Monascus Source: Integrative Medicine Communications; www.drkoop.com Phylloquinone Source: Integrative Medicine Communications; www.drkoop.com Red Koji Source: Integrative Medicine Communications; www.drkoop.com Red Leaven Source: Integrative Medicine Communications; www.drkoop.com Red Rice Source: Integrative Medicine Communications; www.drkoop.com

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Red Yeast Rice Alternative names: Angkak, Beni-koju, Hong Qu, Hung-chu, Monascus, Red Leaven, Red Rice, Red Koji, Zhitai, Xue Zhi Kang Source: Integrative Medicine Communications; www.drkoop.com Red Yeast Rice Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10054,00.html S-adenosylmethionine (SAMe) Source: Integrative Medicine Communications; www.drkoop.com 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 Saw Palmetto Source: Prima Communications, Inc.www.personalhealthzone.com 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 Terminalia Alternative names: Myrobalans; Terminalia arjuna Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Trimethylglycine Source: Integrative Medicine Communications; www.drkoop.com Valproic Acid Derivatives Source: Integrative Medicine Communications; www.drkoop.com White Willow Source: Prima Communications, Inc.www.personalhealthzone.com Zhitai Source: Integrative Medicine Communications; www.drkoop.com

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Zue Zhi Kang 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 LIVER DISEASE Overview In this chapter, we will give you a bibliography on recent dissertations relating to liver disease. 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 “liver disease” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on liver disease, we have not necessarily excluded nonmedical dissertations in this bibliography.

Dissertations on Liver Disease 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 liver disease. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

A Mouse Model of Human Liver Disease due to Inherited Mutations in the Atp8b1 (FIC1) Gene by Pawlikowska, Ludmila; PhD from University of California, San Francisco, 2002, 212 pages http://wwwlib.umi.com/dissertations/fullcit/3051047

•

Computer System Modeling and Diagnosis of Liver Disease Using Pattern Recognition and Stochastic Techniques by Ismail, Mohamed A; PhD from University of Waterloo (Canada), 1980 http://wwwlib.umi.com/dissertations/fullcit/NK49795

•

Glycoproteins and Chronic Liver Disease in the Dog: Biochemical, Immunohistochemical and Ultrastructural Studies by Vatne, Malfrid; Vetmeddr from Sveriges Lantbruksuniversitet (Sweden), 2002, 58 pages http://wwwlib.umi.com/dissertations/fullcit/f260577

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•

Serum Lecithin Cholesterol Acyltransferase and Liver Cholesterol Ester Hydrolase in Patients with Liver Disease by Poon, Raymond Wai-man; PhD from Queen's University at Kingston (Canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK52920

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 LIVER DISEASE Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning liver disease.

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

Detection and Cytotoxic T Lymphocyte Therapy Lymphoproliferative Disorder After Liver Transplant

of

Post-Transplant

Condition(s): Liver Disease; Lymphoproliferative Disorders Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: Despite advances in medical and gene therapy, orthotopic liver transplantation remains the only definitive therapeutic option for children with endstage liver disease. Recent advances in pre-, intra-, and early post-transplant care have resulted in a dramatic improvement in survival of the pediatric liver transplant patient. The broad long-range goal of our research program is directed at enhancing the patient's long-term survival. Our primary focus relates to obligate life-long immunosuppression, with its inherent complications including severe infection and development of cancer. These two complications come together in a single disease, Epstein-Barr Virus (EBV)associated post-transplant lymphoproliferative disorder (PTLD). EBV, a latent human lymphotrophic herpes virus infects and immortalizes B cells. Primary infection usually occurs via salivary exchange and results in a mild, self-limited illness followed by lifelong EBV-specific T cell controlled EBV latency. T cell-based immunosuppression prevents allograft rejection, however, it also suppresses cytotoxic T lymphocyte (CTL) function, generating an environment in which EBV-infected cells can proliferate. Patients receiving life-long T cell-based immunosuppression have an increased risk of developing PTLD due to their inability to produce normal immunoregulatory 8

These are listed at www.ClinicalTrials.gov.

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responses. This disease is particularly devastating to the pediatric patient as its incidence is at least 4-fold greater than in the adult liver transplant patient population. In fact, PTLD is the number one cause of death following pediatric liver transplantation. At this time, there is no definitive method of prospectively detecting, diagnosing, or treating PTLD, and current treatment protocols place the liver allograft and patient at risk. Therefore, a diagnostic tool that is both sensitive and specific, and a treatment strategy with low toxicity are greatly needed to decrease the morbidity and mortality suffered by the pediatric liver transplant patient with PTLD. Our proposed studies will support our hypothesis that the combination of a persistently elevated EBV load in the setting of a diminished immune response to EBV will be an early risk indicator associated with PTLD development, and that pre-emptive treatment utilizing autologous adoptive EBV-specific CTL immunotherapy will provide a low toxicity treatment option. Phase(s): Phase I Study Type: Interventional Contact(s): John A Goss, MD 713-798-8355 [email protected] Web Site: http://clinicaltrials.gov/ct/show/NCT00063648 •

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

•

Genetics of Hepatitis C Virus Infection Condition(s): Hepatitis C; Liver Disease Study Status: This study is currently recruiting patients.

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Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The course of hepatitis C varies among people infected with the virus. Some people respond to treatment while many do not; some recover completely while others remain chronically infected; and among those who remain infected, some have mild symptoms while others' symptoms are severe. This study will look for genetic factors that may contribute to these differences. Children over 2 years of age and adults with hepatitis C virus infection or with other kinds of liver disease (such as hepatitis B virus infection, primary biliary cirrhosis, Wilson's disease and others), and normal volunteers may be eligible for this study. Participants will provide 40 to 60 centiliters (1 to 2 ounces) of blood. DNA will be isolated from the white blood cells for analysis of genes involved in certain immune functions. The genetic findings from patients with hepatitis C, patients with other forms of liver disease, and normal volunteers will be compared to try to learn how the differences may influence the symptoms and course of hepatitis C and to understand how the virus causes disease. The results of this study may provide information useful for developing a vaccine and better treatments for hepatitis C. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005657 •

Total Parenteral Nutrition-Associated Liver Disease Condition(s): Liver Diseases Study Status: This study is currently recruiting patients. Sponsor(s): FDA Office of Orphan Products Development Purpose - Excerpt: This is a study to determine whether choline, when added to total parenteral nutrition (TPN), can help prevent the development of hepatic steatosis, a liver disease, in patients on TPN. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00031135

•

Phase II Pilot Study to Compare the Bioavailability of Buffered, Enteric-Coated Ursodiol with Unmodified Ursodiol for Chronic Cholestatic Liver Disease and Cystic Fibrosis-Associated Liver Disease Condition(s): Cystic Fibrosis; Gastrointestinal Diseases; Cholestasis Study Status: This study is no longer recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Children's Hospital Medical Center - Cincinnati Purpose - Excerpt: Objectives: I. Compare the bioavailability of polymer-coated and buffered ursodiol (ursodeoxycholic acid) to unmodified ursodiol in patients with cystic fibrosis-associated liver disease or chronic cholestatic liver disease. II. Compare the differences in pruritus, weight gain, and liver function for both treatments. Phase(s): Phase II Study Type: Interventional

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004315 •

Vancomycin Resistant Enterococci in Patients Awaiting Liver Transplantation at the University of Michigan: Prevalence, Risk Factors, Natural History and Outcome of Colonization Condition(s): Liver Diseases Study Status: This study is no longer recruiting patients. Sponsor(s): National Center for Research Resources (NCRR) Purpose - Excerpt: Enterococci, especially vancomycin resistant enterococci (VRE), are increasing in prevalence in many hospitals in the United States. Patients undergoing liver transplantation are at particular risk for developing infection due to VRE. The effect of prior colonization with VRE on the outcome of liver transplantation is unknown. This prospective study will ascertain the prevalence of gastrointestinal colonization with vancomycin resistant enterococci among patients awaiting liver transplantation at the University of Michigan Health System. Risk factors for acquisition of the organism, natural history of colonization and outcome in colonized patients will also be determined. All patients currently listed on a priority waiting list for liver transplantation at UMHS will be invited to participate. Patients will receive a standardized letter from their primary gastroenterologist describing the rationale for the study. Patients will be contacted by telephone by a member of the study team in order to arrange an appointment in the GCRC at the time of their regularly scheduled Transplant Clinic appointment in order discuss their potential participation in the study. Patients who give informed consent, will be interviewed using a standard interview questionnaire. Demographic and historical data relevant to the risk of VRE colonization will be collected during the interview. A sample will be obtained via rectal swab for culture. Rectal swabs for culture and collection of information on the standardized questionnaire will be repeated every six months while the patient is awaiting liver transplantation. When a patient undergoes liver transplantation, a culture will be obtained at the time of admission and weekly after post-operatively until discharge. All patients will be followed for 60 days after transplantation to assess several primary outcomes, including operative and post-operative complications, VRE infection and mortality. Rectal swabs will be the only procedure performed for the purposes of this study. Culture results will not be made available to the transplant team in order to avoid bias in clinical care. All data will be entered into an electronic database. GCRC statisticians will assist in the analysis of risk factors and outcome analysis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005667

•

A Study of Zidovudine in HIV-Infected Patients with Liver Disease Condition(s): HIV Infections; Liver Diseases Study Status: This study is completed. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: To examine the pharmacokinetics (blood levels) and bioavailability of zidovudine (AZT) given to patients with HIV infection and chronic liver disease. The specific aim of the study is to provide data permitting the development of guidelines for

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use of AZT in patients with mild, moderate, or severe liver disease. AZT is the only antiviral agent that has been shown to be effective in patients with severe HIV infection. However, AZT is largely eliminated from the body through a biochemical reaction that takes place in the liver, and it is possible that patients with underlying liver disease may have altered AZT pharmacokinetics and may metabolize AZT differently, with the result that they are susceptible to an increased risk of serious drug toxicity. This study will examine the pharmacokinetics, elimination, and metabolism of AZT in patients with liver disease. Guidelines developed from the data will be helpful in managing AZT treatment of these HIV-infected persons and will indicate whether the dose of AZT administered should be adjusted to compensate for any changes in its bioavailability and/or pharmacokinetics. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001001 •

Clinical Research Network in Non-Alcoholic Steatohepatitis - Adult Trial Condition(s): Liver Diseases Study Status: This study is not yet open for patient recruitment. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The purpose of this study is to determine if therapy with pioglitazone or vitamin E will lead to an improvement in liver histology in non-diabetic adult patients with NASH. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00063622

•

Delta Hepatitis and Liver Disease in Hemophiliacs Condition(s): Blood Disease; Hepatitis, Viral, Human; Hemophilia A; Liver Diseases Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the prevalence of hepatitis delta virus (HDV) in a large cohort of hemophiliacs and to elucidate the role of HDV in the development and progression of liver disease in this population. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005304

•

Hepatic Artery Infusion of CD34+ Cells Condition(s): Stem Cell Transplantation; Liver Diseases Study Status: This study is suspended. Sponsor(s): M.D. Anderson Cancer Center

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Purpose - Excerpt: The primary objective is to determine whether donor stem cells administered via hepatic artery infusion can produce liver cells in patients with severe hepatic dysfunction post stem cell transplantation (SCT) and the safety of this procedure. The secondary objective is to improve liver function and improve survival. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00062543 •

Hepatitis B Vaccine Clinical Trial Condition(s): Hepatitis B; Hepatitis, Viral, Human; Liver Diseases Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the efficacy of a hepatitis vaccine in preventing hepatitis B. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000583

•

Hepatitis Delta Infections in Hemophiliacs Condition(s): Blood Disease; Hepatitis, Viral, Human; Liver Diseases; Hemophilia A Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To elucidate the role of hepatitis delta virus (HDV) in the development of chronic liver disease in patients with hemophilia. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005305

•

Interruption of Maternal-to-Infant Transmission of Hepatitis B by Means of Hepatitis B Immune Globulin Condition(s): Hepatitis B; Hepatitis, Viral, Human; Liver Diseases Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To evaluate whether hepatitis B immune globulin with a high level of antibody against the hepatitis B antigen would be capable of interrupting maternal-fetal transmission of hepatitis B virus, the single most important route of hepatitis spread in the entire Third World. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below

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Web Site: http://clinicaltrials.gov/ct/show/NCT00000580 •

Magnetic Resonance Imaging of Blood Flow in the Liver and Abdomen Condition(s): Healthy; Liver Disease Study Status: This study is completed. Sponsor(s): Warren G Magnuson Clinical Center (CC) Purpose - Excerpt: This study will use magnetic resonance imaging (MRI) to examine blood flow patterns in the arteries and veins of the liver and abdomen. It will 1) determine the best way to measure blood flow in these vessels, and 2) make detailed measurements of the blood flow patterns of these vessels. Information about normal liver blood flow may help explain the role of blood flow in liver disease. Normal healthy volunteers 18 years of age and older may be eligible for this study. They will undergo MRI-a diagnostic tool that uses a strong magnetic field and radio waves to show structural and chemical changes in tissue and the speed of moving blood. The patient lies on a stretcher inside a metal cylinder (the scanner) for 1 to 1.5 hours and will be required to lie very still for 10 to 15 minutes at a time. Blood pressure, heart rate, breathing and the amount of oxygen in the fingertip are measured during the scan. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001719

•

Mechanisms of Inflammatory Liver Injury Condition(s): Liver Diseases Study Status: This study is completed. Sponsor(s): National Institute of Environmental Health Sciences (NIEHS) Purpose - Excerpt: White blood cells can cause liver damage if they inappropriately accumulate in the liver in large numbers. Such an event can occur if an individual's blood is exposed to endotoxin, a substance released from the cell walls of many species of bacteria. The purpose of this study is to isolate neutrophils, an important white blood cell, from the blood of normal volunteers, and put them in tissue culture with isolated liver cells. The experiments will determine how endotoxin can increase the ability of neutrophils to damage liver cells. All studies supported by this grant will be done with isolated cells in tissue culture. This experimental model will reveal possible mechanisms that can in the future be evaluated in human diseases such as bacterial sepsis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00011284

•

Natural History of Post-transfusion Non-A, Non-B Hepatitis Condition(s): Hepatitis, Viral, Human; Blood Transfusion; Liver Diseases Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI)

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Purpose - Excerpt: To compare the clinical, biochemical, and histological status of NonA, Non-B post-transfusion hepatitis patients with that of patients who did not develop post-transfusion hepatitis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005306 •

Oxaliplatin to Treat Advanced Cancers With Liver Dysfunction Condition(s): Liver Disease Study Status: This study is completed. Sponsor(s): National Cancer Institute (NCI) Purpose - Excerpt: This is a phase I study of the experimental anticancer drug oxaliplatin. It is designed to establish the maximum dose of the drug that can be given safely to patients with cancer who have impaired liver function and to determine the drug's side effects. It will also examine how liver function affects the drug's elimination from the body. The liver plays an important role in the elimination of many anticancer drugs, and patients with impaired liver function should not take certain drugs or should take them in reduced doses. Patients 18 years of age and older with cancer that has metastasized (spread from the original tumor site) and for whom standard treatment is not available or is no longer effective may be eligible for this study. Candidates will be screened with various tests and procedures that may include physical examination, computerized tomography (CT) or magnetic resonance imaging (MRI) scans, chest Xrays, and blood and urine tests. Participants will be given oxaliplatin in doses determined according to their level of liver function. Patients may have normal liver function or mildly, moderately or severely impaired liver function, or may have had a liver transplant. Oxaliplatin will be infused intravenously (through a vein) over two hours on the first day of 21-day treatment cycles-that is, once every 3 weeks. Treatment will continue as long as the cancer is under control and side effects do not require stopping the drug. Urine will be collected over 48 hours after the infusion to determine how much of the drug is eliminated in urine. Blood tests will be done to monitor safety of the treatment, and imaging studies, such as X-rays, CT and MRI scans, will be done periodically to evaluate the tumor's response to treatment. Special blood tests will also be done to study how oxaliplatin is eliminated from the body. With the first dose of the drug, blood samples will be collected just before the infusion begins, just before it ends, 15 minutes, 30 minutes, 1, 2, 4, 6, 24, 48, and 72 hours after the infusion, and again 1 week and 3 weeks later. Additional blood samples may be collected at the third treatment cycle. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006062

•

Study of Magnesium Sulfate in Children With Reduced Bone Density Secondary to Chronic Cholestatic Liver Disease Condition(s): Alagille Syndrome; Cholestasis; Biliary Atresia Study Status: This study is completed.

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Sponsor(s): National Center for Research Resources (NCRR); Children's Hospital Medical Center - Cincinnati Purpose - Excerpt: Objectives: I. Determine the role of magnesium deficiency in the pathogenesis of decreased serum vitamin D and reduced bone density in children with chronic cholestatic liver disease. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00007033

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 “liver disease” (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 LIVER DISEASE 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 “liver disease” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on liver disease, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Liver Disease By performing a patent search focusing on liver disease, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 9Adapted

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

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example of the type of information that you can expect to obtain from a patent search on liver disease: •

Acetaldehyde and malondialdehyde protein adducts Inventor(s): Klassen; Lynell W. (Omaha, NE), McDonald; Thomas L. (Omaha, NE), Sorrell; Michael F. (Omaha, NE), Thiele; Geoffrey M. (Omaha, NE), Tuma; Dean J. (Omaha, NE) Assignee(s): The Board of Regents of the University of Nebraska (Lincoln, NE) Patent Number: 5,939,535 Date filed: April 8, 1997 Abstract: A novel protein adduct is disclosed which is associated with the presence of alcohol liver disease. The adduct is a hybrid product of malondialdehyde and acetaldehyde which act synergistically to bind hepatic proteins. The adduct is highly immunogenic and fluorescent. Methods of detection are also disclosed including monoclonal and polyclonal antibodies. Excerpt(s): The chronic consumption of alcoholic beverages is the major cause of serious liver disease. Ethanol is an extremely potent hepatotoxin and can lead to cirrhosis of the liver upon prolonged exposure. In fact 20% of chronic alcoholics will eventually experience cirrhosis. The process of cirrhosis of the liver involves a series of steps beginning with fatty infiltration which leads to necrosis or cell death, then fibrosis which in turn leads to cirrhosis. Despite considerable research in this area, the underlying pathogenic mechanisms of ethanol induced liver injury, including the underlying biochemical reactions, remain obscure. In recent years extensive evidence has come forward supporting a role of acetaldehyde in the detrimental actions of ethanol in the liver as well as other organs. Numerous studies have shown that acetaldehyde can react with proteins in vitro under physiological conditions to form both stable and unstable adducts. Because of this chemical reactivity, the covalent binding of acetaldehyde to hepatic proteins has been proposed as a key event leading to alcohol liver injury. Many groups have demonstrated by immunoassays, using antibodies directed against acetaldehyde-modified proteins, the presence of acetaldehyde adducts in the livers of rats, guinea pigs, and humans chronically consuming ethanol. Studies involving the chemistry of acetaldehyde protein adduct formation have shown that acetaldehyde forms both unstable and stable adducts and that the.epsilon.-amino group of lysine participates in binding and, further, that unstable adducts serve as intermediates in stable adduct formation. It has also been found that proteins contain lysine residues with varying reactivities towards acetaldehyde adduct formation and that certain proteins (such as.alpha.-tubulin) may be selective targets for adduct formation by virtue of containing a specially reactive "key" lysine residue. Further information about acetaldehyde adducts is present in Tuma, D. J. "The Role of Acetaldehyde Adducts in Liver Injury", Hall P. Editors, Alcoholic Liver Disease Pathology and Pathogenesis, Ed. 2, London: Edward Arnold, 1995, 89-99 incorporated herein by reference. Web site: http://www.delphion.com/details?pn=US05939535__

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Anti liver disease drug R-YEEE and method of synthesizing branched galactoseterminal glycoproteins Inventor(s): Chen; Shui-Tein (Taipei, TW), Huang; Chun-Ming (Kaoshiung, TW), Jiaang; Weir-Torn (Taipei, TW), Tseng; Ping-Hui (Wur, TW) Assignee(s): Academia Sinica (Taipei, TW) Patent Number: 6,383,812 Date filed: January 25, 2000 Abstract: The present invention provides a novel method of synthesizing branched galactose-terminal glycoproteins. A number of these glycoproteins have binding affinity to the asialoglycoprotein receptor. The present invention also provides novel conjugates having branched galactose-terminal glycoproteins that is complexed to a therapeutically effective agent, such as an isolated protein, polysacharides, lipids and radioactive isotope. These conjugates may be used to deliver the therapeutically effective agent to mammalian cells generally, and to hepatocytes specifically. Excerpt(s): The present invention relates to a novel method of synthesizing ligands for the asialoglycoprotein receptor, a recycling endocytotic receptor on the surface of mammalian hepatocytes. Novel ligands having affinity to the asialoglycoprotein receptor and a method of synthesizing thereof are also disclosed. Mammalian liver cells possess specific membrane-bound receptors, asialoglycoprotein receptors (ASGPr), which receive ligands having terminal galactose/N-acetylgalactosamine residues. Ashwell el al., Annu. Rev. Biochem., 1982, 51, 531. The affinity of such a receptor to its ligand depends on the valency of the terminal galactose (Gal) or N-acetylgalactosamine (GalNAc), Lee et al., Biochem, Biophys. Res. Commun., 1988, 155, 1444, as well as on the three-dimensional arrangement of the sugar residues. Lee, FASEB. 1992, 6, 3193-3200. The use of YEE(GalNAcAH).sub.3 as a vehicle for delivery of a gene or an antisense oligodeoxynucleotide to the liver has been also reported recently. Merwin et al. Bioconjugate Chem. 1994, 5, 612-620; Hangeland et al., Bioconjugate Chem. 1995, 5, 695701. However, synthesis of YEE(GalNAcAH).sub.3 suffers from some practical problems mainly due to the poor solubility of its peptide intermediates in either aqueous or organic solvents. Web site: http://www.delphion.com/details?pn=US06383812__

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Budesonide alone or in combination with ursodeoxycholic acid in the therapy of cholestatic liver diseases Inventor(s): Leuschner; Maria (Frankfurt, DE) Assignee(s): Dr. Falk Pharma GmbH (Freiburg, DE) Patent Number: 5,858,998 Date filed: September 30, 1997 Abstract: According to the invention it was unexpectedly found that budesonide can be used for the treatment of cholestatic liver diseases such as PBC, PSC and AC. In particular budesonide is highly effective when administered together with ursodeoxycholic acid. Excerpt(s): The present invention relates to the use of budesonide either alone or in combination with ursodeoxycholic acid for the treatment of cholestatic liver diseases, in particular of primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune

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cholangitis. Pharmaceutical compositions comprising immuno suppressives, e.g. corticosteroids such as prednisolone or budesonide are well known for the treatment of hepatic diseases (Danielsson et al., Aliment. Pharmacol. Ther., 1994, 8, 585-590). Different in many aspects from other hepatic diseases, however, are, cholestatic diseases such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune cholangitis (AC). It was the general belief in the art that the therapy with such immuno suppressives is not promising for the treatment of cholestatic diseases. In particular, there were controlled clinical investigations whether prednisolone can be used for the treatment of PBC (Mitchison et al., Hepatology, 1989, 4, 420-429; Mitchison et al., Journal of Hepatology, 1992, 15, 336-344), however, the therapy with prednisolone is controversially discussed. The activity of prednisolone is not without doubt and, furthermore, severe side effects were observed. For this reason, up to now a therapy of PBC, PSC and AC with glucocorticoids was not considered being helpful (Paumgartner & Beuers, In: Falk Symposium 87, Acute and chronic liver diseases, 1996, 96-106; Rasenack and Gerok in Hepatologie (Ed. Gerok & Blum), 1995, page 435 and 439; Praktische Gastroenterologie, (Ed. Layer et al.), 1996, 397-398). Web site: http://www.delphion.com/details?pn=US05858998__ •

Complexes of flavanolignans with phospholipids, preparation thereof and associated pharmaceutical compositions Inventor(s): Bombardelli; Ezio (Milan, IT), Gabetta; Bruno (Milan, IT), Pifferi; Giorgio (Milan, IT) Assignee(s): Inverni Della Beffa S.p.A. (Milan, IT) Patent Number: 4,764,508 Date filed: July 7, 1986 Abstract: The invention relates to novel compounds comprising lipophilic complexes of silybin, silidianin, and silicristin with phospholipids, and the preparation of these complexes by non-conventional methods. Absorption of the novel compounds in the gastrointestinal tract is appreciably greater, resulting in higher plasma levels than for the individual flavanolignans. The resulting improvement in the pharmacokinetic and pharmacological parameters is such that the substances can advantageously be used in the treatment of acute and chronic liver disease of toxic, metabolic or infective origin or of degenerative nature. Excerpt(s): The invention relates to novel complexes of phospholipids with the main constituents of silymarin, a known standardized extract obtained from seeds of Silybum marianum and used in the treatment of liver disease of varying origin. Silymarin contains three main constituents: silybin, silidianin and silicristin, which are assumed to be responsible for the therapeutic liver-protecting activity of the extract. The main constituent is silybin, which is a mixture of two diasteroisomers (Chem. Commun. 696, 1979) in the ratio of about 1:1, for which the largest amount of pharmaco-toxicological and clinical documentation exists, with regard to the hydrosoluble hemisuccinic diester. The activity of silybin and the other constituents of silymarin, particularly when administered by injection, occurs at the liver cell, where the flavanolignans intervene in the process of stabilizing and protecting the liver-cell membrane against injurious agents such as carbon tetrachloride, phalloidine, amanitine, some heavy metals, galactosamine and various antibiotics which interfere with its function by liberating enzymes resulting in the formation of necrosis. Some of these injurious agents simulate the damage produced by viruses responsible for common forms of hepatitis in man--hence the

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therapeutic importance of antihepatotoxic molecules of this kind. As the reported data in the literature show, the best protection against the aforementioned injurious agents is obtained in the animal when the compounds are administered intraperitoneally or intravenously so as rapidly to obtain high concentrations in the bloodstream and the target organ. In spite of occasional reports of oral absorption of silybin (Arzneim. Forsch. 23, 1322, 1973; Arzneim. Forsch. 25, 902, 1975; Planta Medica 45, 216, 1982), the relevant pharmacological investigations are scanty and difficult to reproduce. This indicates that the drug does not have really high or adequate bioavailability when administered by this method. The invention relates to the production of novel compounds obtained by chemical interaction between one or more phospholipids and one or more of the aforementioned flavanolignans. Web site: http://www.delphion.com/details?pn=US04764508__ •

Dietary formulation comprising arachidonic acid and methods of use Inventor(s): Bistrian; Bruce R. (Ipswich, MA) Assignee(s): Beth Israel Deaconess Medical Center, Inc. (Boston, MA) Patent Number: 5,993,221 Date filed: May 1, 1997 Abstract: A novel formulation which contains about 2-60% by calories of a C.sub.20 or longer.omega.3 fatty acid moiety and about 2-60% by calories of an arachidonic acid moiety has been developed. This formulation is particularly useful for restoring arachidonic acid levels, increasing immunity or minimizing risk of infection in critically ill patients, and treating functional essential fatty acid deficiency in patients suffering from end stage liver disease. A structured lipid which has a C.sub.20 or longer.omega.3 fatty acid moiety and an arachidonic acid moiety has also been developed. Excerpt(s): Protein calorie malnutrition is a common complicating condition in patients with alcoholic chronic liver disease (Mendenhall et al. Am J Med 1984;76:211-222; Mendenhall et al. Am J Clin Nutr 1986;43:213-218) and non-alcoholic chronic liver disease (O'Keefe et al. Lancet 1980;2:615-617; Morgan et al. Gut 1976;17:113-118). Factors contributing to the high prevalence include poor dietary intake, elevated resting energy expenditure, and nutrient malabsorption (McCullough A J and Tavill A S. Seminars in Liver Disease 1991;11:265-277). Patients with end stage liver disease complicated by portal hypertension are particularly likely to be malnourished and, when hospitalized, frequently require active nutritional therapy. While the effects of malnutrition in chronic liver disease on fatty acid nutrition have not been extensively studied, because of an increased resting energy expenditure, fat malabsorption and abnormal fat catabolism, these patients may have significant abnormalities in fatty acid metabolism (Cabre et al. Am J Gastroent 1988;83:712-717; Palombo et al. Gastroenterology 1987;93: 1170-1177). One potential mechanism for such a disturbance would be an inadequate intake of essential fatty acids as part of the global protein calorie malnutrition. Dietary fatty acids are classified according to their chain length. Long chain fatty acids contain 14 carbons or greater and can be further characterized by the number of double bonds contained in their structure into saturated, monounsaturated and polyunsaturated subgroups. The two fatty acids essential in human nutrition are linoleic acid and alpha-linolenic acid from which polyunsaturated fatty acids of the omega 6 series and omega 3 series are formed through enzymatic desaturation and elongation by the liver. The body cannot convert omega 3 fatty acids to omega 6 fatty acids or vice versa. Patients with advanced liver disease may have an impaired ability to form polyunsaturated fatty acids,

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including arachidonic and eicosapentaenoic acid, from their essential fatty acid precursors, potentially altering membrane composition and eicosanoid production. It has now been demonstrated that there is a defect in elongation and desaturation in end stage liver disease, resulting in dramatically reduced levels of the polyunsaturated fatty acids such as arachidonic, eicosapentaenoic, and docosahexaenoic acid. Although there may be some degree of concurrent linoleic acid deficiency, the ratio of linoleic/arachidonate confirms that elongation and desaturation is the limiting factor. Arachidonic acid levels in tissue phospholipids are usually very tightly regulated, such that arachidonic acid levels are stable at varying levels of linoleic acid content in the diet. Only with essential (linoleic) fatty acid deficiency or with the consumption of omega 3 fatty acids in place of omega 6 fatty acids do arachidonic acid levels fall. Given the importance of arachidonic acid in second messenger metabolism, it is reasonable to suspect that some of the untoward side effects of end stage liver disease, including decreased immunocompetence and increased risk of infection and infectious mortality, may be a consequence of functional essential fatty acid deficiency. In the normal diet arachidonic acid is very low, because it is only found in any quantity in the membranes of animal flesh. To add arachidonic acid alone to a diet formulation is problematic, since arachidonic acid supplementation in normal individuals is pro-inflammatory and immunosuppressive. In the alternative, to give eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which provide benefits regarding immunosuppression, would likely lead to a worsening of arachidonic acid levels, and potentially essential fatty acid deficiency. Web site: http://www.delphion.com/details?pn=US05993221__ •

Genes coding proteins for early liver development and their use in diagnosing and treating liver disease Inventor(s): Mishra; Lopa (6910 Oakridge Ave., Bethesda, MD 20815) Assignee(s): none reported Patent Number: 6,642,362 Date filed: November 1, 1999 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, and antibodies, such as the antibodies to mouse elf protein, may be raised which recognize these proteins or to peptides derived from these proteins. Since the early developing liver proteins 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 these 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 peptides and proteins isolated during early liver development, genes coding for these peptides and proteins, and antibodies raised to

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these proteins, 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=US06642362__ •

Glycosylated cytokines Inventor(s): Doken; Kazuhiro (Osaka, JP), Hamaguchi; Naoru (Osaka, JP), Sato; Jun (Kawanishi, JP) Assignee(s): Takeda Chemical Industries, Ltd. (Osaka, JP) Patent Number: 5,643,564 Date filed: May 31, 1995 Abstract: Disclosed is a sugar-modified cytokine which ensures migration of almost all of the dose of cytokine to the liver rapidly after administration to the live body and which can be advantageously used to enhance the effect of liver disease therapy and mitigate side effects. Excerpt(s): The present invention relates to a sugar-modified cytokine useful as a pharmaceutical. With the recent advances in biotechnology, a large number of cytokines have been isolated and purified. Also, as their mass production has become possible, they are now expected as candidate substances for new pharmaceuticals. However, many problems remain to be solved before such expectation is realized, among which is the development of a targeting drug delivery system for the desired cytokine. To strictly control cytokine behavior in vivo is assumed to be a key to enhancement of therapeutic effects and mitigation of side effects. For example, interferon, a kind of cytokine, is a protein possessing diverse bioactivities such as antiviral activity and cell growth inhibition. For this pharmacological action, interferon is used to treat a large number of diseases, particularly chronic active hepatitis B and C and renal cancer. However, because interferon hardly migrates to the liver when administered to the live body and because it is quickly excreted from the body, it is difficult to maintain an effective

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concentration of interferon in the liver. For this reason, in order for the treatment of liver disease to be effective, high-dose long-term therapy is necessary, which involves the risk of side effects. Web site: http://www.delphion.com/details?pn=US05643564__ •

HAS2 splicing variant HOEFC11: a target in chronic renal failure, inflammatory diseases and myocardial ischemia Inventor(s): Nambi; Ponnal (Berwyn, PA), Pullen; Mark A (Colmar, PA), Zhu; Yuan (Blue Bell, PA) Assignee(s): SmithKline Beecham Corporation (Philadelphia, PA) Patent Number: 5,994,100 Date filed: May 29, 1997 Abstract: HOEFC11 polypeptides and polynucleotides and methods for producing such polypeptides by recombinant techniques are disclosed. Also disclosed are methods for utilizing HOEFC11 polypeptides and polynucleotides in the design of protocols for the treatment of chronic renal failure, inflammatory diseases, myocardial ischemia, cancer, rheumatoid arthritis, cirrhotic liver disease, 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 hyaluronan synthase family, hereinafter referred to as HOEFC11. The invention also relates to inhibiting or activating the action of such polynucleotides and polypeptides. Hyaluronic acid (HA), an important constituent of extracellular matrix, is a linear polysaccharide of alternating glucuronic acid and N-acetyl glucosamine residues. It is synthesized by a membrane-bound enzyme hyaluronan synthase (HAS) and extruded into the extracellular space. Cloning of two human HAS (HAS 1 and HAS 2) has been reported very recently (K. Watanabe and Y. Yamaguchi, J. Biol. Chem. 271:22945-22948, 1996) (N. Itano and K. Kimata, Biochem. Biophy. Res. Communications, 222:816-820, 1996). HA synthesis is involved in many cellular functions such as migration, invasion, adhesion, transformation, proliferation and wound healing. HA synthesis has been shown to be induced by FBS, PDGF, EGF, IL-1, retinoic acid, IGF, TGF beta, etc. Increased HA production is: (a) a general phenomenon in various organs attached by inflammatory cells, (b) implicated in tissue edema, (c) a characteristic of tissue remodeling and (d) a marker for early stage of extracellular matrix remodeling following vascular injury. Increased levels of HA have been reported in chronic renal failure, inflammatory diseases, cancer (prostate, mammary and other invasive tumors), aortas from diabetic patients, smaller airways of patients with acute alveolitis, transplantation edema in rejecting heart and kidney, myocardial ischemia, balloon injury, liver cirrhosis, wound healing and angiogenesis. Hyaluronidase (breaks down HA) is reported to be beneficial in limiting cellular damage during myocardial ischemia in rat, dog and man. This indicates that the hyaluronan synthase family has an established, proven history as therapeutic targets. Clearly there is a need for identification and characterization of further members of the hyaluronan synthase family which can play a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, chronic renal failure, inflammatory diseases, myocardial ischemia, cancer, rheumatoid arthritis, cirrhotic liver disease. In one aspect, the invention relates to HOEFC11 polypeptides and recombinant materials and methods

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for their production. Another aspect of the invention relates to methods for using such HOEFC11 polypeptides and polynucleotides. Such uses include the treatment of chronic renal failure, inflammatory diseases, myocardial ischemia, cancer, rheumatoid arthritis, cirrhotic liver disease, among others. In still another aspect, the invention relates to methods to identify agonists and antagonists using the materials provided by the invention, and treating conditions associated with HOEFC11 imbalance with the identified compounds. Yet another aspect of the invention relates to diagnostic assays for detecting diseases associated with inappropriate HOEFC11 activity or levels. Web site: http://www.delphion.com/details?pn=US05994100__ •

Hepatitis C virus-derived peptides capable of inducing cytotoxic T lymphocyte responses Inventor(s): Cerny; Andreas (La Jolla, CA), Chisari; Francis V. (Del Mar, CA) Assignee(s): The Scripps Research Institute (La Jolla, CA) Patent Number: 5,709,995 Date filed: March 17, 1994 Abstract: The hepatitis C virus (HCV) is the major cause of non-A, non-B vital hepatitis. The most striking feature of HCV induced liver disease is its tendency toward chronicity and slowly progressive liver cell injury. HLA Class I-restricted cytotoxic T lymphocyte (CTL) responses are considered to be a sine qua non for the effective clearance of vital infections. However, the characteristics of HCV-specific cytotoxic effector cells and identification of their cognate target antigens remains to be elucidated. This invention discloses novel HCV-derived peptides that are recognized by patient CTL. Peripheral blood mononuclear cells (PBMC) were obtained from HLA-A2 positive patients with chronic HCV infection and stimulated with HCV-derived peptides. Effector cells were tested for their ability to lyse HLA-A2-matched target cells sensitized either with a peptide or a vaccinia virus construct containing HCV sequences. Immunogenic HCV CTL peptides were identified in the putative core protein and nonstructural proteins (e.g., NS3-5). These peptides have the following amino acid sequences: ADLMGYIPLV (Core.sub.131-140), LLALLSCLTV (Core.sub.178-187), QLRRHIDLLV (E1.sub.257-266) , LLCPAGHAV (NS3.sub.1169-1177), KLVALGINAV (NS3.sub.1406-1415), SLMAFTAAV (NS4.sub.1789-1797) , LLFNILGGWV (NS4.sub.1807-1816), ILDSFDPLV (NS5.sub.2252-2260), and DMLGYIPLV (Core.sub.132-140). These peptides facilitate the stimulation and identification of HCVspecific CTL and should provide useful diagnostic reagents for the detection of HCV infection. Excerpt(s): The present invention relates to the isolation and use of compounds having substantial homology to hepatitis C virus-specific cytotoxic T cell lymphocyte epitopes for the immunization and treatment of mammals afflicted with or at risk of exposure to chronic and acute hepatitis C viral hepatitis. Hepatitis C virus ("HCV") was originally identified as a causative agent of transfusion-associated hepatitis that had a propensity to induce acute and chronic hepatitis and hepatocellular carcinoma. Choo et al., Science, 244, 359-362 (1989). It is a major cause of morbidity and mortality worldwide, considering that at least 50% of infected persons will develop chronic hepatitis, and 20% of these will further develop cirrhosis. Dienstag, Gastroenterology, 85, 439 (1983). No cure is currently available for treatment of chronic or acute HCV infection. The complete nucleotide sequence and genetic organization of HCV has been fully elucidated by Choo et al., Proc. Natl. Acad. Sci. USA, 88, 2451-2455 (1991). The HCV genome of positive-

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stranded RNA consists of 9,379 nucleotides and has a single large open reading frame that could encode a viral polyprotein precursor of 3,011 amino acids. Although there is little overall similarity in sequence between that of HCV and other viruses whose sequence is known, a portion of the sequence (upstream of the 5' end of the open reading frame) is similar to the analogously positioned sequence of pestiviral genomes. The polyprotein also displays significant sequence similarity to helicases encoded by animal pestiviruses and human flaviviruses, among others. Comparison of the hydrophobicity profiles of the sequence of encoded amino acids, and comparison of such a profile between HCV and a flavivirus (yellow fever virus), for example, has resulted in the assignment of regions of the HCV genome as relating to proteins forming the capsid or core (C), and the envelope (E1 and E2), as well as five regions that specify nonstructural proteins (NS1 through NS5). Web site: http://www.delphion.com/details?pn=US05709995__ •

HMVAB41 Inventor(s): Gallagher; Kathleen Theresa (Willow Grove, PA), Hurle; Mark R (Norristown, PA), Kikly; Kristine Kay (Linfield, PA) Assignee(s): SmithKline Beecham Corporation (Philadelphia, PA) Patent Number: 5,932,446 Date filed: November 26, 1997 Abstract: HMVAB41 polypeptides and polynucleotides and methods for producing such polypeptides by recombinant techniques are disclosed. Also disclosed are methods for utilizing HMVAB41 polypeptides and polynucleotides in the design of protocols for the treatment of cancer, inflammation, autoimmunity, allergy, asthma, rheumatoid arthritis, CNS inflammation, cerebellar degeneration, Alzheimer's disease, Parkison's disease, multiple sclerosis, amylotrophic lateral sclerosis, head injury damage, and other neurological abnormalities, septic shock, sepsis, stroke, osteoporosis, osteoarthritis, ischemia reperfusion injury, cardiovascular disease, kidney disease, liver disease, ischemic injury, myocardial infarction, hypotension, hypertension, AIDS, myelodysplastic syndromes and other hematologic abnormalities, aplastic anemia, male pattern bladness, and bacterial, fungal, protozoan and viral infections, 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, hereinafter referred to as HMVAB41. The invention also relates to inhibiting or activating the action of such polynucleotides and polypeptides. The drug discovery process is currently undergoing a fundamental revolution as it embraces `functional genomics`, that is, high throughput genome- or gene-based biology. This approach is rapidly superceding earlier approaches based on `positional cloning`. A phenotype, that is a biological function or genetic disease, would be identified and this would then be tracked back to the responsible gene, based on its genetic map position. Functional genomics relies heavily on the various tools of bioinformatics to identify gene sequences of potential interest from the many molecular biology databases now available. There is a continuing need to identify and characterise further genes and their related polypeptides/proteins, as targets for drug discovery. This indicates that HMVAB41 related genes have an established, proven history as therapeutic targets. Clearly there is a need for identification and characterization of further members of this family which can play a role in preventing, ameliorating or correcting dysfunctions or diseases,

Patents 165

including, but not limited to, cancer, inflammation, autoimmunity, allergy, asthma, rheumatoid arthritis, CNS inflammation, cerebellar degeneration, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amylotrophic lateral sclerosis, head injury damage, and other neurological abnormalities, septic shock, sepsis, stroke, osteoporosis, osteoarthritis, ischemia reperfusion injury, cardiovascular disease, kidney disease, liver disease, ischemic injury, myocardial infarction, hypotension, hypertension, AIDS, myelodysplastic syndromes and other hematologic abnormalities, aplastic anemia, male pattern baldness, and bacterial, fungal, protozoan and viral infections. Web site: http://www.delphion.com/details?pn=US05932446__ •

Human requiem Inventor(s): Gross; Mitchell S (Wayne, PA), Hurle; Mark Robert (Norristown, PA), Kikly; Kristine Kay (Linfield, PA) Assignee(s): SmithKline Beecham Corporation (Philadelphia, PA) Patent Number: 5,919,660 Date filed: June 24, 1997 Abstract: Human REQUIEM polypeptides and DNA (RNA) encoding such REQUIEM and a procedure for producing such polypeptides by recombinant techniques is disclosed. Also disclosed are methods for utilizing such REQUIEM for the treatment of a susceptibility to viral infection, tumorogenesis and to diseases and defects in the control embryogenesis and tissue homeostasis, and the nucleic acid sequences described above may be employed in an assay for ascertaining such susceptibility. Antagonists against such REQUIEM and their use as a therapeutic to treat Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, septic shock, sepsis, stroke, CNS inflammation, osteoporosis, ischemia reperfusion injury, cell death associated with cardiovascular disease, polycystic kidney disease, apoptosis of endothelial cells in cardiovascular disease, degenerative liver disease, MS, ALS, cererbellar degeneration, ischemic injury, myocardial infarction, AIDS, myelodysplastic syndromes, aplastic anemia, male pattern baldness, and head injury damage are also disclosed. Also disclosed are diagnostic assays for detecting diseases related to mutations in the nucleic acid sequences and altered concentrations of the polypeptides. Also disclosed are diagnostic assays for detecting mutations in the polynucleotides encoding REQUIEM polypeptide and for detecting altered levels of the polypeptide in a host. Excerpt(s): This invention relates, in part, to newly identified polynucleotides and polypeptides; variants and derivatives of the polynucleotides and polypeptides; processes for making the polynucleotides and the polypeptides, and their variants and derivatives; agonists and antagonists of the polypeptides; and uses of the polynucleotides, polypeptides, variants, derivatives, agonists and antagonists. In particular, in these and in other regards, the invention relates to polynucleotides and polypeptides of a human homologue of murine requiem gene, hereinafter referred to as "REQUIEM". Hematopoietic stem cell proliferation, differentiation and apoptosis, are regulated by various growth factors and cytokines (Metcalf, D., Science 254, 529-531 (1992) and Vaux et al., Nature 335, 440-442 (1988)). Such cells committed to the myeloid lineage express high affinity receptors for GM-CSF1 and IL-3 (Miyajima et al., Blood 82,1960-1973 (1993)). Moreover, such cells develop a requirement for GM-CSF or IL-3 to survive and undergo apoptosis in response to GM-CSF or IL-3 deprivation (Williams et al., Nature 343, 76-79 (1990)). Hematopoietic cells are not unique in their requirement for growth factors for survival. Throughout development, cells of all lineages require

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proper signals to grow and differentiate. Failure to receive these signals often results in death of the cells by apoptosis. Even in the adult organism there is constant renewal and/or maintence of cells that requires growth factors and cytokines. Inappropriate cessation of signals from these growth factors may result in apoptosis thereby causing disfunction or disease. Web site: http://www.delphion.com/details?pn=US05919660__ •

Ileal bile acid transporter compositions and methods Inventor(s): Dawson; Paul A. (2111 Carriage Way, Chapel Hill, NC 27514) Assignee(s): none reported Patent Number: 5,589,358 Date filed: December 29, 1993 Abstract: Bile acids are absorbed from the small intestine by an passive and an active mechanism. The active mechanism involves a Na.sup.+ /bile acid cotransporter. A cDNA encoding the ileal bile acid cotransporter has been isolated and sequenced. The amino acid sequence of the cotransporter protein is also disclosed. The renal bile acid cotransporter is also shown to be identical to the ileal cotransporter. The cotransporter disclosed herein will have use in treatment of hypercholesterolemia, diabetes, heart disease and liver disease. In addition, methods of screening man made and naturally occurring substances for the discovery of new bile acid transport inhibitors and activators and methods of detecting mutations in human ileal/renal bile acid transporter genes are disclosed. Excerpt(s): The present invention relates generally to the fields of sodium/bile acid cotransport systems in the ileum and kidney. Certain embodiments of the invention relate to the medically related fields of the control of blood cholesterol levels and treatments of diabetes, heart disease, liver disease and various digestive disorders. More particularly, the invention concerns the isolation and purification of bile acid cotransporter proteins and cDNA clones encoding the proteins and the use of these proteins and nucleic acids in therapeutic, preventative, genetic counseling and reagent screening applications. Bile acids are acidic sterols synthesized from cholesterol in the liver. Following synthesis, the bile acids are secreted into bile and enter the lumen of the small intestine, where they facilitate absorption of fat-soluble vitamins and cholesterol. Bile acids are then absorbed from the small intestine, returned to the liver via the portal circulation, and resecreted into bile. In the small intestine, bile acids are absorbed by both passive and active mechanisms (Dietschy, 1968). The active absorption of bile acids, first described by Lack and Weiner (1961), has been shown in man and experimental animals to be restricted to the ileum (Krag and Phillips, 1974; Schiff et al., 1972; Lack, 1979). The first step in the active uptake of bile acids is mediated by a Na.sup.+ gradientdriven transporter located at the brush border (apical) membrane of the ileocyte (Wilson, 1981). Once inside the enterocyte, bile acids are transported across the cell to the basolateral membrane and secreted into the portal circulation via a Na.sup.+ independent organic anion exchange system (Weinberg et al., 1986). The transport kinetics and specificity of this Na.sup.+ /bile acid cotransport system have been studied extensively using everted ileal gut sacs (Schiff et al., 1972; Lack, 1979), isolated ileocytes (Wilson et al., 1975; Schwenk et al., 1983), and ileal brush border membranes (Barnard and Ghishan, 1987; Kramer et al., 1992; Wilson and Treanor, 1979). Web site: http://www.delphion.com/details?pn=US05589358__

Patents 167

•

Immunoassay means and methods useful in human native prothrombin and human abnormal prothorombin determinations Inventor(s): Blanchard; Rita A. (Newton, MA), Furie; Barbara C. (Wellesley, MA), Furie; Bruce E. (Wellesley, MA) Assignee(s): New England Medical Center Hospitals, Inc. (Boston, MA) Patent Number: 4,769,320 Date filed: October 15, 1984 Abstract: Antibodies which form immune complexes with human native prothrombin only, in the presence of mixtures of human native prothrombin and human abnormal prothrombin as well as antibodies which form antibody antigen complexes with human abnormal prothrombin in the presence of such mixtures have been obtained. Immunoassay techniques are used for qualitative and quantitative determinations of these antigens in human plasma or serum. Unique methods of obtaining the antibodies are described including obtaining antibodies to native prothrombin by dissociation of antigen antibody complexes formed in the presence of calcium ions with a material having a greater affinity constant for binding with calcium ions than does prothrombin. Dissociation of the complex in this manner yields human native prothrombin antibodies which are specific and non-reactive with human abnormal prothrombin. A process is described in which assays are applied to the sensitive detection of vitamin K deficiency and various forms of liver disease including hepatocellular carcinoma, and to monitoring of anticoagulant therapy with sodium warfarin. The invention described herein was made in the course of working under a grant from the Department of Health and Human Services. Excerpt(s): Prothrombin is a vitamin K dependent plasma protein involved in the final stages of blood coagulation as has been well-known for some time. It has a molecular weight of about 72,000 and contains about 12% carbohydrate. Prothrombin is a calciumbinding protein that undergoes a conformational transition in the presence of calcium as is known. The proteolytic activation of prothrombin to thrombin is a critical step in normal hemostasis. Prothrombin is synthesized in the liver where a prothrombin precursor undergoes post-translational modification to yield the functional form of prothrombin which is known as "native prothrombin" and contains.gamma.carboxyglutamic acid. In the presence of vitamin K antagonists, such as sodium warfarin also known as Coumadin, a trademarked product of Endo Laboratories division of DuPont Corp. of Wilmington, Del., or in the absence of vitamin K, the prothrombin activity in the blood may be significantly diminished. This can be measured indirectly by the prothrombin time, a one-stage coagulation assay, or by direct measurement of prothrombin coagulant activity using prothrombin deficient substrate plasma. Severe liver disease may also be associated with low plasma prothrombin activity. Thus impaired synthesis of protein (liver disease), inadequate supplies of vitamin K (vitamin K deficiency) or drugs that inhibit the action of vitamin K (sodium warfarin) lead to diminished plasma prothrombin activity in humans and other mammals. Coumadin is the trade name for warfarin. When Coumadin is used as an oral anticoagulant as is widely done in the therapy or prevention of thrombotic disease, it lowers the activity of vitamin K dependent blood coagulation proteins such as prothrombin. The appropriate Coumadin dose is established by monitoring the prothrombin time. The prothrombin time is maintained at one and a half to two and a half times that obtained with normal plasma. In 1968 an altered from of prothrombin known as "abnormal prothrombin" and "human abnormal prothrombin" as opposed to human native prothrombin was discovered in the plasma of human patients treated

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with sodium warfarin. Abnormal prothrombin has low prothrombin activity but cross reacts with many prothrombin antisera. Abnormal prothrombin from bovine blood was first isolated in 1972. Such abnormal prothrombin was found to have about 3% of the coagulant activity of an equivalent amount of native prothrombin. Otherwise, the molecular weight, carbohydrate composition and amino acid composition of the acid hydrolysate were substantially identical within experimental error. In the early 70's it was discovered that bovine abnormal prothrombin unlike prothrombin does not bind to barium salts and does not bind to calcium ions. It was subsequently shown that the functional differences between abnormal and native prothrombin relate to the structural differences between these proteins and full prothrombin function requires intact calcium binding sites. In the mid-70's it was discovered that a theretofore unknown amino acid.gamma.-carboxyglutamic acid occurred in bovine prothrombin and was lacking in abnormal bovine prothrombin. This amino acid seemed to be required for the full expression of prothrombin coagulant activity. Abnormal prothrombin is known to have no coagulant activity, does not bind metal ions and does not contain.gamma.carboxyglutamic acid. Other researchers have theorized that prothrombin is synthesized in the liver in a precursor form containing glutamic acid instead of.gamma.carboxyglutamic acid. A carboxylation process in the liver modifies glutamic acid to form.gamma.-carboxyglutamic acid. This enzyme system requires vitamin K and is inhibited by vitamin K antagonists. Web site: http://www.delphion.com/details?pn=US04769320__ •

Interleukin-1.beta. converting enzyme like apoptotic protease-6 Inventor(s): Dixit; Vishva M. (AnnArbor, MI), He; Wei-Wu (Columbia, MD), Kikly; Kristine K. (Linfield, PA), Ruben; Steven M. (Olney, MD) Assignee(s): Smithkline Beecham Corporation (Philadelphia, PA) Patent Number: 6,010,878 Date filed: May 8, 1997 Abstract: Human ICE LAP-6 polypeptides and DNA (RNA) encoding such ICE LAP-6 and a procedure for producing such polypeptides by recombinant techniques is disclosed. Also disclosed are methods for utilizing such ICE LAP-6 for the treatment of a susceptibility to viral infection, tumorogenesis and to diseases and defects in the control embryogenesis and tissue homeostasis, and the nucleic acid sequences described above may be employed in an assay for ascertaining such susceptibility. Antagonists against such ICE LAP-6 and their use as a therapeutic to treat Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, septic shock, sepsis, stroke, chronic inflammation, acute inflammation, CNS inflammation, osteoporosis, ischemia reperfusion injury, cell death associated with cardiovascular disease, polycystic kidney disease, apoptosis of endothelial cells in cardiovascular disease, degenerative liver disease, MS, ALS, cererbellar degeneration, ischemic injury, myocardial infarction, AIDS, myelodysplastic syndromes, aplastic anemia, male pattern baldness, and head injury damage are also disclosed. Also disclosed are diagnostic assays for detecting diseases related to mutations in the nucleic acid sequences and altered concentrations of the polypeptides. Also disclosed are diagnostic assays for detecting mutations in the polynucleotides encoding the interleukin-1 beta converting enzyme apoptosis proteases and for detecting altered levels of the polypeptide in a host. Excerpt(s): This invention relates, in part, to newly identified polynucleotides and polypeptides; variants and derivatives of the polynucleotides and polypeptides;

Patents 169

processes for making the polynucleotides and the polypeptides, and their variants and derivatives; agonists and antagonists of the polypeptides; and uses of the polynucleotides, polypeptides, variants, derivatives, agonists and antagonists. In particular, in these and in other regards, the invention relates to polynucleotides and polypeptides of human interleukin-1 beta converting enzyme apoptosis protease-6, hereinafter referred to as "ICE LAP-6". It has recently been discovered that an interleukin-1.beta. converting enzyme (ICE) is responsible for cleaving pro-IL-1.beta. into mature and active IL-1.beta. and is also responsible for programmed cell death (or apoptosis), which is a process through which organisms get rid of unwanted cells. In the nematode Caenorhabditis elegans, a genetic pathway of programmed cell death has been identified (Ellis, R. E., et al. Annu. Rev. Cell Biol., 7:663-698 (1991)). Two genes, ced-3 and ced-4, are essential for cells to undergo programmed cell death in C. elegans (Ellis, H. M., and Horvitz, H. R., Cell, 44:817-829 (1986)). It is becoming apparent that a class of cysteine proteases homologous to Caenorhabditis elegans Ced-3 play the role of "executioner" in the apoptotic mechanism (Martin, S. J., and Green, D. R. (1995) Cell 82, 349-352; Chinnaiyan, A. a. D., VM. (1996) Current Biology 6; Henkart, P. (1996) Immunity 4, 195-201). Recessive mutations that eliminate the function of these two genes prevent normal programmed cell death during the development of C. elegans. The known vertebrate counterpart to ced-3 protein is ICE. The overall amino acid identity between ced-3 and ICE is 28%, with a region of 115 amino acids (residues 246360 of ced-3 and 164-278 of ICE) that shows the highest identity (43%). This region contains a conserved pentapeptide, QACRG (SEQ ID NO:10) (residues 356-360 of ced-3), which contains a cysteine known to be essential for ICE function. Web site: http://www.delphion.com/details?pn=US06010878__ •

Interleukin-1 beta converting enzyme like apoptotic protease-7 Inventor(s): Dixit; Vishva M. (Ann Arbor, MI), Kikly; Kristine K. (Linfield, PA), Ni; Jian (Rockville, MD), Rosen; Craig A. (Laytonsville, MD), Ruben; Steven M. (Olney, MD) Assignee(s): Human Genome Sciences, Inc. (Rockville, MD), Smithkline Beecham Corporation (Philadelphia, PA), The Regents of the University of Michigan (Ann Arbor, MI) Patent Number: 6,008,042 Date filed: May 7, 1997 Abstract: Human ICE LAP-7 polypeptides and DNA (RNA) encoding such ICE LAP-7 and a procedure for producing such polypeptides by recombinant techniques is disclosed. Also disclosed are methods for utilizing such ICE LAP-7 for the treatment of a susceptibility to viral infection, tumorogenesis and to diseases and defects in the control embryogenesis and tissue homeostasis, and the nucleic acid sequences described above may be employed in an assay for ascertaining such susceptibility. Antagonists against such ICE LAP-7 and their use as a therapeutic to treat Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, septic shock, sepsis, stroke, chronic inflammation, acute inflammation, CNS inflammation, osteoporosis, ischemia reperfusion injury, cell death associated with cardiovascular disease, polycystic kidney disease, apoptosis of endothelial cells in cardiovascular disease, degenerative liver disease, MS, ALS, cererbellar degeneration, ischemic injury, myocardial infarction, AIDS, myelodysplastic syndromes, aplastic anemia, male pattern baldness, and head injury damage are also disclosed. Also disclosed are diagnostic assays for detecting diseases related to mutations in the nucleic acid sequences and altered concentrations of the polypeptides.

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Also disclosed are diagnostic assays for detecting mutations in the polynucleotides encoding the interleukin-1 beta converting enzyme apoptosis proteases and for detecting altered levels of the polypeptide in a host. Excerpt(s): Apoptosis, or programmed cell death (PCD), is a genetically regulated mechanism with a central role in both metazoan development and homeostasis. (Raff, 1992; Steller, 1995). The cell death machinery is conserved throughout evolution (Vaux et al., 1994) and is composed of several distinct parts including effectors, inhibitors and activators (Chinnaiyan and Dixit, 1996; Steller, 1995). Invertebrate model systems have been invaluable in identifying and characterizing the genes that control apoptosis. (Hengartner, 1996). While numerous candidate genes have been identified, how they interact to execute the apoptotic program is poorly understood. It is becoming apparent that cysteine proteases related to the Caenorhabditis elegans cell death gene ced-3 represent the effector components of the apoptotic machinery. The first mammalian homolog of CED-3 identified was interleukin-1.beta. converting enzyme (ICE). (Yuan et al., 1993). Overexpression of ICE or CED-3 in Rat-1 fibroblasts induced apoptosis, suggesting that ICE was functionally, as well as structurally, related to CED-3. (Miura et al., 1993). However, such evidence is only a correlation, as ectopic expression of a number of proteases, including chymotrypsin, proteinase K and trypsin, cause significant apoptosis. (Williams and Henkart, 1994). Further studies suggested that proteases related to ICE, rather than ICE itself, may play a more important role in the apoptotic mechanism. First, a number of cell types stably secrete mature IL-1.beta. without undergoing apoptosis. Second, ICE-deficient mice, although unable to generate active IL-1.beta., fail to exhibit a prominent cell death defective phenotype,(Kuida et al., 1995; Li et al., 1995). Third, in an in vitro model of apoptosis, condemned phase extracts prepared from chicken DU249 cells failed to cleave the primary substrate of ICE, pro-IL1b. (Lazebnik et al., 1994). Instead, a proteolytic activity in these extracts, termed prICE, cleaved the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) into signature apoptotic fragments. (Lazebnik et al., 1994). Purified ICE failed to cleave PARP (Lazebnik et al., 1994; Tewari et al., 1995), suggesting that prICE was distinct from ICE. Web site: http://www.delphion.com/details?pn=US06008042__ •

Medicinal herbal composition for treating liver diseases and HIV Inventor(s): Wu; Tzu-Sheng (No. 3, Lane 14, Jian-Gung 1st Road, Hsinchu, 300, TW) Assignee(s): none reported Patent Number: 6,455,078 Date filed: July 18, 2001 Abstract: The present invention provides a herbal pharmaceutical composition for treating patients with liver diseases and/or HIV. The composition contains fifteen (15) ingredients, which are diffuse hedyotis, bistort rhizome, giant knotweed rhizome, Asiatic moonseed rhizome, baical skullcap root, bovine biliary powder, milkvetch root, barbary wolfberry fruit, sanqi, red ginseng, figwort root, Chinese magnoliavine fruit, turmeric root-tuber, hawthorn fruit, and Chinese angelica. Among the fifteen (15) ingredients, diffuse hedyotis, bistort rhizome, giant knotweed rhizome, and Chinese magnoliavine fruit are the required herbs which contribute to the efficacy of the pharmaceutical composition. Excerpt(s): The present invention relates to a novel herbal pharmaceutical composition and its use for treating patients with liver diseases (e.g., viral hepatitis [such as

Patents 171

Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, and Hepatitis E], alcoholic or fatty liver, liver cirrhosis, and liver cancer) and HIV. The major ingredients in the herbal composition are diffuse hedyotis, bistort rhizome, giant knotweed rhizome, and Chinese magnoliavine fruit. The composition further contains Asiatic moonseed rhizome, baical skullcap root, bovine biliary powder, tumeric root-tuber, hawthorn fruit, sanqi, barbary wolfberry fruit, red ginseng, figwort root, Chinese angelica, and milkvetch root. The present invention also relates to a method for making the medicinal herbal composition and methods for treating patients with the medicinal herbal composition. Liver diseases have great impact on human health. Hepatitis is a kind of liver diseases, which is caused by liver inflammation due to infection of a variety of pathogens, which include, but are not limited to, viruses, bacteria, fungi, and protozoa. Hepatitis can be categorized as acute, chronic, or fulminant. Viral hepatitis is an enterically transmitted liver disease due to viral infection. The major transmission means for viral hepatitis is through ingestion. Viral hepatitis can also be transmitted through blood transfusion or similar means of hepatitis-virus-carrying blood or blood product such as blood plasma. Viral hepatitis is widespread around the world. For example, there are approximately thirty million (30,000,000) viral hepatitis patients in China including an estimated number of nine million (9,000,000) new patients each year, and about one hundred million (100,000,000) hepatitis B virus (HBV) carriers. It is estimated that 10% of the pregnant women in China are HBV carriers. About one hundred thousand (100,000) people in China die of liver cancer originated as liver diseases each year. Web site: http://www.delphion.com/details?pn=US06455078__ •

Medicines for use in the therapy and prevention of kidney and liver diseases Inventor(s): Kakegawa; Hisao (Tokushima, JP), Matsumoto; Hitoshi (Tokushima, JP), Sato; Toshio (Tokushima, JP) Assignee(s): Dainippon Ink and Chemicals, Inc. (Tokyo, JP), Nippon Hypox Laboratories Incorporated (Tokyo, JP) Patent Number: 4,898,890 Date filed: December 23, 1987 Abstract: A novel medicine containing isoliquiritigenin as the active ingredient is disclosed, which exhibits excellent effects when used as a medicine for the therapy and prevention of kidney diseases, a medicine for the therapy and prevention of liver diseases, and a medicine for the therapy and prevention of complication resulting from diseases of these organs. Excerpt(s): The present invention relates to medicines for use in the therapy and prevention of kidney and liver diseases, and more particularly to medicines of this kind which can exhibit excellent therapeutic and preventive effects with respect to kidney or liver diseases individually developed or to complications resulting from diseases of these organs. As is well known, the kidney in a vital organism performs at its renal tubule and with its filtration and secretion mechanism the function of excreting into the urine waste substances from blood and noxious substances taken up by the vital organism, such as drugs and toxic substances. On the other hand, the liver in a vital organism performs three major functions, as listed below. Namely, the liver first acts as a digestive gland and secretes 500 to 1000 cc of bile per day to assist in the digestion and absorption of fats by the small intestines. Its second function is to process chemical changes, storage, and use of various nutrients within the body; in brief, it is an intermediate metabolism. Thirdly, the liver performs detoxication by subjecting noxious

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substances, such as toxin, from outside the body and toxic substances produced within the body, to detoxication treatments such as oxidization, reduction and inclusion, and by mixing these substances with bile to dispose of them or by sending them to the kidney for excretion into the urine. Web site: http://www.delphion.com/details?pn=US04898890__ •

Method and composition for treatment of patients having decompensated liver disease Inventor(s): Chretien; Paul B. (Rockville, MD), Mutchnick; Milton G. (West Bloomfield, MI) Assignee(s): Alpha 1 Biomedicals, Inc. (Bethesda, MD), The Board of Governors of Wayne State Univ. (Detroit, MI) Patent Number: 5,750,501 Date filed: September 26, 1996 Abstract: A method and composition for treating a Hepatitis B patient having hepatic decompensation utilizes Hepatitis B virus-reducing amounts of T.alpha.sub.1, administered to a patient having decompensated liver disease so as to render the patient seronegative for Hepatitis B virus DNA. Excerpt(s): The present invention relates to a method and composition for treating patients having hepatic decompensation. Hepatic decompensation is liver failure which can result from chronic or chronic active infection of a patient by Hepatitis B virus. Of several known therapeutic agents which have been proposed for use in the treatment of Hepatitis B, the most extensively evaluated is interferon alpha-2b (hereinafter ".alpha.interferon"), available commercially as INTRON.RTM. A. Unfortunately, the response rate of chronic Hepatitis B patients to.alpha.-interferon has been less than 50%. With the establishment of liver transplantation as a therapeutic modality for a variety of liver diseases, new expectations were raised for a cure of hepatic decompensation resulting from Hepatitis B infection. Unfortunately after some years of experience with liver transplantation, it is apparent that the rate of reoccurrence of Hepatitis B infection following transplantation is high. Web site: http://www.delphion.com/details?pn=US05750501__

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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

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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__ •

Method for the measurement of serum bile acids by elisa and method for the diagnosis of liver disease Inventor(s): Kano; Motonari (Tokyo, JP), Matsumoto; Masaru (Tokyo, JP) Assignee(s): Yuugengaisha B.S.R. (Tokyo, JP) Patent Number: 5,631,138 Date filed: January 31, 1995 Abstract: A method for the measurement of serum bile acids by ELISA comprising: preparing a bile acid active ester, reacting the ester with a bovine serum albumin solution, dialyzing, and immunizing a mammal other than human being with the dialyzate thus obtained as an antigen to thereby give an anti-bile acid antibody; reacting said active ester with an enzyme to thereby prepare an enzyme-labeled bile acid as an enzyme-labeled antigen; to a secondary antibody-coated plate, adding a dilution of the serum to be assayed, an anti-bile acid antibody solution and an enzyme-labeled antigen solution and reacting these substances followed by the addition of a substrate and the reaction therewith; measuring the absorbance of the reaction mixture and determining the concentration of each bile acid on the basis of the standard curve measured simultaneously; and referring the sum of the concentrations of these bile acids to the total bile acid concentration; and a method for the diagnosis of a liver disease comprising: calculating the concentration ratio of each bile acid from the values measured by the former method; and comparing the concentration ratio thus obtained

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with the standard level scope of said concentration ratio obtained from healthy subjects are provided. Excerpt(s): This invention relates to a method of ELISA (enzyme linked immunosorbent assay) for the measurement of serum bile acids and a method for the diagnosis of liver disease on the basis of the measurement data thus obtained. Bile acids are one of the major components of bile. In liver cells, cholesterol is formed from acetyl coA (coenzyme A) and further primary bile acids [cholic acid (CA) and chenodeoxycholic acid (CDCA)] are formed therefrom. The primary bile acid conjugated with glycine or taurine undergoes 7.alpha. dehydroxylation by enteric bacteria in the intestinal tract and thus secondary bile acids [deoxycholic acid (DCA) and lithocholic acid (LCA)] are formed. At the same time, ursodeoxycholic acid (UDCA) is also formed. After facilitating the absorption of fat-soluble substances in the intestinal tract, the bile acids are mostly reabsorbed at the end of the ileum and returned to the liver through the portal vein, thus repeating the closed enterohepatic circulation. Bile acids pooled in the body (mainly in the gallbladder and the intestine) amount to about 3 to 5 g. A trace amount of bile acids deviate from the enterohepatic circulation and migrate into the greater blood circulation, which causes a trace bile acid level (about 2.mu.g/ml) in the peripheral blood of a healthy person in the morning (fasting). The blood bile acid level shows a daily variation in association with meals. Namely, the morning (fasting) blood bile acid level is the lowest and an increase is observed after each meal. After showing a decrease at the bed time, the blood bile acid level returns to the morning (fasting) level. Web site: http://www.delphion.com/details?pn=US05631138__ •

Method for treating alcoholic liver disease Inventor(s): Christ; William J. (Andover, MA), Lewis; Michael D. (Andover, MA), Rossignol; Daniel P. (Andover, MA), Thurman; Ronald G. (Chapel Hill, NC) Assignee(s): Eisai Company, Ltd. (Tokyo, JP) Patent Number: 5,952,309 Date filed: September 27, 1996 Abstract: A method for the inhibition and amelioration of alcholic liver disease in a mammal in need of such treatment by administering novel analogs of Lipid A which act as endotoxin antagonists. These antagonists compounds are found to inhibit the swift increase in alcohol metabolism which typically accompanies ingestion of alcohol and which may lead to the pathophysiological abnormalities associated with alcoholic liver disease. Excerpt(s): Alcoholic liver disease is a progressive disease with approximately 600,000 new cases a year world-wide. The incidence of mortality from this disease is high (e.g. it is the fourth leading cause of death in U.S. urban males), and current effective treatments are nonexistent except for drastic measures such as liver transplantation. Often a consequence of alcoholic liver disease, cirrhosis follows deposition of fatty and fibrous tissue in the liver with diffuse damage to the hepatic parenchymal cells. Loss of proper metabolic functioning in these cells leads to interference with liver blood flow, jaundice, portal hypertension, ascites, and hepatic failure. While it is well recognized that alcohol consumption leads to liver disease, the exact mechanism(s) by which alcohol exerts its toxic effect remains unclear (Lelbach, W. K. Acta Hepatospenol. 13: 321-349 (1966)). One hypothesis which the present inventors have investigated implicates an interactive toxicity between alcohol and endotoxin (Adachi et al. J

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Hepatol, 16: 171-176. (1992), Adachi, Y. et al. Hepatol. 20: 453-460 (1994), Knecht, K. T. et al. Mol. Pharmacol. 47:1028-1034 (1995)). Web site: http://www.delphion.com/details?pn=US05952309__ •

Method for treating heartworm-infected canines Inventor(s): Kerz; Phillip D. (Rte. 4, Box 12, Charleston, IL 61920) Assignee(s): none reported Patent Number: 5,550,153 Date filed: November 14, 1994 Abstract: Successful treatment of adult canine heartworm disease (dirofilaria immitis) has been very difficult to achieve. Presently, only one drug is approved for this application by the Counsel of the American Veterinary Medical Association and the Executive Committee of the American Heartworm Society. This drug is thiacetarsimide, an intravenously administered and arsenic-derived compound which has proven moderately efficacious at destroying adult heartworms which are responsible for producing the adverse physiological effects that characterize dirofilaria immitis. Thiacetarsimide is known to induce a host of possible adverse side-effects including anaphylactic shock, liver disease, kidney disease and patient mortality. It has been found that ivermectin, one of a broad class of antiparasiticidal avermectins, is efficacious in destroying both adult and immature heartworms in canines when administered in an effective dose. As compared to thiacetarsimide-based regimes, methods employing ivermectin are efficacious yet less expensive and more convenient for treating canines afflicted with adult heartworms. Excerpt(s): This invention relates generally to a non-invasive method for treating dirofilaria immitis in canines and, more particularly, to a method for treating that stage of the disease caused by adult heartworms. Still further, the invention employs ivermectin--a composition hereto-fore unknown in the primary treatment of adult heartworms. Heartworms are commonly found to reside in the right ventricle of a dog's heart and the adjacent blood vessels. Adult heartworms cause inflammation of the walls of the arteries in the lungs, obstruct blood vessels and interfere with the blood supply to vital organs. Common symptoms of adult heartworm disease in canines include lowgrade nocturnal cough, distension of the limbs and lower abdomen and lethargy. Left Untreated, heartworm parasites can result in the death of the host canine and can be infectiously transmitted to other canines by way of numerous mosquito species which function as an intermediate host. Dirofilaria immitis, the disease caused by parasitic adult heartworms in canines, is characterized by several developmental stages. Specifically, microfilariae are known to be deposited by female heartworms into the bloodstream of canines. The microfilariae develop further once ingested by a mosquito which functions as an intermediate host. Within the mosquito, microfilariae develop into infective larvae which, once a dog is bitten by the mosquito, migrate to the dog's heart where maturation into adult worms occurs. Web site: http://www.delphion.com/details?pn=US05550153__

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Method for treatment of patients with chronic liver disease Inventor(s): Moeller; Soren (Frederiksberg C., DK), Skakkeb k; Niels E. (Farum, DK) Assignee(s): Novo Nordisk A/S (Bagsvaerd, DK) Patent Number: 5,492,891 Date filed: March 2, 1994 Abstract: Patients with chronic liver disease and consequently very low concentrations of IGF-1 in the blood, in spite of increased GH concentrations, are treated with periodically injections of hGH for a period both parameters being individually adjusted for the patients. Excerpt(s): The present invention concerns a method for treatment of patients with chronic liver disease and an agent for use in the method. The frequency of patients with chronic liver diseases is unknown, but in Europe the number of patients with newly recognized liver diseases seems to be increasing concurrently with the increasing consumption of alcohol. The chronic liver diseases includes the alcoholic liver cirrhosis, which is dominating in number, liver cirrhosis caused by chronic infection after acute inflammation of the liver and last and more seldom occurring immunological liver diseases characterized by chronic inflammation without known reason. Web site: http://www.delphion.com/details?pn=US05492891__

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Method of curing liver diseases by using pyrrolo quinoline quinone triesters and novel pyrrolo quinoline quinone triesters Inventor(s): Itoh; Chieko (Niigata, JP), Oda; Mitsunori (Niigata, JP), Urakami; Teizi (Tokyo, JP) Assignee(s): Mitsubishi Gas Chemical Company, Inc. (Tokyo, JP) Patent Number: 5,061,711 Date filed: October 3, 1990 Abstract: Disclosed is a method of curing liver diseases by administration of pyrrolo quinoline quinon triesters (PQQ triesters). The PQQ triesters include PQQ triallyl ester and PQQ tribenzyl ester which are novel. The PQQ triesters being ester form, they have no toxicity and can be orally adminstered. Excerpt(s): The present invention relates to a method for curing liver diseases by using pyrrolo quinoline quinone triesters (hereinafter referred to as "PQQ triesters"). The invention also relates to two novel PQQ triester compounds, PQQ triallyl ester and PQQ tribenzyl ester. Liver is an important organ which participates in most of metabolisms and regulation thereof in a living body including metabolization of carbohydrate, protein, lipid, nucleic acid, vitamin, and hormone, production of bilirubin, secretion of bile, detoxification of endogeneous or exogeneous substances by oxidation, reduction and conjugation.degree. and excretion of them into bile or water-solubilization of them to accelerate excretion into urine. These functions may be damaged by toxic substances, medicines, alcohols, radiation and viruses to cause diseases such as medicinal liver diseases, alcoholic liver diseases, virus-caused hepatitis, fatty liver, jaundice, and the like. If these diseases are protracted, sometimes liver cirrhosis and liver cancer are developed. However, medicines effective to cure these liver diseases have not yet been developed and at present, treatments therefor are only alimentotherapy and rest cure.

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Web site: http://www.delphion.com/details?pn=US05061711__ •

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, GB2) Patent Number: 5,854,233 Date filed: June 20, 1996 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)-1,5benzothiazepine-4)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=US05854233__

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Method of treating liver disorders with a macrolide antibiotic Inventor(s): Klein; Ira (5 Windermere, Houston, TX 77063) Assignee(s): none reported Patent Number: 5,760,010 Date filed: May 7, 1996 Abstract: This invention is directed to a novel method for treating humans with liver diseases or liver disorders with a macrolide antibiotic. Many different liver disorders can be treated with the claimed invention but this invention is specifically directed to treating nonalcoholic steatohepatitis, alcoholic hepatitis, and Reye's Syndrome. More specifically, this invention is directed to the oral administration of an erythromycin compound or an erythromycin derivative for the treatment of liver disease or liver disorders. The routes of administration can include oral, intramuscular, subcutaneous, transdermal, intravenous or other common routes of administering a drug to a patient. Alternate routes for patients diagnosed with alcoholic hepatitis or Reye's Syndrome are extremely important as oral administration would not be effective due to the patient's clinical symptoms. Most specifically, this invention teaches the novel oral administration of clarithromycin, troleandomycin, erythromycin, or azithromycin for treating human

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patients with liver disease or liver disorders, including but not limited to nonalcoholic steatohepatitis, alcoholic hepatitis, and Reye's Syndrome. Excerpt(s): This application is related to the provisional application filed Jun. 28, 1995 having Ser. No. 60/000,531. This invention is related to U.S. patent application having Ser. No. 08/348,366 which was filed on Nov. 30, 1994, now U.S. Pat. No. 5,498,424, and is entitled "Method of Treating Obesity" (herein incorporated by reference). This invention relates to methods and compositions for treating human patients with liver diseases or liver disorders with a macrolide antibiotic. Many different liver disorders can be treated by the method of the claimed invention, including nonalcoholic steatohepatitis, alcoholic hepatitis and Reye's Syndrome. More specifically, this invention is directed to the administration (oral or by any other route) of an erythromycin compound or an erythromycin derivative for the treatment of liver diseases or liver disorders. Most specifically, this invention teaches the oral administration of clarithromycin, troleandomycin, erythromycin, or azithromycin for treating human patients with liver disease or liver disorders, including but not limited to nonalcoholic steatohepatitis (fatty liver associated with obesity), alcoholic hepatitis and Reye's Syndrome. Web site: http://www.delphion.com/details?pn=US05760010__ •

Oxazopyrroloquinolines and use of oxazopyrroloquinolines Inventor(s): Itoh; Chieko (Niigata, JP), Kobayashi; Hisao (Niigata, JP), Nagai; Toshio (Niigata, JP), Oda; Mitsunori (Niigata, JP), Sugamura; Kazuhiro (Niigata, JP), Urakami; Teizi (Tokyo, JP) Assignee(s): Mitbushi Gas Chemical Company, Inc. (Tokyo, JP) Patent Number: 5,236,930 Date filed: January 23, 1992 Abstract: The present invention provides a process for producing oxazopyrroloquinolines which comprises culturing microorganisms to produce pyrroloquinolinequinone and adding.alpha.-amino acids or monomethylamine to the resulting culture broth which contains the pyrroloquinolinequinone and from which cells of microorganisms are not separated, thereby to convert the pyrroloquinolinequinone to the corresponding oxazopyrroloquinolines.The thus obtained oxazopyrroloquinolines include novel compounds.The present invention further provides aldose reductase inhibitors, diabetic combined disease curing agents, immunopotentiating agents and liver disease inhibiting agents which contain as active ingredient these oxazopyrroloquinolines having excellent physiological activity. Excerpt(s): The present invention relates to a process for producing oxazopyrroloquinolines and more particularly it relates to a process for producing oxazopyrroloquinolines from pyrroloquinoline quinone obtained using microorganisms. It further relates to novel oxazopyrroloquinolines and use of oxazopyrroloquinolines. However, it has been clarified recently that PQQ has toxicity to kidney (Watanabe et al. "Hiroshima J. Med. Sci.", Vol. 38, No. 1, pages 49-51 (1989)), and development of safe PQQ derivatives which are low in both general toxicity and toxicity to kidney has been desired. The inventors have conducted tests for toxicity to kidney and acute toxicity test on various PQQ derivatives to find that oxazopyrroloquinolines (OPQs) markedly diminished these toxicities. Web site: http://www.delphion.com/details?pn=US05236930__

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Polynucleotide and polypeptide sequences encoding murine organic anion transporter 5 (mOATP5) Inventor(s): Ellens; Harma (Norristown, PA), Feild; John (Wayne, PA), Yue; Lin (Phoenixville, PA) Assignee(s): SmithKline Beecham Corporation (Philadelphia, PA) Patent Number: 6,420,544 Date filed: May 17, 2000 Abstract: Mouse OATP5 polypeptides and polynucleotides and method for producing such polypeptides by recombinant techniques are disclosed. Also disclosed are methods for screening for compounds which either agonize or antagonize mouse OATP5. Such compounds are expected to be useful in treatment of human diseases, including, but not limited to: cancer, inflammation, cardiovascular disease, central nervous system disorders, auto-immune disease, and kidney and liver disease. Excerpt(s): This invention relates to newly identified polypeptides and polynucleotides encoding such polypeptides, to their use in identifying compounds that may be agonists and/or antagonists that are potentially useful in therapy, and to production of such polypeptides and polynucleotides. The drug discovery process is currently undergoing a fundamental revolution as it embraces `functional genomics`, that is, high throughput genome- or gene-based biology. This approach is rapidly superseding earlier approaches based on `positional cloning`. A phenotype, that is a biological function or genetic disease, would be identified and this would then be tracked back to the responsible gene, based on its genetic map position. Functional genomics relies heavily on the various tools of bioinformatics to identify gene sequences of potential interest from the many molecular biology databases now available. There is a continuing need to identify and characterise further genes and their related polypeptides/proteins, as targets for drug discovery. Web site: http://www.delphion.com/details?pn=US06420544__

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Products displaying the antigenicity of hepatitis B virus e antigens and methods of producing those antigens Inventor(s): MacKay; Patricia (Cornwall, GB2), Murray; Kenneth (Heidelberg, DE) Assignee(s): Biogen N.P. (Curacao, AN) Patent Number: 4,758,507 Date filed: October 4, 1985 Abstract: Polypeptides displaying the antigenicity of hepatitis B virus e antigens, DNA sequences coding for those polypeptides, antibodies to those polypeptides and methods of producing and using those polypeptides, antibodies and DNA sequences. The polypeptides and antibodies of this invention are characterized by their use in compositions and methods for detecting hepatitis B virus infective carriers and in evaluating the course of HBV-related active liver disease. Excerpt(s): This invention relates to products displaying the antigenicity of hepatitis B virus e antigens ("HBeAg") and methods for their production. This invention relates more particularly to polypeptides displaying the antigenicity of HBeAg and their production either from polypeptides displaying the antigenicity of hepatitis B virus core antigen ("HBcAg") or from hosts that have been transformed with DNA sequences

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encoding polypeptides displaying the antigenicity of HBeAg. As will be appreciated from the disclosure to follow, polypeptides displaying the antigenicity of HBeAg may be used in the detection of past or present hepatitis B virus ("HBV") infection, being of particular value in detecting HBV infective carriers and in evaluating the course of HBVrelated chronic liver disease. Hepatitis B virus (or HBV) infects humans at a very high rate. It is estimated that 15% of the U.S. population have been infected, and in some African and Asian countries, as much as 20% of the adult population are contagious chronic HBV carriers, with over 50% infected. Most HBV infections are subclinical, and recovery from both subclinical and clinical infections is usually complete. However, serious long term consequences occur in some cases: (1) about 5% of acute HBV infections result in chronic HBV infection, with the constant potential for infectivity to others and for serious, debilitating liver disease, and (2) it is likely that past infection with HBV may be partly or even wholly responsible for the initiation of fulminant hepatitis, cirrhosis, and primary liver cancer. For example, the normal incidence of primary liver cancer is 1:100,000, but for chronic HBV sufferers the incidence of that cancer is 1:300. Web site: http://www.delphion.com/details?pn=US04758507__ •

Sulfate conjugates of ursodeoxycholic acid, and their beneficial use in inflammatory disorders and other applications Inventor(s): Setchell; Kenneth D. R. (Cincinnati, OH) Assignee(s): Children's Hospital Medical Center (Cincinnati, OH) Patent Number: 6,251,884 Date filed: February 24, 1998 Abstract: One aspect of this invention is directed to a pharmacologically acceptable composition including a sulfate of 3 alpha, 7 beta-dihydroxy-5 beta-cholan-24-oic acid (Ursodeoxycholic acid or "UDCA") and a pharmacologically acceptable carrier. In a preferred composition, the sulfate is UDCA-3-sulfate, UDCA-7-sulfate, UDCA-3,7disulfate, glyco-UDCA-3-sulfate, glyco-UDCA-7-sulfate, glyco-UDCA-3,7-disulfate, tauro-UDCA-3-sulfate, tauro-UDCA-7-sulfate, tauro-UDCA-3,7-disulfate or a combinations thereof. Another aspect of the invention concerns a method of delivering UDCA to a mammal to inhibit or treat a disorder, which includes administering a sulfate of UDCA to the mammal in an amount sufficient to inhibit or treat the disorder. For example, a UDCA sulfate may be used to advantage in inhibiting or treating an inflammatory condition of the gastrointestinal tract, such as colon cancer, rectum cancer, a neoplasm of the colon, a neoplasm of the rectum, carcinogenesis of the colon, carcinogenesis of the rectum, ulcerative colitis, an adenomatous polyp, familial polyposis and the like. A sulfate of UDCA also may be administered to inhibit or treat an inflammatory disorder of the liver. A UDCA sulfate may be used to improve serum biochemistries of liver disease or liver function, to increase bile flow or to decrease biliary secretion of phospholipid or cholesterol. In yet a further aspect, the invention is directed to a method of maintaining an isolated organ by perfusing the organ with a sulfate of UDCA. Excerpt(s): 3 alpha, 7 beta-dihydroxy-5 beta-cholan-24-oic acid ("Ursodeoxycholic acid" or "UDCA") has been used clinically for more than two decades, initially proving effective for the treatment of patients with cholelithiasis and more recently showing promise in the treatment of patients with cholestatic liver diseases. It is well established that oral administration of UDCA leads to a significant improvement in serum liver

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enzymes, and based on results from long-term clinical trials, the consensus opinion is that UDCA is beneficial for the treatment of early-stage primary biliary cirrhosis. In addition, clinical trials have shown that UDCA is beneficial in improving clinical and biochemical indices of hepatic function in patients with sclerosing cholangitis, cystic fibrosis and chronic hepatitis. Despite the promising effects shown by UDCA in liver diseases, the exact mechanism of its action remains unclear. Early speculation suggested that a shift in the hydrophobic/hydrophilic balance of the biliary bile acid pool was an important determinant of its effectiveness, but recent data do not totally support this contention; and the improvement in liver function is almost certainly the result of a marked hypercholeresis induced by UDCA, which facilitates the biliary excretion of potentially more toxic bile acids or other endogenous agents. In studies focussing on the metabolism of UDCA in patients with a variety of liver diseases, the appearance of substantial amounts of the C-3 sulfate ester of UDCA in the urine has been consistently observed, and this specific metabolite has proven to be a useful marker for UDCA compliance. In addition, animal studies have suggested that sulfation of bile acids may represent an important metabolic pathway for preventing cholestasis and limiting hepatocellular damage. Web site: http://www.delphion.com/details?pn=US06251884__ •

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.

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Web site: http://www.delphion.com/details?pn=US06303127__ •

Use of antioxidant agents to treat cholestatic liver disease Inventor(s): Sokol; Ronald J. (Denver, CO) Assignee(s): University Technology Corporation (Boulder, CO) Patent Number: 6,069,167 Date filed: January 15, 1997 Abstract: The present invention relates to formulations and methods for preventing and treating liver injury and fibrosis in cholestasis. This is accomplished by the administration of a composition which includes selected antioxidants. Excerpt(s): The present invention provides formulations and methods for preventing and treating liver injury and fibrosis that occur in cholestatic liver disease and related liver diseases. This is done by administering a composition that includes selected antioxidant compounds. Throughout this application, various publications are referred to by superscript Arabic numerals. Full bibliographic citations for these publications are set forth at the end of the application, immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference. Cholestatic liver diseases, or cholestasis, are a group of disorders of varying causes that result when bile flow is impaired. Cholestasis can cause progressive liver damage and eventually lead to endstage liver disease. The mechanisms by which the liver is injured and fibrosis is stimulated in cholestatic liver disease are unclear. Web site: http://www.delphion.com/details?pn=US06069167__

Patent Applications on Liver Disease 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 liver disease: •

ANTISENSE OLIGONUCLEOTIDES TARGETED TO IL-15 Inventor(s): HAMANAKA, SHOJI; (YOKOSUKA, JP), KUBO, HIROYUKI; (CARLSBAD, CA), NOZAWA, IWAO; (CARLSBAD, CA), VEERAPANANE PH.D, DANGE; (SAN DIEGO, CA) Correspondence: Fish & Richardson, PC; 4350 LA Jolla Village Drive; Suite 500; San Diego; CA; 92122; US Patent Application Number: 20030013668 Date filed: July 7, 1999 Abstract: The invention features antisense oligonucleotide molecules that specifically bind polynucleotides encoding IL-15. The present invention provides antisense oligonucleotides capable of inhibiting IL-15 expression, and methods of use thereof to reduce activity of IL-15 in tissues in order to treat diseases such as rheumatoid arthritis,

10

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

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inflammatory bowel disease, multiple sclerosis, chronic liver disease, ulcerative colitis and cell proliferative disorders. Excerpt(s): This application claims priority from U.S. Provisional Application Ser. No. 60/091,873 filed Jul. 7, 1998, the disclosure of which is incorporated herein by reference. This invention relates generally to the field of therapeutic compositions and more specifically to antisense oligonucleotides that bind to interleukin-15 (IL-15 ) polynucleotides and methods of treatment for diseases associated with IL-15. There are a number of diseases known in humans that affect various tissues, including the joints, and particularly the synovium. These include synovial sarcomas, osteoarthritis, bacterial and fungal infections, and inflammatory, autoimmune, and hemorrhagic diseases. Combined, they are a cause of great pain and suffering in the population, with little effective therapy apart from symptomatic treatment with analgesics and antiinflammatory drugs (reviewed by Gardner, 1994 J. Anat. 184:465-76). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Asialocytokines and treatment of liver disease Inventor(s): Takahashi, Hiroshi; (Boston, MA) Correspondence: Anita L. Meiklejohn, PH.D.; Fish & Richardson P.C.; 225 Franklin Street; Boston; MA; 02110-2804; US Patent Application Number: 20020187124 Date filed: March 29, 2002 Abstract: The invention features methods for treating liver disease (e.g., viral hepatitis) by administering an asialocytokine (e.g., asialointerferon). The invention also includes methods of targeting a glycoprotein to a hepatocyte and a composition containing an asialocytokine. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 08/721,828, filed Sep. 27, 1996, now pending; which claims priority from U.S. Provisional Application Serial No. 60/004,357, filed Sep. 27, 1995, now abandoned. The lack of suitable animal models for hepatitis B has hindered understanding of the molecular mechanisms responsible for hepatocyte death and viral clearance (Ochiya et al., Proc. Natl. Acad. Sci. USA 86:1875, 1989; Gripon et al., J. Virol. 52:4136, 1988). Germline transgenic mouse models have been produced to investigate the pathogenesis of HBV infection, but these animals are immunologically tolerant to HBV antigens and do not spontaneously develop hepatitis (Moriyama et al., Science 248:361, 1990). Hepatitis must be induced in these animals by a complicated, multi-step process involving, e.g. priming lymphocytes with HBV proteins in syngeneic animals and adoptive transfer of the primed cells in vivo (Moriyama et al., supra; Ando et al., J. Exp. Med. 178:1541, 1993). The invention is based, in part, on the discovery that asialo-interferon-.beta. (asialo-IFN-.beta.) effectively inhibits hepatitis B virus (HBV) replication in hepatocytes. Surprisingly, this level of inhibition achieved was higher than that achieved with native interferon-.beta., a result contrary to the previous understanding that asialo-interferon.beta. is less effective than native interferon-.beta. in inhibiting virus replication in hepatocytes. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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COMPOSITIONS AND METHODS TREATMENT OF CHOLESTASIS

FOR

HEPATOPROTECTION

AND

Inventor(s): Kliewer, Steven Anthony; (Dallas, TX), Willson, Timothy Mark; (Durham, NC) Correspondence: David J Levy, Corporate Intellectual Property; Glaxosmithkline; Five Moore DR., PO Box 13398; Research Triangle Park; NC; 27709-3398; US Patent Application Number: 20030203939 Date filed: April 25, 2002 Abstract: Methods for the treatment of cholestatic liver disease and reduction and prevention of hepatic injury resulting from cholestasis via administration of a FXR ligand are provided. Excerpt(s): The present invention relates to the use of nuclear receptor ligands, and in particular ligands for Farnesoid X Receptor (FXR), as hepatoprotective agents against injury from cholestatic liver diseases and in the treatment of cholestasis. Cholestasis is defined as the impairment or cessation of bile flow and occurs in a variety of human liver diseases. Although there are various pathogenic causes of cholestasis, hepatocellular injury and associated liver dysfunction commonly result (Trauner et al. N. Engl. J. Med. 1998 339:1217-27). Ursodeoxycholic acid (UDCA) is currently the only established drug for the treatment of a variety of cholestatic liver diseases, such as primary biliary cirrhosis, primary sclerosing cholangitis, cystic fibrosis, and intrahepatic cholestasis of pregnancy (Kumar, D. and Tnadon, R. K. J. Gastroenterol. Hepatol. 2001 16:3-14; Beuers et al. Hepatology 1998 28:1449-53; Poupon, R. and Poupon, R. E. Pharmacol. Ther. 1995 66:1-15). The molecular mechanisms underlying the therapeutic benefits of UDCA are not fully understood but may be a result of immunomodulatory, antiapoptotic, cytoprotective and choleretic effects (Beuers et al. Hepatology 1998 28:1449-53). Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand activated transcription factors (Lu et al. J. Biol. Chem. 2001 17:17). FXR is reported to bind and be activated by a variety of naturally occurring bile acids, including the primary bile acid chenodeoxycholic acid and its taurine and glycine conjugates (Makishima et al. Science 1999 284:1362-5; Parks et al. Science 1999 284:13658; and Wang et al. Mol. Cell. 1999 3:543-53). A number of recent studies have implicated FXR in the regulation of genes encoding proteins involved in the biosynthesis and transport of bile acids (Sinal et al. Cell 2000 102:731-44; Lu et al. Mol. Cell 2000 6:507-15; Goodwin et al. Mol. Cell. 2000 6:517-26; Grober et al. J. Biol. Chem. 1999 274:29749-54). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compounds for the treatment of metabolic disorders Inventor(s): Sharma, Shalini; (Gaithersburg, MD), von Borstel, Reid W.; (Potomac, MD) Correspondence: Lewis J. Kreisler; Legal Department; 930 Clopper Road; Gaithersburg; MD; 20878; US Patent Application Number: 20030149107 Date filed: June 12, 2002 Abstract: Compounds useful for the treatment of various metabolic disorders, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis, are disclosed.

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Excerpt(s): This application claims the benefit of U.S. Provisional Patent Application No. 60/297,282, filed Jun. 12, 2001, the contents of which are hereby incorporated by reference. Diabetes mellitus is a major cause of morbidity and mortality. Chronically elevated blood glucose leads to debilitating complications: nephropathy, often necessitating dialysis or renal transplant; peripheral neuropathy; retinopathy leading to blindness; ulceration of the legs and feet, leading to amputation; fatty liver disease, sometimes progressing to cirrhosis; and vulnerability to coronary artery disease and myocardial infarction. There are two primary types of diabetes. Type I, or insulindependent diabetes mellitus (IDDM) is due to autoimmune destruction of insulinproducing beta cells in the pancreatic islets. The onset of this disease is usually in childhood or adolescence. Treatment consists primarily of multiple daily injections of insulin, combined with frequent testing of blood glucose levels to guide adjustment of insulin doses, because excess insulin can cause hypoglycemia and consequent impairment of brain and other functions. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Diagnostic markers of liver dysfunction Inventor(s): Hugli, Tony E.; (San Diego, CA), Jackson, Craig M.; (San Diego, CA) Correspondence: Lisa A. Haile, J.D., PH.D.; Gray Cary Ware & Freidenrich Llp; 4365 Executive Drive, Suite 1600; San Diego; CA; 92121-2189; US Patent Application Number: 20030087316 Date filed: August 2, 2001 Abstract: The present invention provides methods and kits for detecting and monitoring liver damage in a subject. The methods and kits rely on the correlation between the presence or increase in a kallikrein-like peptidase in a sample from the subject and liver disease. Additionally, the present invention provides in vivo and in vitro methods for detecting toxicity of a therapeutic agent. Methods for detecting, diagnosing, or monitoring liver damage by measuring a panel of components, including kallikrein-like peptidase, along with other blood enzymes and/or complement components are also provided. Excerpt(s): The invention relates generally to methods and kits for detecting liver dysfunction and more specifically to measurement of a peptidase or peptidases synthesized in and secreted from the liver, such as those of the hemostatic and complement systems, as an indicator of liver damage. Currently, methods for detecting liver disease rely on late stage markers that do not identify liver disease before it is in an advanced stage. This has resulted in a deficiency in modern healthcare related to liver disease management, the importance of which is underscored by the fatal nature of liver disease in many instances. Therefore, there is a need for improved methods for liver screening, monitoring, and diagnosis, especially with respect to early stage disease and damage. The magnitude of this need is immense and growing as more organ transplants are performed. As of the year 2000, there were at least 4,000 liver transplants per year in the United States. In 1998, there were almost 25,000 deaths caused by chronic liver disease. Furthermore, there are estimated to be millions of individuals experiencing a variety of liver diseases from advancing chronic liver disease to acute toxicity and viral injury. Finally, there are perhaps even more individuals with various stages of liver disease that remain undetected. Consequently, a reliable method for detecting early onset liver damage or monitor progressive liver damage or repair is

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needed. Such an assay should find wide application in research, pharmaceutical product evaluation, development and clinical medicine. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Dihydroxyphenyl derivatives for hepatoprotection and treatment of liver diseases Inventor(s): Choi, Hea-Jin; (Hwasung-gun, KR), Chung, Jea-Uk; (Hwasung-gun, KR), Ha, Jong-Ryul; (Hwasung-gun, KR), Jeong, Kwang-Won; (Hwasung-gun, KR), Lee, SuJin; (Hwasung-gun, KR), Moon, Sung-Hwan; (Hwasung-gun, KR), Oh, Se-Woong; (Hwasung-gun, KR) Correspondence: Dike, Bronstein, Roberts And Cushman,; Intellectual Property Practice Group; Edwards & Angell, LLP.; P.O. Box 9169; Boston; MA; 02209; US Patent Application Number: 20030083326 Date filed: April 1, 2002 Abstract: The present invention relates to a pharmaceutical composition for the hepatoprotection and treatment of liver diseases comprising as an active ingredient a dihydroxyphenyl derivative represented by the following formula (1), pharmaceutically acceptable acid addition salt or stereochemical isomer thereof together with a pharmaceutically acceptable inert carrier: 1in whichin whichA, B, D and E are defined as described in the specification. Excerpt(s): This application is a continuation-in-part of Ser. No. 09/674,187 filed on Oct. 27, 2000 as Dihydroxyphenyl derivatives for hepatoprotection and treatment of liver diseases. provided that R4 does not exist when double bond is linked to the nitrogen atom in substituent (a-2). The present invention also relates to a novel dihydroxyphenyl derivative having an excellent protective and therapeutic acitivity for liver which is left after known compounds are removed from the compound of formula (1) above, and to a process for preparing the same. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Galectin expression is induced in cirrhotic liver and hepatocellular carcinoma Inventor(s): Dowling, Christopher; (Freeport, ME), Hsu, Daniel K.; (Davis, CA), Liu, FuTong; (Davis, CA) Correspondence: Knobbe Martens Olson & Bear Llp; 620 Newport Center Drive; Sixteenth Floor; Newport Beach; CA; 92660; US Patent Application Number: 20020155513 Date filed: October 10, 2001 Abstract: The present invention relates to the discovery of a marker for liver disease. Novel diagnostics, prognostics, therapeutics and methods of use of the foregoing for the treatment and prevention of hepatocellular carcinoma are also disclosed. Excerpt(s): This application is a continuation of international application number PCT/US00/08561, and claims the benefit of priority of international application number PCT/US00/08561 having international filing date of Mar. 29, 2000, designating the United States of America and published in English, which claims the benefit of priority of U.S. provisional patent application No. 60/129,111, filed Apr. 13, 1999; both of which

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are hereby expressly incorporated by reference in their entireties. Hepatocellular carcinoma is a major type of cancer causing a quarter of a million deaths worldwide each year (Kew, M. C., Tumors of the liver. In: D. Zakim and T. D. Boyer (eds.), Hepatology. A Textbook of Liver Disease, pp. 1206-1240, W. B. Saunders, Philadelphia (1990)). While various factors have been identified as causes for HCC, the major established factors are infections of hepatitis viruses B (HBV) and C (HCV). Various potential mechanisms exist whereby infection by HBV can result in HCC. These include both chronic liver injury caused by cytotoxic T cell responses to infected hepatocytes and intracellular occlusion resulting from expression of viral protein (Chisari, F. V., Analysis of hepadnavirus gene expression, biology, and pathogenesis in the transgenic mouse. In: Current Topics in Microbiology and Immunology, pp. 85-99, SpringerVerlag, Berlin (1991)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

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

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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 •

L-ergothioneine, milk thistle, and s-adenosylmethionine for the prevention, treatment and repair of liver damage Inventor(s): Corson, Barbara E.; (Fawn Grove, PA), Henderson, Todd R.; (Jarrettsville, MD) Correspondence: Paul J. Berman, EAQ.; Covington & Burling; 1201 Pennsylvania Avenue, N.W.; Washington; DC; 20004-2401; US Patent Application Number: 20010000472 Date filed: December 8, 2000 Abstract: This invention provides therapeutic compositions and combinations for the protection, treatment and repair of liver tissue. The invention relates to novel compositions and combinations comprising two or more compounds selected from the group consisting of S-adenosylmethionine, L-ergothioneine, and a substance selected from the group consisting of constituents of Milk thistle (Silybum marianum), silymarin and active components of silymarin, whether naturally, synthetically, or semisynthetically derived, and to methods of preventing and treating liver disease and of repairing damaged liver tissue. The invention also provides a method of administering these compositions and combinations to humans or animals in need thereof. Excerpt(s): 1. The present application is a continuation-in-part application of U.S. patent application Ser. No. 09/256,352, filed Feb. 24, 1999, the disclosure of which is hereby incorporated by reference herein in its entirety. That application claimed priority to provisional application: "L-ERGOTHIONEINE, MILK THISTLE, AND SADENOSYLMETHIONINE FOR LIVER FAILURE," U.S. Ser. No. 60/076,347, filed Feb. 27, 1998, the disclosure of which is hereby incorporated by reference herein in its entirety. 2. The present invention relates to compositions and combinations for the protection, treatment and repair of liver tissues in humans and animals. 3. The liver is an extremely important organ. As the major metabolic organ of the body, the liver plays some role in almost every biochemical process, including the deamination of amino acids and the formation of urea, the regulation of blood sugar through the formation of glycogen, the production of plasma proteins, the production and secretion of bile, phagocytosis of particulate matter from the splanchnic (intestinal) circulation, and the detoxification and elimination of both endogenous and exogenous toxins. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method for providing seasonings for box lunches, and storage midium and resin food container used in the method Inventor(s): Ishizaki, Akira; (Kashiba-shi, JP) Correspondence: Platon N. Mandros; Burns, Doane, Swecker & Mathis, L.L.P.; P.O. Box 1404; Alexandria; VA; 22313-1404; US Patent Application Number: 20020015767 Date filed: July 25, 2001 Abstract: A method for providing seasonings for box lunches, the method having the steps of: preparing a resin lunch box which is composed of a body and a lid; putting some kinds of seasonings in a plurality of recesses which are formed on the ceiling of the lid; and thermally welding a top sealing film to cover the recesses. The seasonings are selected depending on the kinds of food to be contained in the body. A computer system may be used so that the seasonings to be put in the recesses can be selected automatically and that the selected seasonings can be put automatically. In this case, depending on the kind of box lunches, such as lunches for old people, lunches for hypertension patients, lunches for liver disease patients, etc., proper seasonings are selected so that each of the box lunches will contain proper salt, calorie, etc. Excerpt(s): The present invention relates to a method for providing seasonings for box lunches and a storage medium and a resin food container used to carry out this method. Conventionally, a resin lunch box has been composed of a body (plate) and a lid. Seasonings and sauces, such as soy sauce, Worcestershire sauce, mayonnaise, ketchup, etc., have been dispensed to small bags, and these small bags have been put in the body together with food. In preparing a large number of box lunches, conventionally, such small bags of seasonings have been put in each of the lunch boxes by hand, which has been troublesome. In addition, these small bags are put in the lunch boxes together with food, and it has been likely that a person who opens the bags may stain his/her fingers with oil because oil of the food may have stuck to the bags. Moreover, there have been no other ways than pouring the seasonings and sauces on the food, and if the person wants a saucer, the person has to get one. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method of determining presence and concentration of lipoprotein X in blood plasma and serum Inventor(s): Jeyarajah, Elias J.; (Raleigh, NC), Otvos, James D.; (Apex, NC), Shalaurova, Irina Y.; (Cary, NC) Correspondence: Myers Bigel Sibley & Sajovec; PO Box 37428; Raleigh; NC; 27627; US Patent Application Number: 20030054559 Date filed: July 30, 2002 Abstract: A method of screening a subject for the presence of lipoprotein X includes the steps of: producing a measured lipid signal lineshape of an NMR spectrum of a blood plasma or serum sample obtained from a subject; generating a calculated lineshape for the sample, the calculated lineshape being based on derived concentrations of lipoprotein components potentially present in the sample, the derived concentration of each of the lipoprotein components being the function of a reference spectrum for that component and a calculated reference coefficient, wherein one of the lipoprotein

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components for which a concentration is calculated is lipoprotein X; and determining the degree of correlation between the calculated lineshape of the sample and the measured lineshape spectrum of the sample. This method can enable the practitioner, during a routine and easily-conducted cholesterol screening, to identify the presence of LP-X in a subject and begin diagnosis and treatment for conditions associated with LP-X (such as liver disease or LCAT deficiency). Excerpt(s): This application claims priority from U.S. Provisional Patent Application Serial No. 60/309,350 filed Aug. 1, 2001, the contents of which are hereby incorporated by reference as if recited in full herein. The present invention relates generally to the determination of constituents in blood plasma and serum and more specifically to the determination of lipoprotein constituents in blood plasma and serum. Lipoprotein X (LP-X) is an abnormal lipoprotein that appears in the sera of patients with obstructive jaundice. LP-X is a spherical particle typically between about 30 and 70 nm in diameter. Its density is between 1.006 and 1.063 g/ml, which is in the same range as normal low density lipoproteins (LDL). Phospolipids (about 66 percent) and unesterified cholesterol (about 22 percent) make up the bulk of LP-X; also, protein, cholesterol esters and triglycerides comprise about 12 percent of LP-X. See Narayanan, Biochemistry and Clinical Relevance of Lipoprotein X, 14 Annals of Clinical and Laboratory Science 371 (1984). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods and compositions relating to modulation of A20 Inventor(s): Boone, David; (Chicago, IL), Lee, Eric; (Torrance, CA), Ma, Averil; (Chicago, IL) Correspondence: Robert E. Hanson; Fulbright & Jaworski L.L.P.; Suite 2400; 600 Congress Avenue; Austin; TX; 78701; US Patent Application Number: 20030171253 Date filed: April 18, 2002 Abstract: The invention provides compositions and methods for treating diseases characterized by aberrant programmed cell death and/or inflammation, comprising mediating A20 function in the subject. Such diseases include Crohn's disease, inflammatory bowel disease, a disease associated with ischemic injury, a toxin-induced liver disease and cancer. The invention further provides methods and compositions for assays for modulators of A20. Excerpt(s): This application claims the priority of U.S. Provisional Patent Application Serial No. 60/285,427, filed Apr. 19, 2001, the entire disclosure of which is specifically incorporated herein by reference. The present invention relates generally to the field of medicine. More particularly, it concerns compositions and methods for treating disease conditions comprising modulating A20. Intestinal inflammatory responses to microbial pathogens must be delicately balanced to effectively eliminate pathogens while preventing autoimmunity. The critical roles of cytokines in maintaining this balance have been demonstrated in both experimental models such as gene targeted transgenic mice and in human IBD patients. (Sadlock et al., 1993; Willerford et al., 1995; Kuhn et al., 1993; Blumberg et al., 1999; Fiocchi, 1999). One of the most important cytokines for regulating intestinal inflammation is tumor necrosis factor (TNF). The critical roles of TNF in this regard are highlighted both by animal studies showing that TNF overexpression by targeted deletion of TNF 3' untranslated mRNA stability elements

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leads to ileitis and arthritis (TNF.sup.DELTA.ARE mice) (Kontoyiannis et al., 1999), and by human studies and clinical experience showing that IBD patients express high levels of TNF and frequently respond to anti-TNF therapy (Targan et al., 1997; Rutgeerts et al., 1999). These observations indicate that TNF is a critical regulator of immune homeostasis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods of treating liver disease and liver damage with growth hormone and foxM1B Inventor(s): Adami, Guy; (Brookfield, IL), Costa, Robert H.; (Oak Park, IL), KrupczakHollis, Katherine; (Chicago, IL), Tan, Yongjun; (Arlington Heights, IL), Wang, Xinhe; (Chicago, IL) Correspondence: Mcdonnell Boehnen Hulbert & Berghoff; 300 South Wacker Drive; Suite 3200; Chicago; IL; 60606; US Patent Application Number: 20020187936 Date filed: May 17, 2002 Abstract: The invention provides a method of treating liver damage or disease in a patient by stimulating liver regeneration. Specifically, the invention provides a method of inducing liver cell proliferation comprising contacting liver cells that express FoxM1B protein with growth hormone. The invention also provides methods of screening for compounds that induce FoxM1B protein expression, nuclear localization, or both expression and nuclear localization. The invention further provides pharmaceutical compositions comprising selected compounds and methods of using such compositions. Excerpt(s): This application is related to U.S. provisional application Serial No. 60/291,789, filed May 17, 2001, No. 60/305,821, filed Jul. 16, 2001, and No. 60/315,484, filed Aug. 28, 2001. One important function of mammalian liver is to detoxify harmful compounds that enter the body. In the liver, toxic substances may be cleared from the body by phagocytosis, secretion into the bile, or by chemical modification of the compound to facilitate elimination by the kidneys. Other functions of the liver include storing vitamins, producing cholesterol and bile to assist digestion, converting excess glucose into glycogen, and releasing glucose into the blood during fasting. The liver is also responsible for secreting all serum carrier proteins and proteins involved in blood coagulation. A healthy liver, therefore, is an important contributor to the overall health of an animal or human individual. Environmental and dietary toxins constantly bombard the liver throughout a lifetime. The potential for liver damage increases with time and as the stress of removing these toxins increases. The mammalian liver is capable of completely regenerating itself in response to such liver damage (Fausto et al., 1995, FASEB J 9: 1527-1536; Michalopoulos et al., 1997, Science 276: 60-66; Taub, 1996, FASEB J. 10: 413-427). However, excessive exposure to toxins such as alcohol or certain drugs can cause severe liver damage leading to disease. During aging, the ability of the liver to regenerate decreases and liver damage and disease becomes more severe and more difficult to treat. Thus, the ability to stimulate hepatocyte proliferation and restore the regenerative potential of these liver cells would prove invaluable in treating liver diseases. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Molecularly imprinted polymers for the treatment and diagnosis of medical conditions Inventor(s): Green, Bernard S.; (Kibbutz Yavne, IL), Priwler, Morris; (Modtin, IL) Correspondence: DR. D. Graeser LTD.; C/o The Polkinhorns; 9003 Florin Way; Upper Marlboro; MD; 20772; US Patent Application Number: 20020015690 Date filed: June 29, 2001 Abstract: Improved molecularly imprinted polymers (MIPs) with both higher and more specific binding capacity for particular bile acids and/or salts, including the synthesis of such MIPs, the compounds themselves, and specific applications thereof. As an example of a particularly preferred specific application of these compounds, the present invention encompasses the use of the MIPs as sequestrants in the gastrointestinal tract, particularly in order to bind and therefore remove toxins from the gastrointestinal tract. In addition, the present invention is also useful for treatment of various diseases which are related to, and/or characterized by, an effect of bile acids and salts, such as atherosclerosis, liver disease and various diseases of the gastrointestinal tract. The MIP compounds of the present invention are also useful for combination therapy with other medications and for diagnosis and monitoring of diseases. Excerpt(s): This Application claims priority from US Provisional Application No. 60/215,882, filed on Jun. 30, 2000, which is currently pending. The present invention is related to novel molecularly imprinted polymers, and in particular to improvements in the production of molecularly imprinted polymers (MIPs), as well as to these specific MIPs, and to the use of MIPs for specific applications. The MIPs of the present invention are particularly suitable for binding to, and thereby removing, toxins in the gastrointestinal tract. As an exemplary implementation, the present invention is described with regard to the removal of bile acids and bile salts from the gastrointestinal tract. In addition, the present invention is also useful for treatment of various diseases which are related to, and/or characterized by an effect of, bile acids and bile salts, such as atherosclerosis, cancer, liver disease and various diseases of the gastrointestinal tract. The MIP compounds of the present invention are also useful for combination therapy with other medications. These medications may involve mechanisms of action that lower or change the composition of bile acids and salts in the body or by a different mechanism. In addition the present invention also is useful for the diagnosis and monitoring of various diseases by selectively binding to an established marker which is then identified using known binding indicator techniques such as fluorescence. As an illustrative example for implementation, the present invention is described with regard to the diagnosis of medical conditions which are related to, and or characterized by an effect of, bile acids and/or bile salts, such as atherosclerosis, various diseases of the gastrointestinal tract, cancer and inflammatory conditions. This is achieved by determining the level of at least one specific bile acid or salt or the ratio of at least one specific bile acid or to at least a second specific bile acid or salt and determining whether these levels fall within an establish range which indicates the potential existence of the relevant disease. The analysis is performed on bile acids and or bile salts found in serum, bile, gastric contents, and feces. The subject of molecularly imprinted polymers has been extensively reviewed (e.g., G. Wulff, Angew. Chem., Int. Ed. Engl. 1995, 34, 1812-1832; A. G. Mayyes and K. Mosbach, Trends Anal. Chem. 1997, 16, 321-332; E. N. Vulfson, C. Alexander, and M. J. Whitcombe Chem. Brit. 1997, 33, 23-26; K. Haupt and K. Mosbach, Trends Biotechnol. 1998, 16, 468-475; Molecular and Ionic Recognition with Imprinted Polymers, ACS Symp. Ser. 703; R. A. Bartsch and M. Maeda, Eds.; American

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Chemical Society, Washington, D.C., 1998) and a number of patents on this topic have been issued [e.g., U.S. Pat. No. 4,127,730 (Wulff, G., Sarhan A.); U.S. Pat. No. 5,110,833 (Mosbach. K.); U.S. Pat. No. 5,630,978 (Domb, A.,); U.S. Pat. No. 5,587,273 (Yan, M. et al.); U.S. Pat. No. 5,872,198 (Mosbach, K. et al;)]. A schematic depiction of the formation of MIPs for deoxycholic acid (DCA) and glycodeoxycholic acid (GDCA) is shown in FIGS. 1A and 1B. Although the binding/recognition site is actually a family of nonhomogeneous sites, the scheme illustrates how the cavities for two similar substances may differ. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel human nucleic acid molecules and polypeptides encoding cation channels Inventor(s): Gaughan, Glen T.; (Cheshire, CT), Ramanathan, Chandra S.; (Wallingford, CT) Correspondence: Pennie And Edmonds; 1155 Avenue OF The Americas; New York; NY; 100362711 Patent Application Number: 20020072101 Date filed: January 18, 2001 Abstract: The present invention relates to novel human nucleic acid molecules encoding novel human cation channels, and proteins and polypeptides encoded by such nucleic acid molecules. More specifically, the nucleic acid molecules of the invention include novel human genes, e.g., hCCh3.1, hCCh3.2, and hCCh4, that encode proteins or polypeptides that display some sequence homology and structural homology to the vanilloid and TRP (transient receptor potential) families of cation channel proteins. The proteins and polypeptides of the invention represent novel cation channels that may be therapeutically valuable targets for drug delivery in the treatment of human diseases which involve calcium, sodium, potassium or other ionic homeostatic dysfunction, such as central nervous system (CNS) disorders, e.g., stroke or degenerative neurological disorders such as Alzheimer's disease, or other disorders such as cardiac disorders, e.g., arrhythmia, diabetes, chronic pain, hypercalcemia, hypocalcemia, hypercalciuria, hypocalciuria, or ion disorders associated with renal or liver disease. Excerpt(s): The present invention relates to the isolation and identification of novel human nucleic acid molecules and proteins and polypeptides encoded by such nucleic acid molecules, or degenerate variants thereof, encoding novel human cation channels. More specifically, the nucleic acid molecules of the invention include two novel human genes encoding proteins or polypeptides that display some sequence homology and structural homology to the vanilloid and TRP (transient receptor potential) families of cation channel proteins. The proteins and polypeptides of the invention represent novel cation channels that may be therapeutically valuable targets for drug delivery in the treatment of human diseases that involve calcium, sodium, potassium or other ionic homeostatic dysfunction, such as central nervous system (CNS) disorders, e.g., stroke or degenerative neurological disorders such as Alzheimer's disease, or other disorders such as cardiac disorders, e.g., arrhythmia, diabetes, chronic pain, hypercalcemia, hypocalcemia, hypercalciuria, hypocalciuria, or ion disorders associated with renal or liver disease. Control of the internal ionic environment is an extremely important function of all living cells. Ion exchange with the external medium is regulated by a variety of means, the most important of which are various transporters and ion channels. Ion channels comprise a very large and diverse family of proteins which play an important role in cell homeostasis, hormone and neurotransmitter release, motility,

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neuronal action potential generation and propagation and other vital intra- and intercellular functions. Thus, these channels are important targets for the development of therapeutic compounds in the treatment of disease. A number of proteins have been described as forming ion channels, including the vanilloid and TRP protein families. These proteins have been shown to function as cation channels of varying degrees of selectivity and with different, and in some cases unknown, mechanisms for channel gating. For example, the TRP family of ion channels comprises a group of proteins some of which are believed to form store-operated calcium (Ca.sup.2+) channels, i.e., ion channels that operate to allow the influx of extracellular Ca.sup.2+ into cells when the intracellular stores of calcium are depleted (Zhu et al., 1996, Cell 85: 661-671). It is believed that TRP ion channels are expressed, in some form, in most, if not all, animal tissues (Zhu et al., supra at 661). Recently a human orthologue of murine Trp12 was localized on human chromosone 12 (Wisenbach et al., 2000, FEBS Letters 485:127-134). In addition, another protein, termed trp-like or trpl, has been disclosed (Phillips et al., 1992, Neuron 8: 631-642; Gillo et al., 1996, PNAS USA 93: 14146-14151) and it has been suggested that there may be a cooperative interaction between TRP and TRPL proteins, perhaps these proteins contributing channel subunits to form a multimeric Ca.sup.2+ channel (Gillo et al., supra). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel medicinal herbal composition for treating liver diseases and HIV Inventor(s): Wu, Tzu-Sheng; (Hsinchu, TW) Correspondence: Venable; Post Office Box 34385; Washington; DC; 20043-9998; US Patent Application Number: 20020076446 Date filed: July 18, 2001 Abstract: The present invention provides a herbal pharmaceutical composition for treating patients with liver diseases and/or HIV. The composition contains fifteen (15) ingredients, which are diffuse hedyotis, bistort rhizome, giant knotweed rhizome, Asiatic moonseed rhizome, baical skullcap root, bovine biliary powder, milkvetch root, barbary wolfberry fruit, sanqi, red ginseng, figwort root, Chinese magnoliavine fruit, turmeric root-tuber, hawthorn fruit, and Chinese angelica. Among the fifteen (15) ingredients, diffuse hedyotis, bistort rhizome, giant knotweed rhizome, and Chinese magnoliavine fruit are the required herbs which contribute to the efficacy of the pharmaceutical composition. Excerpt(s): The present application claims the benefit of the filing date of U.S. Provisional Application No. 60/240,963, filed on Oct. 18, 2000, which is herein incorporated by reference. The present invention relates to a novel herbal pharmaceutical composition and its use for treating patients with liver diseases (e.g., viral hepatitis [such as Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, and Hepatitis E], alcoholic or fatty liver, liver cirrhosis, and liver cancer) and HIV. The major ingredients in the herbal composition are diffuse hedyotis, bistort rhizome, giant knotweed rhizome, and Chinese magnoliavine fruit. The composition further contains Asiatic moonseed rhizome, baical skullcap root, bovine biliary powder, tumeric roottuber, hawthorn fruit, sanqi, barbary wolfberry fruit, red ginseng, figwort root, Chinese angelica, and milkvetch root. The present invention also relates to a method for making the medicinal herbal composition and methods for treating patients with the medicinal herbal composition. Liver diseases have great impact on human health. Hepatitis is a kind of liver diseases, which is caused by liver inflammation due to infection of a

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variety of pathogens, which include, but are not limited to, viruses, bacteria, fungi, and protozoa. Hepatitis can be categorized as acute, chronic, or fulminant. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Nuclear envelope protein recognized by atypical p-ANCA in patients with inflammatory bowel disease and autoimmune liver diseases Inventor(s): Terjung, Birgit; (Swisttal, DE), Worman, Howard J.; (New York, NY) Correspondence: Cooper & Dunham Llp; 1185 Avenue OF The Americas; New York; NY; 10036; US Patent Application Number: 20030003518 Date filed: June 15, 2001 Abstract: The present invention is directed to the molecular characterization of the nuclear antigen recognized by atypical p-antineutrophil cytoplasmic antibodies (pANCA) in order to better diagnose patients with inflammatory bowel diseases such as ulcerative colitis (UC), and autoimmune liver diseases such as primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). Molecular characterization of the target antigen comprises preparing cytoplasmic and nuclear extracts of human neutrophils, human HL-60 and murine 32D myeloid cells. Proteins should then be resolved by 1 and 2 dimensional gel electrophoresis and reactive proteins can then be detected by immunoblotting with sera from individuals, making certain to have both normal and disease controls. Atypical p-ANCA should then be affinity purified against the reactive protein and investigated for their immunofluorescence pattern using confocal microscopy. One could then detect the antigen that atypical p-ANCA can recognize and use that antigen to detect the prescence of atypical p-antineutrophil cytoplasmic antibodies so as to diagnose patients with inflammatory bowel diseases such as ulcerative colitis (UC), and autoimmune liver diseases such as sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). Excerpt(s): Throughout this application, various publications are referenced by author and date. Full citations for these publications may be found listed alphabetically at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. Atypical "antineutrophil cytoplasmic antibodies" (ANCA) are present in patients with ulcerative colitis (UC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) ANCA represent a family of heterogenous autoantibodies directed against constituents of neutrophilic granulocytes. These autoantibodies have become valuable seromarkers for the diagnostic and therapeutic management of patients with systemic vasculitides such as Wegner granulomatosis and microscopic polyangiitis, in which they recognize well defined cytoplasmic antigens such as proteinase 3 and myeloperoxidase. Two well established ANCA staining patterns can be distinguished on ethanol-fixed neutrophils: a difuse cytoplasmic fluorescence pattern (c-ANCA) and a fine homogeneous labeling of the perinuclear cytoplasm (p-ANCA). Autoantibodies that are similar to p-ANCA in patients with systemic vasculitides are detected in individuals with chronic inflammatory bowel diseases (IBD) such as ulcerative colitis or autoimmune liver disorders such as primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). Contrary to systemic vasculitides, the role of ANCA in these disorders is not clear. Various cytoplasmic proteins such as bactericidal/permeability increasing protein,

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catalase, cathepsin G, enolase, or lactoferrin have been proposed as putative target antigens of ANCA in these disorders, but reactivity to these proteins has only been detected in less than thirty five percent of cases. The predominant target antigen of ANCA in IBD and autoimmune liver disorders has not been identified. Since their target antigens are unknown, p-ANCA in patients with IBD or autoimmune liver disorders are generally referred to as atypical p-ANCA. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Plant drug for treatment of liver disease Inventor(s): Zhao, Xinxian; (Shenzhen, CN) Correspondence: Xinxian Zhao; 67-08 168th Street; Flushing; NY; 11365; US Patent Application Number: 20030026854 Date filed: April 4, 2001 Abstract: The present invention related to safe plant drug for treatment of liver disease, specifically, this invention proves a safe plant drug Schisandrin and its preparation. Schisandrin has the following pharmaceutical functions: increasing tumor suppresson genes express activity, decreasing activity of oncogenes, increasing immune function, increasing liver DNA synthesis, decreasing serum alamine aminotransferase activity, increasing glutathione level, increasing glutathione reductase activity, decreasing lipid peroxidation of liver, increasing hepatic microsomal monooxygenases activity, increasing ATP content in liver, increasing energy metabolism activity, decreasing density lipoprotein oxidation, protecting gastrointestinal function, increasing killer cell activity, increasing complement activity, decreasing induced liver cancer activity and decreasing grown of cancer cells. Excerpt(s): The present invention related to safe plant drug for treatment of liver disease, specifically, this invention proves a safe plant drug Schisandrin and its preparation. The most common types of liver disease are hepatitis and cirrhosis. So far, no one drug has been succeeded to treat for hepatitis and cirrhosis. The hepatitis victim is always short on appetite and finds it is difficult. Therefore, it is important that to eat the suitable food to supply liver for self-repair. The traditional medical book described that a good treatment for hepatitis is high protein diet, Brewer's yeast, wheat germ, egg yolks, and other high quality protein, which combats the stress damage. Some drugs have been used for treatment of liver disease, but clinical results are not successful. For the reasons given above, to discover an effect safe drug for treating patients with liver disease is necessary and important. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Regulation of human 11 beta-hydroxysteroid dehydrogenase 1-like enzyme Inventor(s): Ramakrishnan, Shyam; (Brighton, MA) Correspondence: Banner & Witcoff; 1001 G Street N W; Suite 1100; Washington; DC; 20001; US Patent Application Number: 20030148349 Date filed: January 3, 2003

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Abstract: Reagents which regulate human 11 beta-hydroxysteroid dehydrogenase 1-like enzyme and reagents which bind to human 11 beta-hydroxysteroid dehydrogenase 1like enzyme gene products can play a role in preventing, ameliorating, or correcting dysfunctions or diseases including, but not limited to CNS disorders, osteoporosis, liver disease, obesity, blood pressure or fetal development abnormalities, and diabetes. Excerpt(s): The invention relates to the regulation of human 11 beta-hydroxysteroid dehydrogenase 1-like enzyme. Glucocorticoid levels in tissues are modulated by the enzyme 11.beta.-hydroxysteroid dehydrogenase. Two isoforms of the enzyme have been isolated. The type I enzyme (11.beta.-HSD1) is a bifunctional enzyme which acts predominantly as an oxoreductase to form the active glucocorticoids cortisol (in man) or corticosterone (in rodents) from their inactive 11-keto metabolites, cortisone and 11dehydrocorticosteron- e, respectively. Agurwal et al., J. Biol. Chem 264, 18939-46, 1989. The type II isoform (11.beta.-HSD2) acts unidirectionally to produce inactive 11-keto metabolites. It utilizes NAD to metabolize glucocorticoids to 11-keto compounds with low affinity for glucocorticoid and mineralocorticoid receptors. Albiston et al., Molec. Cell Endocr 105, R11-17, 1994; Funder et al., Science 242, 583-85, 1988; Edwards et al., Lancet 2, 986-89, 1988. Gene deletion experiments in mice indicate that this enzyme is important for the maintenance of normal serum glucocorticoid levels and is involved in the activation of key hepatic gluconeogenic enzymes. Other important sites of action include omental fat, ovary, kidney, brain, and vasculature. Koozowsky et al., J. Steroid Biochem. Mol. Biol. 69, 391-401, 1999. 11.beta.-HSD1 activity is found in all major blood vessels and the heart and is higher in resistance vessels, suggesting a role of 11.beta.HSD1 in modulating blood pressure. Walker et al, Endocrinol. 129, 3305-12, 1991. 11.beta.-HSD1 and 11.beta.-HSD2 mRNA coexist in rat aortic endothelial cells, with the 11.beta.-HSD1 isoform predominating. Brem et al., Hypertension 31, 459-62, 1998. Selective inhibition of 11.beta.-HSD1 activity attenuates the contractile effect of phenylephrine and angiotensin II on aortic rings. Brem et al., Hypertension 30, 449-54, 1997. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Remedies or preventives for diaminotrifluoromethylpyridine derivatives

liver

diseases

containing

Inventor(s): Sakai, Kimie; (Kusatsu-shi, JP), Yotsuya, Shuichi; (Kusatsu-shi, JP) Correspondence: Oblon Spivak Mcclelland Maier & Neustadt PC; Fourth Floor; 1755 Jefferson Davis Highway; Arlington; VA; 22202; US Patent Application Number: 20030018054 Date filed: July 29, 2002 Abstract: A therapeutic or preventive agent for liver diseases, containing as an active ingredient a diaminotrifluoromethylpyridine derivative represented by the formula (I) or its salt: 1wherein X is a --CW.sup.1R.sup.1 group, a --COCOR.sup.2 group, a -CW.sup.1NHCOR.sup.2 group, a --C(.dbd.W.sup.1)W.sup.2R.sup.3 group or a -CW.sup.1N(R.sup.4)R.sup.5 group; Y is an alkyl group, a --CW.sup.3R.sup.6 group, a -COCOR.sup.7 group, a --NHCOR.sup.7 group, a --C(.dbd.W.sup.3)W.sup.4R.sup.8 group, a --(NH).sub.mSO.sub.2R.sup.9 group, a --(NH).sub.mSO.sub.2OR.sup.10 group or a --(NH).sub.mSO.sub.2N(R-.sup.11)R.sup.12 group; each of R.sup.1, R.sup.6 and R.sup.9 is a chain hydrocarbon group, a monocyclic hydrocarbon group, a polycyclic hydrocarbon group, a monocyclic heterocycle group or a polycyclic heterocycle group; each of R.sup.2 and R.sup.7 is an alkyl group, an alkoxy group, a phenyl group or a

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phenoxy group; each of R.sup.3, R.sup.8 and R.sup.10 is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a phenyl group or a benzyl group; each of R.sup.4, R.sup.5, R.sup.11 and R.sup.12 is an alkyl group; each of W.sup.1, W.sup.2, W.sup.3 and W.sup.4 is an oxygen atom or a sulfur atom; and m is 0 or 1, is provided. Excerpt(s): The present invention relates to a therapeutic or preventive agent for liver diseases, containing as an active ingredient a diaminotrifluoromethylpyridine derivative or its salt. Japanese Patent No. 2762323 and U.S. Pat. No. 5,229,403 disclose that a diaminotrifluoromethylpyridine derivative or its salt has a phospholipase A.sub.2 inhibitory action and is useful as an active ingredient of an anti-inflammatory agent or an anti-pancreatitis agent. They also disclose that (1) phospholipase A.sub.2 is secreted or activated in platlets or inflammatory cells by stimulations and contributes to the production of a platlet activating factor (PAF) and arachidonic acid metabolites, (2) the arachidonic acid metabolites are closely related to various diseases, for example, inflammatory symptoms such as rheumatic arthritis, arthritis deformans, tendinitis, bursitis, psoriasis and related dermatitis; nasal and bronchial airway troubles such as allergic rhinitis and allergic bronchial asthma; and immediate hypersensitive reactions such as allergic conjunctivitis, (3) on the other hand, phospholipase A.sub.2 secreted from pancreas is activated in the intestine and exhibits a digestive action, but once activated in the pancreas, it is believed to be one of the factors causing pancreatitis, and (4) the above diaminotrifluoromethylpyridine derivative inhibits phospholipase A.sub.2 and thus is effective for treatment of diseases related to phospholipase A.sub.2 such as inflammatory symptoms, nasal and bronchial airway troubles, immediate hypersensitive reactions or pancreatitis, and can be used as an anti-inflammatory agent, an agent for treating bronchial asthma, an anti-allergy agent, an anti-pancreatitis agent, an anti-nephritis agent or an anti-multiple organ failure agent. Further, U.S. Pat. No. 5,492,908 discloses that such compounds can be used as a therapeutic agent for rheumatoid arthritis, and JP-A-10-298076 discloses that some of these compounds are effective as an anticancer agent having a carcinogenesis inhibitory effect. 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

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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), 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 •

Use of histamine to treat liver disease Inventor(s): Gehlsen, Kurt R.; (Encinitas, CA) Correspondence: Knobbe Martens Olson & Bear Llp; 2040 Main Street; Fourteenth Floor; Irvine; CA; 92614; US Patent Application Number: 20030091553 Date filed: October 11, 2002 Abstract: The disclosure relates to methods for treating and/or preventing hepatic tissue and cell damage caused by reactive oxygen species in mammals. More specifically, the disclosure relates to the prevention and/or reduction of hepatic tissue and cell damage through the administration of histamine and histamine agonists. Excerpt(s): This application claims priority to U.S. Provisional Application Ser. No. 60/343,628, filed on Oct. 19, 2001, and U.S. Provisional Application Ser. No. 60/340,011, filed on Oct. 30, 2001. The entire contents of these provisional applications are hereby incorporated by reference in their entireties. The disclosure below relates to methods for treating and/or preventing hepatic tissue and cell damage caused by reactive oxygen species in mammals. More specifically, the disclosure relates to the prevention and/or reduction and/or reversal of hepatic tissue and cell damage through the administration of histamine and histamine-related compounds. Oxidative stress, i.e. toxicity inflicted by reactive oxygen species (ROS), is being recognized as a systemic phenomenon in liver disease, whose extent appears to correlate with the severity and stage of disease. The mechanism of action associated with the cellular damage caused by oxidative stress has been implicated in a number of diseases including hepatitis and relates to direct damage of hepatic cells. One author has examined a role for oxidative stress in the development of the hyperdynamic circulation in portal hypertension. Bomzon and Ljubuncic have indicated, however, that it is premature to conclude that oxidative stress per se impacts at least vascular smooth muscle cell function in liver disease. Pharmacol Ther., 89(3):295-308 (2001). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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•

Use of oral beclomethasone dipropionate to treat liver inflammation Inventor(s): McDonald, George B.; (Bellevue, WA) Correspondence: Lyon & Lyon Llp; 633 West Fifth Street; Suite 4700; Los Angeles; CA; 90071; US Patent Application Number: 20010036938 Date filed: January 3, 2001 Abstract: Liver inflammation caused by liver disease is treated orally with biclomethasone dipropionate or a metabolite thereof. Excerpt(s): This invention relates to the treatment of liver inflammation and more particularly to the treatment of liver inflammation by an orally effective therapeutic agent. There are a number of liver diseases characterized by inflammation of the liver, that is, infiltration of the liver with lymphocytes, plasma cells, and neutrophils. These inflammatory cells accumulate in the liver in response to numerous stimuli, for example, ethanol-induced liver injury (alcoholic hepatitis), fatty liver (non-alcoholic steatohepatitis), viral infection (chronic hepatitis B or C), medications (drug-liver injury), as well as in diseases whose cause or stimulus to inflammation is unknown, for example, primary biliary cirrhosis, sclerosing cholangitis, and autoimmune hepatitis. There is evidence in many of these disorders that the damage to the liver is not as much related to the initial insult or primary cause as to the inflammatory response. There is evidence that inflammatory cells cause damage to liver cells (hepatocytes) and also stimulate other cells in the liver, for example, Kupffer cells (derived from monocytemacrophage cells) and stellate cells (a form of myofibroblast). For example, the development of fibrosis (scarring) in the liver that can lead to cirrhosis of the liver results from the constant stimulus of stellate cells by proteins released by inflammatory cells and Kupffer cells that lead to production of collagen by the affected stellate cells. Treatment of inflammatory diseases of the liver can be directed at either the primary stimulus, when one is known, or at the inflammatory process or at the actions of Kupffer cells and stellate cells. Examples of treatment of the primary stimulus to liver inflammation would be cessation of alcohol consumption by patients who have alcoholic hepatitis and the treatment of hepatitis B or hepatitis C with antiviral drugs. However, these treatments are not always effective. For example, the ability to eliminate hepatitis C virus from the liver with the best currently available antiviral therapy is about 50% and sometimes the inflammatory liver disease persists even when the original stimulus has been eliminated, for example, alcoholic hepatitis. The other disadvantage to treatments which seek to treat the inflammatory response is that the medications used for this purpose, corticosteroids such as prednisone, antimetabolites such as methotrexate, alkylating agents such as cyclophosphamide and azathioprine, is that they cause a generalized immunosuppression throughout the body, and their side effects occur throughout the body. While these treatments may be effective in suppressing liver inflammation, they are limited by side effects because they are not liver-specific. For most other inflammatory liver diseases where the primary stinumus is not known, there are no known effective treatments. According to this invention, liver diseases characterized by inflammation of the liver can be effectively treated by oral administration of beclomethasone dipropionate (BDP) or a metabolite thereof to a patient having such a liver disease. BDP or a metabolite thereof is administered orally to a patient suffering from a liver disease characterized by inflammation of the liver in any therapeutically effective dosage amount, generally in an amount of from about 2 mg/day to about 12 mg/day in any form suitable for oral administration, such as

Patents 201

capsules, pills or emulsions. If desired, other agents may be included in such oral formulations. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Xanthine oxidase inhibition as a strategy to alleviate oxidative impairment of vascular function Inventor(s): Aslan, Mutay; (Antalya, TR), Freeman, Bruce A.; (Birmingham, AL), Ryan, Tom; (Birmingham, AL), Tarpey, Margaret; (Birmingham, AL), Townes, Tim; (Birmingham, AL) Correspondence: Bradley Arant Rose & White, Llp; Intellectual Property Departmentnwj; 1819 Fifth Avenue North; Birmingham; AL; 35203-2104; US Patent Application Number: 20030158213 Date filed: November 18, 2002 Abstract: Disclosed is a method for alleviating the oxidative impairment of vascular function by inhibiting the activity of xanthine oxidase, or active forms thereof. Xanthine oxidase levels have been shown to be increased by a variety of conditions, including sickle cell disease. In the present disclosure, allopurinol is used to inhibit xanthine oxidase activity. As a result of the inhibition of xanthine oxidase,.NO levels in a subject can be maintained. In addition to sickle cell disease, allopurinol inhibition of xanthine oxidase may be used to treat other conditions, including, but not limited to, respiratory distress, kidney disease, liver disease, ischemia-reperfusion injury, organ transplant, sepsis, burns, viral infections and hemorrhagic shock. Excerpt(s): This disclosure claims the benefit of U.S. Provisional Patent Application No. 60/333,268, filed on Nov. 16, 2001. The present disclosure is directed to a method of using compounds which inhibit the activity of xanthine oxidase in order to alleviate the inhibition of vascular function caused by oxidative events and/or inflammatory conditions. The production of oxygen radical species, such as O.sub.2. and H.sub.2O.sub.2, have been know to cause tissue injury in living organisms and contribute to a wide variety of disease processes. Multiple features of sickle cell disease (SCD) reveal that inflammatory-derived oxidative reactions lead to impaired nitric oxide (.NO)-dependent vascular function. Nitric oxide is a free radical mediator of neurotransmitter, cell-mediated immunity and tissue redox reactions. In regulating endothelial-dependent vascular relaxation,.NO diffuses to target cells to stimulate cGMP production by guanylate cyclase and activate a chain of events in the vasculature including smooth muscle cell relaxation, inhibition of platelet aggregation and neutrophil margination and regulation of gene expression. In SCD, the production of.NO appears to be chronically activated to maintain vasodilation, as indicated by low baseline blood pressure, decreased pressor responses to angiotensin II, renal hyperfiltration and a tendency for priapism. Plasma arginine levels drop precipitously during pain crises, indicating a possible demand for, or insufficient synthesis of,.NO. The mechanisms underlying blood flow deprivation, the associated pain and consequent tissue injury in SCD remain poorly understood. If the tissue ischemia that is a hallmark of SCD resulted solely from polymerized, sickled red cells, occlusion of predominantly small blood vessels would occur. In contrast, stroke in SCD results from occlusion of large and medium-sized arteries (internal carotid and middle cerebral arteries). Importantly, levels of sickled erythrocytes or dense cells do not correlate with painful episodes and other manifestations of vascular occlusion, inferring that morbidity is due to vascular functional defects that occur in response to sickling, rather than

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mechanical effects of sickling. Increased oxidant production in the vasculature of SCD patients has been recognized for almost two decades. However, this disclosure reveals that the endogenous rate of production of superoxide (O.sub.2.--) and hydrogen peroxide (H.sub.2O.sub.2) by human sickle red cells is not significantly increased. In contrast, elevated plasma and vessel wall xanthine oxidase (XO) and myeloperoxidase activity in SCD patients and SCD mice, and increased vessel wall O.sub.2.-- and H.sub.2O.sub.2 generation in SCD mice is observed. This is ascribed to the a) vessel wall binding of liver-derived circulating XO, released following repeated hepatic hypoxiareoxygenation events, b) release and vessel wall binding of of neutrophil myeloperoxidase, and c) possible increased vessel wall expression of XO or other oxidases. This vascular inflammatory condition in SCD can induce O.sub.2.-- and H.sub.2O.sub.2 dependent inhibition of the salutary actions of.NO, while concomitantly yielding the potent and versatile reaction products, peroxynitrite (ONOO--) and nitrogen dioxide, oxidizing and nitrating species capable of further impairing vascular function. Thus, it is viewed that XO-derived reactive species impair nitric oxidedependent systemic vascular function in SCD patients and contribute to the pathogenesis of acute sickle cell crises and end-organ damage. Therefore, a therapeutic regime to target and inhibit the XO-dependent production of O.sub.2. and H.sub.2O.sub.2 should be effective in treating SCD patients by preserving.NO functions and endothelial dependent function in SCD patients. 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 liver disease, 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 “liver disease” (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 liver disease. You can also use this procedure to view pending patent applications concerning liver disease. 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 LIVER DISEASE Overview This chapter provides bibliographic book references relating to liver disease. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on liver disease 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 “liver disease” (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 liver disease: •

Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment Source: Malden, MA: Blackwell Science, Inc. 1999. 568 p. 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: Cirrhosis (liver scarring) is a very prevalent disease and ascites (fluid accumulation) is the most frequent complication. The development of ascites in cirrhosis is the consequence of the simultaneous occurrence of very complex processes leading to impairment in hepatic, circulatory, and renal function. The textbook offers 32 chapters on the pathogenesis, diagnosis and treatment of ascites and renal dysfunction in liver disease. Topics include historical notes on ascites in cirrhosis; characteristics of ascites;

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clinical disorders of renal function in cirrhosis with ascites; clinical disorders of renal function in acute liver failure; renal dysfunction and postoperative renal failure in obstructive jaundice; spontaneous bacterial peritonitis; the etiology, diagnosis, and management of noncirrhotic ascites; extracellular fluid volume homeostasis; physiology of the renal circulation; physiology of the gastrointestinal and liver circulation; the renin angiotensin aldosterone system in cirrhosis; the sympathetic nervous system in cirrhosis; arginine vasopressin in cirrhosis; atrial natriuretic peptide and other natriuretic factors in cirrhosis; arachidonic acid metabolites and the kidney in cirrhosis; nitric oxide and systemic and renal hemodynamic disturbances in cirrhosis; endothelin and systemic, renal, and hepatic hemodynamic disturbances in cirrhosis; the systemic circulation in cirrhosis; the splanchnic circulation in cirrhosis; alterations of hepatic and splanchnic microvascular exchange in cirrhosis (local factors in the formation of ascites); experimental models in the investigation of portal hypertension; renal dysfunction and ascites in carbon tetrachloride induced cirrhosis in rates; bacterial infection of the ascitic fluid in rates with carbon tetrachloride induced cirrhosis; the arterial vasodilation hypothesis of ascites formation in cirrhosis; prognosis of cirrhosis with ascites; the medical treatment of ascites in cirrhosis; treatment of ascites by paracentesis; the treatment of refractory ascites in cirrhosis; the treatment of hepatorenal syndrome in cirrhosis; drug induced renal failure in cirrhosis; liver transplantation in cirrhotic patients with ascites; and the treatment and prophylaxis of spontaneous bacterial peritonitis. Each chapter is written by experts in the field and includes extensive references. The text concludes with a subject index. •

Autoimmune Liver Diseases. 2nd ed Source: New York, NY: Elsevier Science, Inc. 1998. 656 p. Contact: Available from Elsevier Science, Inc. P.O. Box 945, Madison Square Station, New York, NY 10160-0757. (888) 437-4636 or (212) 633-3730. Fax (212) 633-3680. E-mail: [email protected]. PRICE: $284.50. ISBN: 0444828036. Summary: This book is devoted to summarizing the current knowledge of autoimmune liver diseases, focusing on potential pathogenic mechanisms and potential therapies that may prove to be of benefit in treating these diseases. Thirty-four chapters, each written by experts in the field, cover topics including: the concept of autoimmunity and autoimmune disease; the pathogenesis of autoimmune hepatitis; the pathogenesis of primary biliary cirrhosis; immunogenetic studies; the histopathology of autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis; current medical therapies of primary biliary cirrhosis and primary sclerosing cholangitis; drug-induced autoimmune liver disease; and autoimmune manifestations of alcoholic liver disease. Each chapter includes extensive references and a detailed subject index concludes the volume.

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Handbook of Liver Disease Source: Philadelphia, PA: Churchill-Livingstone. 1998. 534 p. Contact: Available from W.B. Saunders Company. Book Order Fulfillment Department, 6277 Sea Harbor Drive, Orlando, FL 32887-4430. (800) 545-2522. Fax (800) 874-6418. Email: [email protected]. PRICE: $73.00 plus shipping and handling. ISBN: 0443055203. Summary: This comprehensive handbook in outline format offers easy access to information on the full range of liver disorders, and covers symptoms, signs, differential diagnoses, and treatments. A total of 34 chapters cover the following topics: assessment

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of liver function and diagnostic studies, acute liver failure, chronic viral hepatitis, acute viral hepatitis, autoimmune hepatitis, alcoholic liver disease, fatty liver and nonalcoholic steatohepatitis, drug induced and toxic liver disease, cirrhosis and portal hypertension, portal hypertension and gastrointestinal bleeding, ascites and spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy, primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, Wilson's disease and related disorders, alpha 1 antitrypsin deficiency and other metabolic liver diseases, Budd Chiari syndrome and other vascular disorders, the liver in heart failure, the liver in pregnancy, the liver in systemic disease, pediatric liver disease, liver disease in the elderly, HIV and the liver, granulomatous liver disease, hepatic tumors, hepatic abscesses and cysts, other infections involving the liver, surgery in the patient with liver disease and postoperative jaundice, liver transplantation, cholelithiasis and cholecystitis, diseases of the bile ducts, and tumors of the biliary tract. The book features lists that summarize key information and numerous figures and tables on topics such as acetaminophen toxicity, classifications of chronic hepatitis, and indications for liver transplantation. Each chapter was written by an acknowledged expert in the field and includes references for additional study. A subject index concludes the volume. •

Medical Management of Liver Disease Source: New York, NY: Marcel Dekker, Inc. 1999. 634 p. Contact: Available from Marcel Dekker, Inc. Cimarron Road, P.O. Box 5005, Monticello, NY 12701-5185. (800) 228-1160 or (914) 796-1919. Fax (914) 796-1772. Website: www.dekker.com. PRICE: $185.00 plus shipping and handling. ISBN: 0824719689. Summary: This textbook on the treatment of liver disease is designed for practicing primary care physicians, intensive care physicians, gastroenterologists, and hepatologists, and is also useful for students and physicians in training. Part I, Approach to the Patient with Hepatobiliary Disease, is most helpful for physicians less experienced in caring for patients with liver disease, particularly considering the array of diagnostic studies available at this time. Parts II through VIII are designed to help physicians develop a treatment plan for specific liver diseases. These sections are divided into chapters that cover viral hepatitis, autoimmune liver disease, alcoholic liver disease, gallstones, liver infections, and hepatobiliary neoplasms, as well as a variety of other less common liver diseases. Part IX outlines the management of both common and rare complications of liver disease and Part X details important measures in the management of patients before and after liver transplantation. Each chapter, written by experts in the field, includes charts, diagrams, and extensive references. A subject index concludes the textbook.

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Drug Therapy for Gastrointestinal and Liver Diseases Source: Florence, KY: Martin Dunitz. 2001. 352 p. Contact:.AV.-Available from Martin Dunitz. Fulfillment Center, Taylor and Francis, 7625 Empire Drive, Florence, KY 41042. (800) 634-7064. E-mail: cserve@routledge_ny.com. Website: www.dunitz.co.uk. PRICE: $75.00 plus shipping and handling. ISBN: 1853177334. Summary: This textbook reviews the drug therapy for gastrointestinal and liver diseases. Fifteen chapters cover drug therapy of gastroesophageal reflux disease (GERD), peptic ulcer disease, emesis (vomiting), gastrointestinal bleeding, inflammatory bowel disease, gastrointestinal and liver infections, motility disorders, functional abdominal disorders, gastrointestinal cancer, pancreatitis and pancreatic insufficiency,

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viral hepatitis, non-viral liver disease, drug therapy for portal hypertension, hepatic (liver) failure, and the adverse effects of drugs on the gastrointestinal tract. Each chapter provides a brief summary of the pathophysiology of the disease, the rationale for drug intervention, and appropriate treatment regimens as indicated by current knowledge. Also includes is a drug list that summarizes mode of action, and other aspects of clinical pharmacology where appropriate, drug doses, common adverse affects, and drug interactions. A subject index concludes the volume.

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 “liver disease” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “liver disease” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “liver disease” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

A Colour Atlas of Liver Disease by Sheila Sherlock, J. Summerfield; ISBN: 0723416869; http://www.amazon.com/exec/obidos/ASIN/0723416869/icongroupinterna

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Acute and Chronic Liver Diseases: Molecular Biology and Clinics (Falk Symposium, Vol 87) by R. Schmid (Editor), et al (1996); ISBN: 0792387015; http://www.amazon.com/exec/obidos/ASIN/0792387015/icongroupinterna

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Advanced Therapy in Gastroenterology and Liver Disease by Theodore M. MD Bayless, B C Decker (2004); ISBN: 1550092480; http://www.amazon.com/exec/obidos/ASIN/1550092480/icongroupinterna

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Adverse Drug Reactions in the Differential Diagnosis of GI and Liver Diseases (Bailliere's Clinical Gastroenterology) by Bircher; ISBN: 0702012734; http://www.amazon.com/exec/obidos/ASIN/0702012734/icongroupinterna

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Alcoholic Liver Disease (Bailliere's Clinical Gastroenterology) by P.C. Hayes; ISBN: 0702017485; http://www.amazon.com/exec/obidos/ASIN/0702017485/icongroupinterna

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Alcoholic Liver Disease: Pathobiology, Epidemiology and Clinical Aspects by Pauline Hall (Editor); ISBN: 0471824690; http://www.amazon.com/exec/obidos/ASIN/0471824690/icongroupinterna

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Alcoholic Liver Disease: Pathology and Pathogenesis by Pauline Hall (Editor), Nancy Coffelt (1995); ISBN: 0340571942; http://www.amazon.com/exec/obidos/ASIN/0340571942/icongroupinterna

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An Atlas of Liver Disease by A. Burroughs, D. Price; ISBN: 1842140124; http://www.amazon.com/exec/obidos/ASIN/1842140124/icongroupinterna

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Anesthesia and Intensive Care for Patients With Liver Disease by Gilbert R. Park, et al; ISBN: 0750695544; http://www.amazon.com/exec/obidos/ASIN/0750695544/icongroupinterna

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Anesthesia and Intensive Care for the Patient with Liver Disease by Park (1995); ISBN: 0750612495; http://www.amazon.com/exec/obidos/ASIN/0750612495/icongroupinterna

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Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment by Vincente Arroyo (Editor), et al; ISBN: 0632043423; http://www.amazon.com/exec/obidos/ASIN/0632043423/icongroupinterna

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Autoimmune Liver Disease by P.A. Berg (Editor), et al; ISBN: 0792387309; http://www.amazon.com/exec/obidos/ASIN/0792387309/icongroupinterna

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Autoimmune Liver Disease - Its Recent Advances by International Symposium of Digestive Diseases Week, et al; ISBN: 044450527X; http://www.amazon.com/exec/obidos/ASIN/044450527X/icongroupinterna

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Autoimmune Liver Diseases by Edward L. Krawitt (Editor), et al; ISBN: 0444828036; http://www.amazon.com/exec/obidos/ASIN/0444828036/icongroupinterna

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Bile Acids in Liver Diseases: Proceedings of the International Falk Workshop Held in Munich, Germany, January 26-27, 1995 (Falk Symposium, Vol 82B) by Germany)/ Beuers, U./ Paumgartner, G. Falk Symposium 1995 Munich, G. Paumgartner (1995); ISBN: 0792388917; http://www.amazon.com/exec/obidos/ASIN/0792388917/icongroupinterna

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Cardiovascular Complications of Liver Disease by Arieh Bomzon, et al; ISBN: 0849347351; http://www.amazon.com/exec/obidos/ASIN/0849347351/icongroupinterna

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Cholestatic Liver Diseases in Children and Adults (Falk Symposium, Vol 89B) by C.E. Broelsch (Editor), et al (1996); ISBN: 0792387104; http://www.amazon.com/exec/obidos/ASIN/0792387104/icongroupinterna

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Cholestatic Liver Diseases: New Strategies for Prevention and Treatment of Hepatobiliary and Cholestatic Liver Diseases (Falk Symposium, Vol 75) by B. Van Hoek, et al (1994); ISBN: 0792388674; http://www.amazon.com/exec/obidos/ASIN/0792388674/icongroupinterna

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Chronic Active Liver Disease by Sidney Cohen (Editor), Roger D. Soloway (Editor) (1998); ISBN: 0783725655; http://www.amazon.com/exec/obidos/ASIN/0783725655/icongroupinterna

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Chronic Active Liver Disease: Contemporary Issues in Gastroentrology by Sidney Cohen (Editor) (1983); ISBN: 0443082235; http://www.amazon.com/exec/obidos/ASIN/0443082235/icongroupinterna

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Chronic Liver Disease (Frontiers of Gastrointestinal Research, Vol 9) by P. Gentilini (Editor), M. U. Dianzani (Editor) (1986); ISBN: 3805542054; http://www.amazon.com/exec/obidos/ASIN/3805542054/icongroupinterna

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Clinical use of drugs in patients with kidney and liver disease; ISBN: 0721612393; http://www.amazon.com/exec/obidos/ASIN/0721612393/icongroupinterna

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Color Atlas of Liver Disease by Sheila Sherlock, John A. Summerfield; ISBN: 0815166346; http://www.amazon.com/exec/obidos/ASIN/0815166346/icongroupinterna

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Colour Atlas of Liver Disease by Dame S Sherlock (Author); ISBN: 0723415587; http://www.amazon.com/exec/obidos/ASIN/0723415587/icongroupinterna

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Complications of Chronic Liver Disease by William G. Rector; ISBN: 0815172362; http://www.amazon.com/exec/obidos/ASIN/0815172362/icongroupinterna

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Contrast-Enhanced Ultrasound of Liver Diseases by A. Martegani, et al (2003); ISBN: 8847002079; http://www.amazon.com/exec/obidos/ASIN/8847002079/icongroupinterna

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Current Therapy in Gastroenterology and Liver Disease, 1984-1985 by Theodore M. Bayless (1984); ISBN: 0941158268; http://www.amazon.com/exec/obidos/ASIN/0941158268/icongroupinterna

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Diagnosis and Management of Liver Disease by Ralph E. Kirsch (Editor), et al (1995); ISBN: 0412575701; http://www.amazon.com/exec/obidos/ASIN/0412575701/icongroupinterna

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Dr. Melissa Palmer's Guide to Hepatitis & Liver Disease: What You Need to Know by Melissa Palmer; ISBN: 0895299224; http://www.amazon.com/exec/obidos/ASIN/0895299224/icongroupinterna

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Drug-Induced Liver Disease by Neil Kaplowitz (Editor), Laurie D. Deleve (Editor) (2003); ISBN: 0824708113; http://www.amazon.com/exec/obidos/ASIN/0824708113/icongroupinterna

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Extrahepatic Manifestations in Liver Diseases: Proceedings of the 69th Falk Symposium Held in Basel, Switzerland, October 15-17, 1992 (Falk Symposium, Vol 69) by W. Gerok, et al (1993); ISBN: 0792388216; http://www.amazon.com/exec/obidos/ASIN/0792388216/icongroupinterna

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Frontiers in Liver Disease by Paul D. Berk, Thomas C. Chalmers (Editor); ISBN: 0865770174; http://www.amazon.com/exec/obidos/ASIN/0865770174/icongroupinterna

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Gallstones and Liver Disease (The BMA Family Doctor Guides) by Malcolm Bateson; ISBN: 1853360775; http://www.amazon.com/exec/obidos/ASIN/1853360775/icongroupinterna

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Gastroenterology and Liver Disease (Colour AIDS) by Gregory Holdstock, Ralph Wright (1997); ISBN: 0443030332; http://www.amazon.com/exec/obidos/ASIN/0443030332/icongroupinterna

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Gastroenterology and Liver Disease (Colour Guide) by Peter C. Hayes; ISBN: 0443049556; http://www.amazon.com/exec/obidos/ASIN/0443049556/icongroupinterna

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Gastrointestinal and liver disease by Gary L. Gitnick; ISBN: 0892892021; http://www.amazon.com/exec/obidos/ASIN/0892892021/icongroupinterna

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Get hooked on seafood safety : important health information for people with liver disease (SuDoc HE 20.4002:H 76/LIVER/993) by U.S. Dept of Health and Human Services; ISBN: B00010FOPK; http://www.amazon.com/exec/obidos/ASIN/B00010FOPK/icongroupinterna

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Greens Are Good for You!: How Green Power Protects You Against Heart Disease, Cancer, Diabetes, Macular Degeneration, Poor Night Vision, Senile Dementia, Liver Disease, fatigue by Tony O'Donnell; ISBN: 1591200369; http://www.amazon.com/exec/obidos/ASIN/1591200369/icongroupinterna

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Guide to Hepatitis Liver Disease ('Gan bing quan shu', in traditional Chinese, NOT in English) by Dr. Palmer (Author); ISBN: 9574695131; http://www.amazon.com/exec/obidos/ASIN/9574695131/icongroupinterna

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Handbook of Liver Disease by Lawrence S. Friedman (Editor), Emmet B. Keeffe (Editor); ISBN: 0443055203; http://www.amazon.com/exec/obidos/ASIN/0443055203/icongroupinterna

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Hcv and Related Liver Diseases by K. Okita (Editor), K. Ckita (Editor) (1999); ISBN: 4431702350; http://www.amazon.com/exec/obidos/ASIN/4431702350/icongroupinterna

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HCV/Oxidative Stress and Liver Disease by Kiwamu Okita, M. S. Model' (2002); ISBN: 4431703241; http://www.amazon.com/exec/obidos/ASIN/4431703241/icongroupinterna

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Hepatitis C: State of the Art at the Millennium: A Bound Compilation of Issues 1 and 2 of Seminars in Liver Disease (2000 by C. L., Jr Branch, L. B. Seeff (2000); ISBN: 0865779988; http://www.amazon.com/exec/obidos/ASIN/0865779988/icongroupinterna

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Hepatology : a textbook of liver disease; ISBN: 072164838X; http://www.amazon.com/exec/obidos/ASIN/072164838X/icongroupinterna

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Hepatology: A Textbook of Liver Disease by David Zakim (Editor), et al (2003); ISBN: 0721690513; http://www.amazon.com/exec/obidos/ASIN/0721690513/icongroupinterna

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Imaging in Liver Disease: From Diagnosis to Treatment by Kenichi Takayasu, K. Okuda (Contributor); ISBN: 0192626345; http://www.amazon.com/exec/obidos/ASIN/0192626345/icongroupinterna

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Immune reactions in liver disease; ISBN: 0272795097; http://www.amazon.com/exec/obidos/ASIN/0272795097/icongroupinterna

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Immunology of gastrointestinal and liver disease by Ralph Wright; ISBN: 0713142804; http://www.amazon.com/exec/obidos/ASIN/0713142804/icongroupinterna

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Immunology of Liver Disease (Immunology and Medicine Series, Vol 21) by H. C. Thomas, J. Waters (Editor) (1994); ISBN: 0792389751; http://www.amazon.com/exec/obidos/ASIN/0792389751/icongroupinterna

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Kidney in Liver Disease (1988); ISBN: 0444006559; http://www.amazon.com/exec/obidos/ASIN/0444006559/icongroupinterna

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Liver disease by Alexander Paton; ISBN: 0433247207; http://www.amazon.com/exec/obidos/ASIN/0433247207/icongroupinterna

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Liver Disease and Gallstones (Oxford Medical Publications) by Alan G. Johnson, David R. Triger (Contributor); ISBN: 0192623052; http://www.amazon.com/exec/obidos/ASIN/0192623052/icongroupinterna

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Liver Disease and Renal Transplantation by Morales; ISBN: 1841843067; http://www.amazon.com/exec/obidos/ASIN/1841843067/icongroupinterna

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Liver Disease in Children by Frederick J., Md. Suchy (Editor), et al; ISBN: 0781720982; http://www.amazon.com/exec/obidos/ASIN/0781720982/icongroupinterna

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Liver Disease in Children: An Atlas of Angiography and Cholangiography by Francis Brunelle (1993); ISBN: 3540196749; http://www.amazon.com/exec/obidos/ASIN/3540196749/icongroupinterna

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Liver Disease in Primary Care Medicine by Raymond S. Koff; ISBN: 0838556787; http://www.amazon.com/exec/obidos/ASIN/0838556787/icongroupinterna

210 Liver Disease

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Liver Disease: Diagnosis and Management by Adrian M. Di Bisceglie, B. R. Bacon (Editor) (2000); ISBN: 0443057125; http://www.amazon.com/exec/obidos/ASIN/0443057125/icongroupinterna

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Liver Diseases and Hepatic Sinusoidal Cells by Kyuichi Tanikawa (Editor), T. Ueno (Editor) (1999); ISBN: 4431702377; http://www.amazon.com/exec/obidos/ASIN/4431702377/icongroupinterna

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Liver diseases in infancy and childhood; ISBN: 9024719216; http://www.amazon.com/exec/obidos/ASIN/9024719216/icongroupinterna

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Liver Diseases: An Atlas of Histopathology by Whan Kook Chung; ISBN: 0444815422; http://www.amazon.com/exec/obidos/ASIN/0444815422/icongroupinterna

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Liver Diseases: Medical Subject Analysis With Bibliography by Adolfo L. Santos (1987); ISBN: 0881645540; http://www.amazon.com/exec/obidos/ASIN/0881645540/icongroupinterna

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Liver Diseases: Targeted Diagnosis and Therapy Using Specific Receptors and Ligands (Targeted Diagnosis and Therapy Series, No 4) by George Y. Wu, Catherine H. Wu (Editor); ISBN: 0824784863; http://www.amazon.com/exec/obidos/ASIN/0824784863/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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Medical Management of Liver Disease by Edward L. Krawitt (Editor) (1999); ISBN: 0824719689; http://www.amazon.com/exec/obidos/ASIN/0824719689/icongroupinterna

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Metabolism and Nutrition in Liver Disease by E. Holm (Editor), H. Kasper (Editor) (1986); ISBN: 0852009070; http://www.amazon.com/exec/obidos/ASIN/0852009070/icongroupinterna

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Mosby's Color Atlas and Text of Gastroenterology and Liver Disease by Richard J. Aspinall, et al; ISBN: 0723431035; http://www.amazon.com/exec/obidos/ASIN/0723431035/icongroupinterna

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New Trends in the Therapy of Liver Disease: Proceedings of the International Symposium on Tirrenia, June, 1974 by A. Bertelli (Editor) (1975); ISBN: 3805521189; http://www.amazon.com/exec/obidos/ASIN/3805521189/icongroupinterna

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Osteoporosis in Chronic Liver Disease (Comprehensive Summaries of Uppsala Dissertations from the Faculty of mediciNe, 1037) by Sif Ormarsdottir (2001); ISBN: 9155450210; http://www.amazon.com/exec/obidos/ASIN/9155450210/icongroupinterna

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Pathogenesis of Liver Diseases (International Academy of Pathology Monograph, No 28) by Emmmanuel Farber, et al (1987); ISBN: 0683030388; http://www.amazon.com/exec/obidos/ASIN/0683030388/icongroupinterna

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Pathology of Pediatric Gastrointestinal and Liver Disease by Pierre Russo, et al (2004); ISBN: 0387406549; http://www.amazon.com/exec/obidos/ASIN/0387406549/icongroupinterna

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Pediatric Liver Disease by M.M. Fisher, C.C. Roy (Editor); ISBN: 0306411644; http://www.amazon.com/exec/obidos/ASIN/0306411644/icongroupinterna

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Practical Management of Liver Disease; ISBN: 0632007192; http://www.amazon.com/exec/obidos/ASIN/0632007192/icongroupinterna

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Progress in Liver Diseases by Hans Popper; ISBN: 0808914677; http://www.amazon.com/exec/obidos/ASIN/0808914677/icongroupinterna

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Sleisenger & Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management by Carola Maung Kessler (2002); ISBN: 9997619277; http://www.amazon.com/exec/obidos/ASIN/9997619277/icongroupinterna

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Sleisenger & Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management by Mark Feldman, et al (2002); ISBN: 0721692842; http://www.amazon.com/exec/obidos/ASIN/0721692842/icongroupinterna

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Sleisenger & Fordtran's Gastrointestinal and Liver Disease: Review and Assessment: to Accompany Sleisenger & Fordtran's Gastrointestinal and Liver Diseases, 6th Edition by Richard A. Weisiger, et al; ISBN: 0721677037; http://www.amazon.com/exec/obidos/ASIN/0721677037/icongroupinterna

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Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/ Management (2 Volume Set) by Mark Feldman, et al; ISBN: 0721689736; http://www.amazon.com/exec/obidos/ASIN/0721689736/icongroupinterna

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Surgery of Liver Disease in Children by Edward R. Howard (Editor) (1991); ISBN: 0750613602; http://www.amazon.com/exec/obidos/ASIN/0750613602/icongroupinterna

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Surrogate Markers to Assess Efficacy of Treatment in Chronic Liver Diseases: Proceedings of the International Falk Workshop Held in Basel, Switzerland, October 23-24, 1995 (Falk Symposium, Vol 88B) by Falk Symposium, et al (1996); ISBN: 0792387058; http://www.amazon.com/exec/obidos/ASIN/0792387058/icongroupinterna

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Surviving Liver Diseases - Life with a Liver Transplant by Moustafa Ahmed, G.M. Dusheiko; ISBN: 095360070X; http://www.amazon.com/exec/obidos/ASIN/095360070X/icongroupinterna

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The Kidney in Liver Disease by Murray Epstein (Editor) (1996); ISBN: 1560531665; http://www.amazon.com/exec/obidos/ASIN/1560531665/icongroupinterna

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The Kidney in liver disease; ISBN: 0444002405; http://www.amazon.com/exec/obidos/ASIN/0444002405/icongroupinterna

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The Laboratory Investigation of Liver Disease by P. J. Johnson, et al (1989); ISBN: 0702013765; http://www.amazon.com/exec/obidos/ASIN/0702013765/icongroupinterna

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Therapy of Digestive Disorders: A Companion to Sleisenger and Fordtran's Gastrointestinal and Liver Disease by M. Michael Wolfe (Editor), Sidney Cohen (Editor); ISBN: 0721673406; http://www.amazon.com/exec/obidos/ASIN/0721673406/icongroupinterna

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Therapy of Liver Disease (Bailliere's Clinical Gastroenterology) by Davis; ISBN: 0702013315; http://www.amazon.com/exec/obidos/ASIN/0702013315/icongroupinterna

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Viral Hepatitis and Liver Disease by Girish Vyas, et al; ISBN: 0808916785; http://www.amazon.com/exec/obidos/ASIN/0808916785/icongroupinterna

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Viral hepatitis and liver disease : proceedings of the International Symposium on Viral Hepatitis and Liver Disease : molecules today, more cures tomorrow : Tokyo, May 10-14, 1993, (1993 ISVHLD); ISBN: 443170132X; http://www.amazon.com/exec/obidos/ASIN/443170132X/icongroupinterna

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Viral Hepatitis and Liver Disease: Proceedings by A.J. Zuckerman (Editor); ISBN: 0471612707; http://www.amazon.com/exec/obidos/ASIN/0471612707/icongroupinterna

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Viral Hepatitis and Liver Disease: Proceedings of the 1990 International Symposium on Viral Hepatitis and Liver Disease: Contemporary Issues and Fu by International Symposium on Viral Hepatitis and Liver Disease, et al; ISBN: 0683041207; http://www.amazon.com/exec/obidos/ASIN/0683041207/icongroupinterna

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Viral Hepatitis and Liver Disease: Proceedings of the International Symposium on Viral Hepatitis and Liver Disease: Molecules Today, More Cures by Kusuya Nishioka; ISBN: 038770132X; http://www.amazon.com/exec/obidos/ASIN/038770132X/icongroupinterna

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “liver disease” (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 •

A domestic medical treatise on the nature, causes, and cure of dyspepsia and liver disease. Intended for the perusal and guide of every dyspeptic individual. By Dr. Ralph. Author: Ralph, Joseph.; Year: 1975; New York, Sold at the general office of the Domestic medicine [etc.] 1835

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A study of the mechanisms of the anemia of liver disease utilizing radioactive chromium. Author: Cawein, Madison Julius,; Year: 1962; [Minneapolis] 1958

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Anesthesia and the patient with liver disease Author: Brown, Burnell R.; Year: 1982; Philadelphia: Davis, c1981; ISBN: 0803612680 http://www.amazon.com/exec/obidos/ASIN/0803612680/icongroupinterna

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Autoimmune liver disease Author: Thomas, H. C. (Howard C.); Year: 1980; [Berlin; New York]: Springer International, 1980

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Bilirubin congugates [sic] in liver disease. Author: McGill, Douglas Brown,; Year: 1957; [Minneapolis] 1961

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Color atlas of liver disease Author: Sherlock, Sheila,; Year: 1979; Chicago: Year Book Medical Publishers, c1979; ISBN: 0815176449

11

In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a "Books" button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

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http://www.amazon.com/exec/obidos/ASIN/0815176449/icongroupinterna •

Diseases of the nervous system described for practitioners and students; with chapters on the neurological complications of liver disease and hepatolenticular degeneration, by J. M. Walshe. Author: Walshe, Francis Martin Rouse,; Year: 1975; Edinburgh, Livingstone, 1958

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Enzymatic studies in liver disease. Studies of certain flocculation tests. Final report. [By] John G. Reinhold. Author: William Pepper Laboratory (University of Pennsylvania); Year: 1961; [Washington] 1961

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Fatty liver disease in infants in the British West Indies. Author: Waterlow, J. C. (John Conrad); Year: 1948; London, H. M. Stationery Off., 1948

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Hepatic bilirubin glucuronyl transferase activity in experimental and clinical liver disease. Author: Metge, William Ray,; Year: 1950; [Minneapolis] 1962

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Hepatology, a textbook of liver disease Author: Boyer, Thomas D.; Year: 1981; Philadelphia: Saunders, 1982; ISBN: 0721696821 http://www.amazon.com/exec/obidos/ASIN/0721696821/icongroupinterna

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Immunology of GI and liver disease Author: Wright, Ralph.; Year: 1969; London; Philadelphia: Saunders, 1976

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Liver disease. Author: Paton, Alex.; Year: 1969; London, Heinemann [1969]; ISBN: 433247207

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Liver disease. Consulting editor: Sheila Sherlock; editor for the Ciba Foundation: G. E. W. Wolstenholme. Author: Sherlock, Sheila,; Year: 1961; London, Churchill, 1951

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Ornithine carbamyl transferase activity in serum, its determination and relationship to serum glutamic oxalacetic transaminase activity and thymol turbidity in liver disease [by] Francis H. Fukunaga. Author: United States. Army. Tripler Army Hospital, Moanalua, Hawaii.; Year: 1960; [Moanalua?] 1960

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Practical diagnosis and treatment of liver disease. Author: Leevy, Carroll Moton.; Year: 1958; [New York] Hoeber-Harper [c1957]

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Practical management of liver disease Author: Triger, David R.; Year: 1958; Oxford; Boston: Blackwell Scientific Publications; St. Louis, Mo.: [Distributed by] Blackwell Mosby Book Distributors, 1981

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Proceedings of a Symposium on Coagulation and Liver Disease, held in Geneva, Nov. 1972. Editor: Helge Stormorken. Author: Symposium on Coagulation and Liver Diseases, Geneva, 1972.; Year: 1973; Oslo, Universitetsforlaget [c1973]

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Survey of research in the field of liver disease, in progress and believed to be needed. Author: United States. Armed Forces Epidemiological Board. Commission on Liver Disease.; Year: 1835; [Washington? 1950?]

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Symposium on gastrointestinal and liver disease Author: Grand, Richard J.,; Year: 1978; Philadelphia: Saunders, 1975

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Symposium on treatment of liver disease Author: Leevy, Carroll Moton.; Year: 1980; Philadelphia: Saunders, 1979 http://www.amazon.com/exec/obidos/ASIN/0444802401/icongroupinterna

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Ultrasonography in liver disease diagnosis Author: Youssef, Mohamed Mokhtar Mahmoud.; Year: 1951; Oulu, Finland: [s.n.], 1980; ISBN: 9519347127

214 Liver Disease

Chapters on Liver Disease In order to find chapters that specifically relate to liver disease, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and liver disease 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 “liver disease” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on liver disease: •

Learning About Your Liver: Your Body's Chemical Factory: Liver Facts and Liver Disease Symptoms Source: in Everson, G.T.; Weinberg, H. Living with Hepatitis B: A Survivor's Guide. Long Island, NY: Hatherleigh Press. 2002. p.53-77. Contact: Available from Hatherleigh Press. 5-22 46th Avenue Suite 200, Long Island City, NY 11101. (800) 528-2550. E-mail: [email protected]. Website: http://store.yahoo.com/hatherleighpress/index.html. PRICE: $15.95 plus shipping and handling. ISBN: 1578260841. Summary: Chronic hepatitis B can lead to cirrhosis (liver scarring), liver cancer, and the need for liver transplantation. This chapter on the physiology and anatomy of the liver is from a book that helps readers diagnosed with hepatitis B virus (HBV) infection educate themselves about the disease and its treatment. The authors discuss what the liver looks like, how it functions, and what happens to the liver when it is infected with hepatitis B, including ten warning signals that demonstrate that liver function is compromised. Topics include the history of medical understanding of the liver and its functions; the gross and microscopic anatomy of the liver; how the liver works, including blood, bile, lymph, immune system, chemical factory, bilirubin, ALT, AST, GGT, alkaline phosphatase, albumin, clotting factors, and hormones; the phases of hepatitis B, i.e., infection, inflammation, fibrosis, and cirrhosis; the ten danger signs of liver disease, including early symptoms, changes in liver functions, compensated cirrhosis, decompensated cirrhosis, changes in the appearance of the skin, fluid buildup (ascites), bleeding (variceal hemorrhage), mental confusion (encephalopathy), weight loss, thinning of bones and fractures, blood clotting problems, itching (pruritus); and extra-liver conditions associated with hepatitis B, including kidney damage, inflammation of the arteries (polyarteritis nodosa), hives, arthritis, inflammation of skeletal muscle, Sjogren syndrome, carditis, and neuritis. Throughout the chapter the authors include quotes from real people who are living with hepatitis. 1 figure. 2 references.

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Approach to Gastrointestinal and Liver Diseases in the Female Patient Source: in Textbook of Gastroenterology. 4th ed. [2-volume set]. Hagerstown, MD: Lippincott Williams and Wilkins. 2003. p. 1033-1055. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-6423. Fax: (301) 223-2400. Website: www.lww.com. PRICE: $289.00. ISBN: 781728614. Summary: Gastrointestinal diseases in women, particularly in pregnant female patients, have unique diagnostic and therapeutic implications and warrant specific consideration.

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This chapter reviews the gastrointestinal diseases associated with pregnancy and the gynecologic diseases relevant to the evaluation of gastrointestinal symptoms. Diseases such as hyperemesis gravidarum and intrahepatic cholestasis of pregnancy are unique to pregnancy, whereas other common gastrointestinal diseases, including gastroesophageal reflux disease (GERD), may be more severe during pregnancy. Chronic diseases such as inflammatory bowel disease often initially present in women of childbearing age. In addition, it is important to consider the impact of pregnancy on the course and therapy of preexisting chronic gastrointestinal and liver diseases even before conception. The chapter is from a lengthy, two-volume textbook that integrates the various demands of science, technology, expanding information, good judgment, and common sense into the diagnosis and management of gastrointestinal patients. 2 figures. 2 tables. 339 references. •

Learning About Your Liver: Your Body's Chemical Factory. Liver Facts and Liver Disease Symptoms Source: in Everson, G.T. and Weinberg, H. Living with Hepatitis C: A Survivor's Guide. New York, NY: Hatherleigh Press. 1999. p. 48-71. Contact: Available from Hatherleigh Company, Ltd. 1114 First Avenue, Suite 500, New York, NY 10021. (800) 367-2550 or (212) 832-1039. Website: hatherleigh.com. PRICE: $14.95 plus shipping and handling. ISBN: 1578260345. Summary: Hepatitis C is a viral infection that causes inflammation, injury, and ultimately scarring of the liver (cirrhosis). This chapter on the anatomy and physiology of the liver is from a book that offers information and guidance for people living with hepatitis C. The authors explain in nontechnical language some basic facts about what the liver looks like, how it functions, and what happens to the liver when it is infected with hepatitis C virus (HCV). Topics include how the liver works in relation to the blood, bile, lymph, immune system, bilirubin, ALT, AST, GGT, alkaline phosphatase, albumin, clotting factors, and hormones; the phases of hepatitis C, from infection to inflammation to fibrosis to cirrhosis; and the 10 danger signs of liver disease, including early symptoms, changes in liver functions, compensated and decompensated cirrhosis, jaundice, ascites (fluid buildup), variceal hemorrhage (bleeding), mental confusion (encephalopathy), weight loss, metabolic bone disease (osteoporosis and fractures), coagulopathy (blood clotting problems), and pruritus (itching). The authors also discuss related clinical conditions of hepatitis C, including kidney damage, cryoglobulinemia, thyroid disease, skin conditions, and autoimmune conditions. The chapter includes lengthy quotes from patients with hepatitis, which offer the patients' perspectives, insights, and experiences to the reader. 2 figures. 2 references.

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Liver Disease Caused by Drugs, Anesthetics, and Toxins Source: in Feldman, M.; Friedman, L.S.; Sleisenger, M.H. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 7th ed. [2-volume set]. St. Louis, MO: Saunders. 2002. p. 1403-1447. Contact: Available from Elsevier. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 545-2522. Fax (800) 568-5136. Website: www.us.elsevierhealth.com. PRICE: $229.00 plus shipping and handling. ISBN: 0721689736. Summary: Hepatotoxicity is liver injury caused by drugs and other chemicals. Adverse drug reactions are noxious, unintentional effects that occur at doses used for prophylaxis and therapy. This chapter on liver disease caused by drugs, anesthetics, and toxins is from a comprehensive and authoritative textbook that covers disorders of the

216 Liver Disease

gastrointestinal tract, biliary tree, pancreas, and liver, as well as the related topics of nutrition and peritoneal disorders. Topics include definitions and the general importance of drugs and toxins as causes of liver disease; epidemiology, including individual risk factors; pathophysiology; the clinicopathologic features of drug-induced liver disease, including classification and histopathology; prevention and management; dose-dependent hepatotoxicity, including that due to acetaminophen and niacin (nicotinic acid); drug-induced acute hepatitis; drug-induced granulomatous hepatitis; drug-induced chronic hepatitis; drug-induced cholestasis; chronic cholestasis; liver disease caused by anesthetic agents and jaundice in the postoperative period; druginduced steatohepatitis, hepatic fibrosis, and cirrhosis; vascular toxicity; liver tumors; and complementary and alternative medicines and environmental agents. The chapter includes a mini-outline with page citations, full-color illustrations, and extensive references. 1 figure. 12 tables. 437 references. •

Skin Lesions Associated with Gastrointestinal and Liver Diseases Source: in Textbook of Gastroenterology. 4th ed. [2-volume set]. Hagerstown, MD: Lippincott Williams and Wilkins. 2003. p. 992-1009. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-6423. Fax: (301) 223-2400. Website: www.lww.com. PRICE: $289.00. ISBN: 781728614. Summary: Many diseases can involve both the skin and gastrointestinal tract. Primary disorders of the gut such as inflammatory bowel disease (IBD) can initially manifest in the skin, and primary skin disorders such as pemphigus vulgaris may present with mucosal lesions. This chapter reviews the skin lesions that may be associated with specific gastrointestinal complaints or known pathological processes. The chapter is from a lengthy, two-volume textbook that integrates the various demands of science, technology, expanding information, good judgment, and common sense into the diagnosis and management of gastrointestinal patients. Topics covered in this chapter include IBD, rheumatologic diseases, skin disease and gastrointestinal bleeding, syndromes associated with gastrointestinal polyps, cutaneous signs of gastrointestinal malignancy, bullous diseases of the skin that can directly affect the gastrointestinal tract, skin conditions associated with abdominal pain, cutaneous signs associated with liver disease, pancreatic disease, dermatologic disorders associated with malabsorption, nutritional disorders, and perineal skin lesions. 17 figures 3 tables. 109 references.

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Non-Viral Liver Disease Source: in Farthing, M.J.G.; Ballinger, A.B., eds. Drug Therapy for Gastrointestinal and Liver Diseases. Florence, KY: Martin Dunitz. 2001. p. 259-288. Contact: Available from Martin Dunitz. Fulfillment Center, Taylor and Francis, 7625 Empire Drive, Florence, KY 41042. (800) 634-7064. E-mail: cserve@routledge_ny.com. Website: www.dunitz.co.uk. PRICE: $75.00 plus shipping and handling. ISBN: 1853177334. Summary: The last decade has seen important advances in the knowledge of the diagnosis, natural history, and treatment of non-viral-induced liver disease, including primary sclerosing cholangitis, primary biliary cirrhosis (PBC), autoimmune hepatitis, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, alcoholic hepatitis, liver storage diseases, Budd-Chiari syndrome, and drug-induced liver disease. This chapter on non-viral liver disease is from a textbook that reviews the drug therapy for gastrointestinal and liver diseases. The chapter provides a brief summary of the

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pathophysiology of each disease, the rationale for drug intervention, and appropriate treatment regimens as indicated by current knowledge. The chapter concludes with a drug list that summarizes mode of action, and other aspects of clinical pharmacology where appropriate, drug doses, common adverse affects, and drug interactions. 3 tables. 113 references. •

Alcoholic Liver Disease Source: in Feldman, M.; Friedman, L.S.; Sleisenger, M.H. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 7th ed. [2-volume set]. St. Louis, MO: Saunders. 2002. p. 1375-1391. Contact: Available from Elsevier. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 545-2522. Fax (800) 568-5136. Website: www.us.elsevierhealth.com. PRICE: $229.00 plus shipping and handling. ISBN: 0721689736. Summary: This chapter on alcoholic liver disease is from a comprehensive and authoritative textbook that covers disorders of the gastrointestinal tract, biliary tree, pancreas, and liver, as well as the related topics of nutrition and peritoneal disorders. Topics include epidemiology, ethanol metabolism (both hepatic, i.e., liver and gastric, i.e., stomach metabolism), the pathogenesis of alcoholic liver injury, cofactors in the development of alcoholic liver disease (heritable factors, gender, diet and nutrition, coexistent viral hepatitis), diagnostic considerations, complications, treatment options, and prognosis. Treatments discussed include abstinence from alcohol intake, nutritional supplements, anti-inflammatory drugs, antioxidants, drugs with unconfirmed benefit, and liver transplantation. The chapter includes a mini-outline with page citations, fullcolor illustrations, and extensive references. 7 figures. 6 tables. 188 references.

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Nutritional and Metabolic Liver Diseases Source: in Sherlock, S.; Dooley, J. Diseases of the Liver and Biliary System. Malden, MA: Blackwell Science, Inc. 2002. p.423-452. 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 nutritional and metabolic liver diseases is from a textbook that presents a comprehensive and up-to-date account of diseases of the liver and biliary system. The chapter covers malnutrition; fatty liver, including diagnosis and classification; non-alcoholic fatty liver disease, including hepatic steatosis, steatonecrosis, the effects of the jejuno-ileal bypass, parenteral nutrition, and vitamins; carbohydrate metabolism in liver disease, including hypoglycemia and hyperglycemia; the liver in diabetes mellitus, including insulin and the liver, hepatic histology, clinical features, and liver function tests; hepatobiliary disease and diabetes, including the glucose intolerance of cirrhosis and the treatment of diabetes in patients with cirrhosis; glycogen storage disease (types I through VI) and hepatic glycogen synthetase deficiency; hereditary fructose intolerance; glutaric aciduria type II, galactosemia; mucopolysaccharidoses; familial hypercholesterolemia; amyloidosis; alpha1-antitrypsin deficiency; hereditary tyrosinemia; cystic fibrosis; liver and thyroid, including thyrotoxicosis, myxoedema, and changes with hepatocellular disease; liver and adrenal; liver and growth hormone; hepatic porphyrias, including acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, porphyria cutanea tarda, erythropoietic protoporphyria, hepato-erythropoietic porphyria, and secondary coproporphyrias;

218 Liver Disease

hereditary hemorrhagic teleangiectasia; and dystrophic myotonica. Each section includes its own list of references for further reading. 19 figures. 6 tables. 184 references. •

Other Causes of Parenchymal Liver Disease Source: in Beckingham, I.J., ed. ABC of Liver, Pancreas and Gallbladder. London, UK: BMJ Publishing Group. 2001. p.15-17. 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. ISBN: 0727915312. Summary: This chapter on other causes of parenchymal (in the body of the organ) liver disease is from an atlas of the liver, pancreas and gallbladder. Topics covered include autoimmune hepatitis; metabolic causes of liver disease, including hemochromatosis (iron overload) and Wilson's disease (copper deposition); drug related hepatitis, including paracetamol and idiosyncratic drug reactions; and cholestatic nonobstructive jaundice, including primary biliary cirrhosis and primary sclerosing cholangitis. The author notes that most drugs have the potential to cause liver injury and 2 to 7 percent of admissions with nonobstructive jaundice are for drug related hepatitis. Herbal remedies and illegal drugs can also cause jaundice and liver damage. The chapter concludes with summary points of the concepts discussed. 6 figures. 3 tables.

Directories In addition to the references and resources discussed earlier in this chapter, a number of directories relating to liver disease 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 •

American Liver Foundation: Directory of Local Chapters Source: Consultant. 39(3): 877-878. March 1999. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Box 4010, Greenwich, CT 06831-0010. Summary: This article provides a directory of local chapters of the American Liver Foundation. Providing support to persons with chronic liver disease is one of the goals of the foundation. Local chapters offer information, referrals, and support groups for patients and their families. The article lists local chapters, organized by State, with their addresses, telephone numbers, and chapter leaders. For more information, the contact information for the national office of the American Liver Foundation is provided (800 GO LIVER and 888 4HEP ABC).

•

Complete Directory for People with Chronic Illness. 4rd ed Source: Lakeville, CT: Grey House Publishing, Inc. 2000. 1047 p.

12

You will need to limit your search to “Directory” and “liver disease” 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 “liver disease” (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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Contact: Available from Grey House Publishing, Inc. Pocket Knife Square, Lakeville, CT 06039. (860) 435-0868. Fax (860) 435-0867. PRICE: $165.00. ISBN: 0939300931. Summary: This directory provides a comprehensive overview of the support services and information resources available for people with any of 80 specific chronic illnesses. It presents information on various organizations, educational materials, publications, and databases. A chapter is devoted to each chronic illness and includes a brief description of it. The digestive diseases covered include celiac disease, Crohn's disease, gastrointestinal disorders, hepatitis, liver disease, substance abuse, and ulcerative colitis. The description of each disease is followed by subchapters that identify national and State associations and agencies, libraries, research centers, reference books, children's books, magazines, newsletters, pamphlets, videotapes and films, support groups and hotlines, and websites. In addition, the directory includes a chapter on death and bereavement, as well as a chapter on Wish Foundations for terminally and chronically ill children.

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CHAPTER 8. MULTIMEDIA ON LIVER DISEASE Overview In this chapter, we show you how to keep current on multimedia sources of information on liver disease. 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 liver disease is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “liver disease” 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 “liver disease” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on liver disease: •

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),

222 Liver Disease

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.

Bibliography: Multimedia on Liver Disease 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 liver disease (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 liver disease: •

Clinical manifestations of chronic liver disease [slide] Source: [authors, Caroline A. Riely, Raymond S. Koff]; Year: 1993; Format: Slide; [Bethesda, Md.]: American Gastroenterological Association, c1993

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Clinical teaching slides on CD-ROM [electronic resource]: 16 chapters of teaching images in gastroenterology & liver disease Source: American Gastroenterological Association; Year: 2001; Format: Electronic resource; Timonium, MD: Distributed by Milner-Fenwick, c2001

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Current status of peritoneoscopy in the evaluation of liver disease [videorecording] Source: Academy of Health Sciences; Year: 1975; Format: Videorecording; Fort Sam Houston, Tex.: The Academy, 1975

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DISIDA kinetic studies in liver disease [slide] Source: produced by Technologist Section, Society of Nuclear Medicine; Year: 1984; Format: Slide; [New York, N.Y.]: The Section, [1984]

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Drug-induced liver disease [videorecording] Source: presented by Department of Medicine, Emory University, School of Medicine; Year: 1981; Format: Videorecording; Atlanta, Ga.: Emory Medical Television Network, 1981

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Immunological basis of therapy for chronic liver disease [sound recording]: recorded at DDW in 1994 in New Orleans. Year: 1994; Format: Sound recording; [Bethesda, Md.]: American Gastroenterological Association, [1994]

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Inherited liver disease [slide] Source: [authors, Caroline A. Riely. et al.]; Year: 1993; Format: Slide; [Bethesda, Md.]: American Gastroenterological Association, c1993

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Laparoscopic cholecystectomy in a patient with massive polycystic kidneys and polycystic liver disease [videorecording]: a case report Source: Steven Wise Unger, Harold M. Unger. A modified laparoscopic cholecystectomy without pneumoperitoneum and with newly d; Year: 1993; Format: Videorecording; [United States]: Society [of] American Gastrointestinal Endoscopic Surgeons, c1993

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Liver disease & hemostasis [slide] Source: McMaster University Health Sciences; Year: 1971; Format: Slide; [Hamilton, Ont.]: Health Sciences McMaster Univ., 1971

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Liver disease [videorecording] Source: presented by the Department of Gynecology & Obstetrics, Emory University, School of Medicine; Year: 1987; Format: Videorecording; Atlanta, Ga.: The University, 1987

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•

Liver disease evaluation [slide] Source: Nuclear Associates, inc.; produced by Medical Multimedia Corp; Year: 1978; Format: Slide; [Carle Place, N. Y.]: The Associates, c1978

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New frontiers in therapy for GI and liver disease [sound recording]: recorded at DDW 1995 in San Diego Source: AGA, American Gastroenterological Association; Year: 1995; Format: Sound recording; [Bethesda, Md.]: The Association, [1995?]

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New therapies of chronic liver disease [sound recording]: recorded at DDW 1990, San Antonio. Year: 1990; Format: Sound recording; [Bethesda, Md.]: American Gastroenterological Association, c1990

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Use of laboratory tests in the diagnosis of liver disease [videorecording] Source: produced for the Department of Pathology, School of Medicine by Health Sciences Television, University of California, Davis; Year: 1988; Format: Videorecording; [Davis, Calif.: The University, 1988]

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CHAPTER 9. PERIODICALS AND NEWS ON LIVER DISEASE Overview In this chapter, we suggest a number of news sources and present various periodicals that cover liver disease.

News Services and Press Releases One of the simplest ways of tracking press releases on liver disease 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 “liver disease” (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 liver disease. 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 “liver disease” (or synonyms). The following was recently listed in this archive for liver disease: •

Actelion eyes Veletri drug for treating liver disease Source: Reuters Industry Breifing Date: March 04, 2003

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Study looks at animal bacteria, liver disease Source: Reuters Health eLine Date: January 21, 2003

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•

Gene therapy treats rare liver disease in rat study Source: Reuters Health eLine Date: December 03, 2002

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Alcohol blamed for rise in liver disease deaths Source: Reuters Health eLine Date: August 09, 2002

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Cancer antigen is elevated in patients with liver disease Source: Reuters Medical News Date: July 10, 2002

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Axcan, NicOx in liver diseases drug development deal Source: Reuters Industry Breifing Date: May 23, 2002

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Roche says Pegasys looks effective in advanced liver disease patients Source: Reuters Industry Breifing Date: May 20, 2002

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Some cases of serious liver disease may result from unrecognized celiac disease Source: Reuters Medical News Date: April 23, 2002

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Chronic liver disease associated with bone loss Source: Reuters Medical News Date: February 13, 2002 The NIH

Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “liver disease” (or synonyms) into the search box, and click on “Search News.” As this service is technology

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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 “liver disease” (or synonyms). If you know the name of a company that is relevant to liver disease, 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 “liver disease” (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 “liver disease” (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 liver disease: •

Hepatitis B in Asia Source: Asian Pacific Gastroenterology News. Issue 4: 12-13. June 2000. Contact: Available from Blackwell Science Asia. 54 University Street, Carlton, Victoria 3053, Australia. 61 3 9347 0300. Fax 61 3 9347 5001. E-mail: [email protected]. Summary: Five to 20 percent of the population of Asia and Africa are chronically infected with hepatitis B virus (HBV). This article reviews the main issues related to hepatitis B in Asia, including the evaluation and treatment of infected but asymptomatic subjects, the so-called HBV carriers; the continued horizontal spread of HBV infection, emergence of HBV mutants, and implementation of vaccination programs. The author contends that the term 'carrier' should therefore be deleted from the terminology of hepatitis B and should be replaced by 'chronic hepatitis B virus infection.' Evaluation of a subject with chronic HBV infection should include a reliable ALT (repeated three times), an HbeAg test, and if needed, an HBV DNA ultrasound and liver biopsy. The prevalence of HBV and hepatitis C (HCV) in chronic liver disease has been reported to be approximately 15 percent in the Asian region. In several countries in Asia, vaccination against HBV has been successfully included in the EPI program. This has

228 Liver Disease

led to a substantial reduction in the chronic HBV infection in the pediatric population. 1 table. 6 references. •

Researchers Investigate New Obesity-related Disease Source: WIN Notes. p. 4, 10. Summer 2002. Contact: Weight-control Information Network, 1 WIN Way, Bethesda, MD 20992-3665. (202) 828-1025. Summary: Nonalcoholic steatohepatitis (NASH) is a liver disease that occurs most often in adults over the age of 40 who are overweight or have diabetes, insulin resistance, or hyperlipidemia. NASH resembles alcoholic liver disease, however, people with NASH drink little or no alcohol. Although most people with NASH are middle-aged, obese, and diabetic, the disease may also strike children and normal-weight adults without diabetes. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is funding a 5-year study of NASH in hopes of finding prevention and treatment approaches. Scientists are uncertain about what causes NASH, but believe it is a combination of insulin resistance and oxidative stress. NIDDK plans to establish a NASH Clinical Research Network to study this poorly understood disease. Researchers will investigate NASH's origin, contributing factors, natural history, and complications. They hope to identify safe and effective methods to prevent and treat this increasingly common disease.

•

Liver Tests: Simple Blood Tests Can Reveal a Lot Source: Mayo Clinic Health Letter. 18(5): 1-3. May 2000. Contact: Available from Mayo Clinic Health Letter. Subscription Services, P.O. Box 53889, Boulder, CO 80322-3889. (800) 333-9037 or (303) 604-1465. Summary: This article, from a health newsletter, reviews the liver function tests that are used to monitor liver health and disease. The author begins by reviewing the healthy functions of the liver, including regulating the composition of the blood, manufacturing vital nutrients (such as cholesterol, vitamin A, certain proteins, bile), and neutralizing toxic substances. Sometimes there is an obvious sign of a problem, such as jaundice, which is a buildup of bilirubin in the blood, resulting in a yellow appearance of the skin and eyes. The various liver tests basically screen for three types of abnormalities: liver cell damage, reduced protein levels in the blood, and failure to eliminate certain substances from the blood. Information from the blood tests, combined with a thorough physical exam and sometimes diagnostic imaging, may be enough to reach a specific diagnosis; sometimes a liver biopsy is added to the list of diagnostic tests. Some of the more common liver disorders that are detected with these tests are viral hepatitis, alcohol or drug related liver disease, liver cancer, nonalcoholic steatohepatitis (a form of fatty liver), and hemochromatosis (high amounts of iron stored in the body). One sidebar reviews the drugs that can lead to liver toxicity. The author concludes that mild liver test abnormalities are normal; however, significantly abnormal test results should never be ignored. 1 figure.

•

Dear Doctor: Responses to Commonly Asked Questions About Alpha 1 Antitrypsin Deficiency with Questions Posed by the Readers of the Alpha 1 News Source: Minneapolis, MN: Alpha 1 Association. 1996. [22 p.]. 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. E-

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mail: [email protected]. Website: www.alpha1.org. PRICE: $10.00 plus shipping and handling. Summary: This document compiles entries from a 'Dear Doctor' newsletter column that addresses Alpha 1 antitrypsin deficiency (A1AD or Alpha 1), a genetic disorder that affects infants, children, and adults. A1AD 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. The newsletter (Alpha 1 News) is published by the Alpha 1 National Association, a group established to support and educate people with A1AD and to act as a clearinghouse for information to assist health care professionals and individuals with A1AD. This collection of 14 letters and responses is one effort to expand communication between health care providers and those affected by A1AD. These types of collaborations have been responsible for instigating research studies including studies of augmentation therapy, the National Registry (of people with Alpha 1 antitrypsin deficiency), and a study on psychosocial effects of A1AD. The first section addresses the basic aspects of A1AD, including a definition of the condition, how it is inherited, the different types, and terminology. The second section addresses symptoms of A1AD and the effects of the disease on specific organs, including the lung, the liver, and the skin. The last section contains letters and responses about treating A1AD and addresses augmentation therapy, lung volume reduction surgery, other medications, and nonpharmacologic therapies, including nutrition. •

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 author stresses abstinence as the cornerstone of therapy for alcoholic liver disease. 45 references.

•

Osteoporosis Source: National Women's Health Report. 25(2): 1-4. April 2003. Contact: Available from National Women's Health Resource Center. 120 Albany Street, Suite 820, New Brunswick, NJ 08901. (877) 986-9472 (toll free). Website: www.healthywomen.org. PRICE: $5.00 an issue. Summary: This newsletter article provides information to women on the risk factors, prevention, and diagnosis of osteoporosis. Osteoporosis is a major health concern currently affecting 8 million women with an estimated 30 million more at risk for developing the disease as they age. The system by which bone is broken down and built up is described. Factors in bone health include bone mass, bone quality, architecture, turnover, and accumulation of damage. Risk factors for osteoporosis include age, having had juvenile arthritis, diabetes mellitus, kidney disease, liver disease, and certain medications. Bone density tests are used to determine low bone mass, predict the risk of

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fracture, and determine the efficacy of treatment. Bone density results are expressed as 'T-scores' which compare the amount of deviation from the patient's bone mineral density to the bone mineral density of young, healthy, caucasian women. To prevent fractures patients should quit smoking, maintain a healthy weight by following a healthy diet, and perform weight-bearing exercises.

Academic Periodicals covering Liver Disease Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to liver disease. In addition to these sources, you can search for articles covering liver disease that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

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CHAPTER 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 liver disease. 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 liver disease. 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 liver disease: Beta-Carotene •

Systemic - U.S. Brands: Lumitene; Max-Caro http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202623.html

Chloroquine •

Systemic - U.S. Brands: Aralen http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202133.html

Clomiphene •

Systemic - U.S. Brands: Clomid; Milophene; Serophene http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202151.html

Folic Acid (Vitamin B 9 ) •

Systemic - U.S. Brands: Folvite http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202250.html

Hepatitis A Vaccine Inactivated •

Systemic - U.S. Brands: Havrix; Vaqta http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202902.html

Hepatitis B Vaccine Recombinant •

Systemic - U.S. Brands: Engerix-B http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202281.html

Hydroxychloroquine •

Systemic - U.S. Brands: Plaquenil http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202288.html

Interferon Alfacon-1 •

Systemic - U.S. Brands: Infergen http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203504.html

Kanamycin •

Oral - U.S. Brands: Kantrex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202312.html

Naratriptan •

Systemic - U.S. Brands: Amerge http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203513.html

Neomycin •

Oral - U.S. Brands: Mycifradin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202396.html

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Niacin (Vitamin B 3 ) •

Systemic - U.S. Brands: Endur-Acin; Nia-Bid; Niac; Niacels; Niacor; Nico-400; Nicobid Tempules; Nicolar; Nicotinex Elixir; Slo-Niacin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202405.html

Peginterferon Alfa-2B •

Systemic - U.S. Brands: PEG-Intron http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500287.html

Pyridoxine (Vitamin B 6 ) •

Systemic - U.S. Brands: Beesix; Doxine; Nestrex; Pyri; Rodex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202493.html

Rimantadine •

Systemic - U.S. Brands: Flumadine http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202771.html

Terbinafine •

Systemic - U.S. Brands: Lamisil http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202760.html

Thiamine (Vitamin B 1 ) •

Systemic - U.S. Brands: Biamine http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202560.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 B 12 •

Systemic - U.S. Brands: Alphamin; Cobex; Cobolin-M; Crystamine; Crysti-12; Cyanoject; Cyomin; Hydrobexan; Hydro-Cobex; Hydro-Crysti-12; HydroxyCobal; LA-12; Nascobal; Neuroforte-R; Primabalt; Rubramin PC; Shovite; Vibal; Vibal LA; Vitabee 12 http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202596.html

Vitamin D and Related Compounds •

Systemic - U.S. Brands: Calciferol; Calciferol Drops; Calcijex; Calderol; DHT; DHT Intensol; Drisdol; Drisdol Drops; Hectorol; Hytakerol; Rocaltrol; Zemplar http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202597.html

Vitamin E •

Systemic - U.S. Brands: Amino-Opti-E; E-Complex-600; Liqui-E; Pheryl-E http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202598.html

234 Liver Disease

Zinc Supplements •

Systemic - U.S. Brands: Orazinc; Verazinc; Zinc 15; Zinc-220; Zinca-Pak; Zincate http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202622.html

Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.

Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. 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. 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.

235

APPENDICES

237

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 “liver disease” 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 “liver disease” (or synonyms) into the “For these words:” box. The following is a sample result: •

Alcohol and Hormones Source: Alcohol Alert. Number 26: 1-4. October 1994. Contact: Available from Scientific Communications Branch, Office of Scientific Affairs, NIAAA, Willco Building, Suite 409, 6000 Executive Boulevard, MSC 7003, Bethesda, MD 20892-7003. (301) 443-3860. Summary: This issue of Alcohol Alert focuses on alcohol and hormones. Topics include how alcohol impairs the regulation of blood glucose levels; how alcohol impairs reproductive functions; how alcohol impairs calcium metabolism and bone structure; and how hormones may influence alcohol-seeking behavior. The section on blood glucose functions discusses pancreatic hormones; how alcohol consumption interferes with glucose sources and the actions of the regulatory hormones; how binge drinking can result in dangerously low blood glucose levels; and how alcoholism can contribute to diabetes in people with alcoholic liver disease. 39 references.

•

Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCV-Related Chronic Disease Contact: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Health Statistics, Office of the Morbidity and Mortality Weekly Report Series, 1600 Clifton Rd NE M/S C-08, Atlanta, GA, 30333, (404) 332-4555, http://www.cdc.gov. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This report discusses the hepatitis C virus (HCV), how it is treated, and how it can be prevented. The report examines the epidemiology of HCV. It discusses the screening tests, history, general treatment, and postexposure prophylaxis for HCV. The report explains the ways that HCV can be transmitted from person to person and how the virus can be spread through bodily fluid. It identifies the most serious high risk behaviors such as injection drug use and certain sexual practices. The report cites the risks associated with health care work. It lists the persons who should be tested regularly for HCV and the procedures involved in the HCV testing process. The national surveillance for acute HCV, laboratory discoveries of anti-HCV positive tests,

Physician Resources

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serological surveys, and surveillance of chronic liver disease are discussed. The report makes predictions and recommendations about the future of HCV. •

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. 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.

•

Guidelines for the Scientific Review of Enteral Food Products for Special Medical Purposes Source: Bethesda, MD: Federation of American Societies for Experimental Biology. 1990. 107 p. Contact: Federation of American Societies for Experimental Biology. Life Sciences Research Office, Special Publications, 9650 Rockville Pike, Room L2310, Bethesda, MD 20814. (301) 530-7000. PRICE: $24 prepaid. Summary: This report reviews available data on the scientific rationale for and clinical experience with medical foods given orally or by tube in four categories of diseases and disorders: end-stage renal disease; liver disease and hepatic coma; pulmonary diseases; and hypermetabolic states associated with injuries, major surgery, and sepsis. This review was conducted as a basis for the development of guidelines useful in scientific evaluation of enteral food products for specific medical purposes. The report also provides background information on the evolution of definitions, regulation, and types of medical foods currently available. The report concludes with suggested guidelines for the design and evaluation of clinical trials to determine the suitability of medical foods for their intended purposes. One of the four appendixes lists selected medical foods and

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other products used for tube or oral feeding by product name, suggested use, and generic description. 354 references. (AA-M). •

Prevention of Hepatitis A Through Active or Passive Immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP) Source: MMWR Morbidity and Mortality Weekly Report Recommendations and Reports 1999 (October 1);48(RR-12):1-37. Contact: US Government Printing Office, PO Box 371954, Pittsburgh, PA, 15250-7954, (202) 512-1800, http://www.access.gpo.gov. CDC National Prevention Information Network, PO Box 6003, Rockville, MD, 20849-6003, (800) 458-5231, http://www.cdcnpin.org. Summary: This report updates the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices' (ACIP) 1996 recommendations on the prevention of hepatitis A through immunization (MMWR 1996;45[RR-15].) and includes (1) new data about the epidemiology of hepatitis A; (2) recent findings about the effectiveness of community-based hepatitis A vaccination programs; and (3) recommendations for the routine vaccination of children in states, counties, and communities with rates that are twice the 1987-1997 national average or greater and consideration of routine vaccination of children in states, counties, and communities with rates exceeding the 1987-1997 national average. Unchanged in this report are previous recommendations regarding the vaccination of persons in groups at increased risk for hepatitis A (i.e., travelers, men who have sex with men, users of injecting and noninjecting drugs, persons who have clotting-factor disorders, persons working with nonhuman primates, and persons with chronic liver disease) or its adverse consequences and recommendations regarding the use of immune globulin for protection against hepatitis A.

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 “liver disease” (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.

16 17

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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Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 247724 1648 1253 287 11 250923

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 “liver disease” (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/.

18

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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Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

The Genome Project and Liver Disease In the following section, we will discuss databases and references which relate to the Genome Project and liver disease. 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 “liver disease” (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 liver disease: •

Nephropathy, Progressive Tubulointerstitial, with Cholestatic Liver Disease Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?602114

•

Polycystic Liver Disease Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?174050 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 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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wish to revisit it from time to time. The following systems and associated disorders are addressed: •

Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html

•

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

•

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

•

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

•

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

•

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:

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•

3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

•

Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

•

NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/

•

Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide

•

OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

•

PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

•

ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

•

PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

•

Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

•

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 “liver disease” (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 “liver disease” (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 liver disease 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 liver disease. 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 liver disease. 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 “liver disease”:

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•

Guides on liver disease Liver Diseases http://www.nlm.nih.gov/medlineplus/liverdiseases.html

•

Other guides Cirrhosis http://www.nlm.nih.gov/medlineplus/cirrhosis.html Hepatitis http://www.nlm.nih.gov/medlineplus/hepatitis.html Hepatitis C http://www.nlm.nih.gov/medlineplus/hepatitisc.html Liver Diseases http://www.nlm.nih.gov/medlineplus/liverdiseases.html Liver Transplantation http://www.nlm.nih.gov/medlineplus/livertransplantation.html

Within the health topic page dedicated to liver disease, the following was listed: •

General/Overviews Liver: A Primer Source: American Liver Foundation http://www.liverfoundation.org/cgibin/dbs/articles.cgi?db=articles&uid=default&ID=1004&view_records=1 What Are the Diseases That Affect the Liver? Source: American Liver Foundation http://www.liverfoundation.org/cgibin/dbs/articles.cgi?db=articles&uid=default&ID=1043&view_records=1

•

Diagnosis/Symptoms ERCP (Endoscopic Retrograde Cholangiopancreatography) Source: National Digestive Diseases Information Clearinghouse http://digestive.niddk.nih.gov/ddiseases/pubs/ercp/index.htm Liver Biopsy Source: National Digestive Diseases Information Clearinghouse http://digestive.niddk.nih.gov/ddiseases/pubs/liverbiopsy/index.htm Liver-Spleen Scan Source: National Institutes of Health, Clinical Center http://www.cc.nih.gov/ccc/patient_education/procdiag/liverspleen.pdf TIBC (Total Iron-Binding Capacity) & Transferrin Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/tibc/test.html 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 FDA Approves Drug to Treat Rare Pediatric Liver Disease Source: Food and Drug Administration http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01131.html Interventional Treatments for Liver Disease Source: Society of Interventional Radiology http://www.sirweb.org/patPub/liverDisease.shtml Shunt Surgical Procedures Source: American Liver Foundation http://www.liverfoundation.org/cgibin/dbs/articles.cgi?db=articles&uid=default&ID=1057&view_records=1

•

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

•

Specific Conditions/Aspects Chemical and Drug Induced Liver Injury Source: American Liver Foundation http://www.liverfoundation.org/cgibin/dbs/articles.cgi?db=articles&uid=default&ID=1056&view_records=1 Cystic Disease of the Liver Source: American Liver Foundation http://www.liverfoundation.org/cgibin/dbs/articles.cgi?db=articles&uid=default&ID=1045&view_records=1 Enlarged Liver (Hepatomegaly) Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=HQ00624 Kava-Containing Dietary Supplements May Be Associated with Severe Liver Injury Source: Center for Food Safety and Applied Nutrition http://www.cfsan.fda.gov/%7Edms/addskava.html Liver Disease and Diabetes Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=AN00193 Primary Sclerosing Cholangitis Source: National Digestive Diseases Information Clearinghouse http://digestive.niddk.nih.gov/ddiseases/pubs/primarysclerosingcholangitis/ind ex.htm What Are the Myths Vs. Facts About Alcohol and the Liver? Source: American Liver Foundation http://www.liverfoundation.org/cgi-

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bin/dbs/articles.cgi?db=articles&uid=default&ID=1009&view_records=1 What is NAFLD/NASH? (Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis) Source: American Liver Foundation http://www.liverfoundation.org/cgibin/dbs/articles.cgi?db=articles&uid=default&ID=1027&view_records=1 Zellweger Syndrome Source: National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/health_and_medical/disorders/zellwege_doc.htm •

Children Alagille Syndrome Source: Children's Liver Association for Support Services http://www.classkids.org/library/alagille.htm Blood Tests: Why Your Child Needs All Those Sticks Source: Children's Liver Association for Support Services http://www.classkids.org/library/bloodtest.htm Galactosemia Source: American Liver Foundation http://www.liverfoundation.org/cgibin/dbs/articles.cgi?db=articles&uid=default&ID=1046&view_records=1 Jaundice in Healthy Newborns Source: Nemours Foundation http://kidshealth.org/parent/pregnancy_newborn/common/jaundice.html Kernicterus - General Information Source: National Center on Birth Defects and Developmental Disabilities http://www.cdc.gov/ncbddd/dd/kernicterus.htm Type I Glycogen Storage Disease Source: American Liver Foundation http://www.liverfoundation.org/cgibin/dbs/articles.cgi?db=articles&uid=default&ID=1053&view_records=1 Tyrosinemia Source: American Liver Foundation http://www.liverfoundation.org/cgibin/dbs/articles.cgi?db=articles&uid=default&ID=1052&view_records=1

•

Men Pregnancy and the Liver Source: American Liver Foundation http://www.liverfoundation.org/cgibin/dbs/articles.cgi?db=articles&uid=default&ID=1078&view_records=1

•

Organizations American Liver Foundation http://www.liverfoundation.org/

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Children's Liver Association for Support Services http://www.classkids.org/ National Digestive Diseases Information Clearinghouse http://digestive.niddk.nih.gov/ •

Prevention/Screening 50 Ways to Love Your Liver Source: American Liver Foundation http://www.liverfoundation.org/cgibin/dbs/articles.cgi?db=articles&uid=default&ID=1021&view_records=1 Albumin Test Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/albumin/test.html ALP (Alkaline Phosphatase) Test Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/alp/test.html 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

•

Research Acute Liver Failure in the United States Source: American College of Physicians http://www.annals.org/cgi/content/full/137/12/I-24 Liver Disease in Persons with Asymptomatic Hepatitis C Virus Infection Source: American College of Physicians http://www.annals.org/cgi/content/full/137/12/I-36 New AHRQ Report Says More Research Is Needed to Help Clinicians Better Manage Jaundice in Newborns Source: Agency for Healthcare Research and Quality http://www.ahrq.gov/news/press/pr2003/jaundpr.htm Oral Administration of an Antibiotic (Norfloxacin) May Help Treat the Cardiac and Circulatory Complications of Liver Failure Source: American College of Physicians http://www.annals.org/cgi/content/full/139/3/I-62

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•

Statistics FASTATS: Chronic Liver Disease/Cirrhosis Source: National Center for Health Statistics http://www.cdc.gov/nchs/fastats/liverdis.htm Hepatitis and Liver Diseases in the United States Source: American Liver Foundation http://www.liverfoundation.org/cgibin/dbs/articles.cgi?db=articles&uid=default&ID=1008&view_records=1

•

Women Pregnancy and the Liver Source: American Liver Foundation http://www.liverfoundation.org/cgibin/dbs/articles.cgi?db=articles&uid=default&ID=1078&view_records=1

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 liver disease. 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: •

Liver Diseases: Options You Can Live with: How to Choose a Doctor and Hospital for Your Treatment Source: Cleveland, OH: Cleveland Clinic Foundation. 1996. 22 p. Contact: Available from Cleveland Clinic Foundation. Department of Nutrition Services, One Clinic Center, 9500 Euclid Avenue, Cleveland, OH 44195. (216) 444-8950. PRICE: Single copy free. Summary: Selecting a doctor and hospital for treatment of liver diseases involves making some difficult and important decisions. Patients must carefully consider where to go and which physicians and surgeons are the most qualified. This brochure offers information for patients with liver disease, focusing on choosing a doctor and hospital for treatment. The brochure describes the different types of liver disease, how liver diseases are diagnosed, treatment options (including nonsurgical therapies and surgical procedures), and six points that indicate quality. The six points that patients should consider are credentials, experience, range of services, participation in research and

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education, patient satisfaction, and outcome indicators. In each area, the brochure offers suggested questions for patients to ask of their health care providers and facilities. Diseases covered include hepatitis, cirrhosis, and liver tumors. Specific procedures discussed include hepatitis screenings and immunization, medical evaluation and physical examination, transplant evaluations, diagnostic tests, liver biopsy, imaging, medical therapy (drug therapy), endoscopy, rubber band ligation of bleeding vessels, nonsurgical shunt placement (TIPS), surgical shunts, surgical removal of benign or malignant liver and bile duct tumors, nutritional therapy, transplantation, psychological care, and comprehensive follow up care for patients with chronic disease. The brochure also provides information about the Cleveland Clinic, the producer of the brochure and a nationally known clinic in the treatment of urologic, gynecologic, and colorectal disorders (www.ccf.org ). 1 table. •

Diet for Liver Disease Source: Birmingham, AL: University of Alabama at Birmingham Hospital. 1997. 24 p. Contact: Available from University of Alabama at Birmingham Hospital. University Hospital. Department of Food and Nutrition Services, 619 South 19th Street, Birmingham, AL 35233. (205) 934-8055. Fax (205) 934-2987. PRICE: $2.25 plus shipping and handling; bulk copies available. Summary: This booklet describes a diet designed for patients who have liver disease and who have experienced hepatic encephalopathy and would therefore benefit from a low protein diet. Protein restriction is not recommended unless encephalopathy is present. The booklet begins with a page for individualizing the reader's dietary requirements for sodium, fluid, and protein and for recording the name and telephone number of the patient's dietitian. The booklet begins by discussing sodium, the mineral that helps regulate the fluid in body tissues. Sodium is often restricted for patients with liver disease to help prevent swelling in the abdomen, hands, and feet. Guidelines for reading food labels (which indicate amounts of sodium) are offered. Sample food labels are given to test readers' ability to determine the presence of sodium in a particular food. Cooking tips and other flavoring options are listed. The second section addresses fluids, noting that they may need to be limited to prevent increased swelling and water gain. The third section considers protein, noting that in liver disease, the body sometimes cannot use protein effectively. This may lead to the accumulation of waste products in the blood, which can cause to central nervous system problems such as mental changes and confusion. The booklet then offers, in chart form, recommended foods in each of these groups: meats, breads and starches, cereals, vegetables, fruits, fats, desserts, sweeteners, and beverages. In each category, the foods to eat and the foods that may cause problems are listed. The booklet concludes with a few recipes, ideas for increasing caloric intake, strategies for eating out at restaurants, sample meal patterns (a blank form for the dietitian and patient to individualize), and sample menus.

•

Alpha 1-Antitrypsin Deficiency Liver Disease Source: Minneapolis, MN: Alpha 1 Association. 2000. [4 p.]. 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: $0.10 plus shipping and handling; bulk copies available. Summary: This brochure describes Alpha 1 antitrypsin deficiency (A1AD or Alpha 1), a genetic disorder that affects infants, children, and adults. It is the most common

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metabolic disorder that causes liver disease in infants and children; the disorder also causes cirrhosis and cancer of the liver in adults. The brochure reviews the functions of the liver, the causes of the deficiency, symptoms in children and adults, and treatment options. Alpha 1 antitrypsin (AAT) is a protein primarily manufactured in the liver and then released into the blood. The normal function of AAT is to protect body tissues from being damaged by neutrophil elastase, a protein found in white blood cells. The backup of abnormal AAT in the liver can cause liver damage. Symptoms of A1AD in children includes 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). Clinical care for all affected individuals largely involves supportive management for liver dysfunction and prevention of complications. For those who develop severe liver injury, liver transplantation is usually recommended. Proper nutrition is essential for everyone with A1AD. The brochure concludes with contact information for the Alpha 1 Association. 1 figure. 3 references. •

Hepatitis A Is a Serious Liver Disease: Should You Be Vaccinated? Source: St. Paul, MN: Immunization Action Coalition. 1996. 2 p. Contact: Available from Immunization Action Coalition and Hepatitis B Coalition. 1573 Selby Avenue, Number 234, St. Paul, MN 55104. (612) 647-9009. Fax (612) 647-9131. PRICE: $1.00. Summary: This brochure encourages readers to learn about hepatitis A and consider getting vaccinated to prevent the disease. Written in a question and answer format, the brochure covers the symptoms of hepatitis A; complications associated with the disease; who should get the vaccine; safety issues for the vaccine; and what to do if one is exposed to hepatitis A. The brochure is written in nontechnical language and is available in English or Spanish.

•

Risk of Eating Raw Oysters: Advice for Persons with Liver Disease, Diabetes, or Weakened Immune Systems Source: Cedar Grove, NJ: American Liver Foundation. 200x. [2 p.]. Contact: Available from American Liver Foundation. Information and Distribution Center, 1425 Pompton Avenue, Suite 3, Cedar Grove, NJ 07009-1000. (800) GO-LIVER, ext. 234 or (888) 4HEP-ABC. Fax (973) 256-3214. E-mail: [email protected]. Website: www.liverfoundation.org. PRICE: $0.75 for single copy; bulk orders available; plus shipping and handling. Summary: This brochure offers advice for persons with liver disease, diabetes, or weakened immune systems about the risk factors of eating raw oysters. The brochure explains how the bacteria Vibrio vulnificus can be present in raw oysters or clams, and the illness that can result from their ingestion. V. vulnificus is found naturally in warm coastal waters, such as the Gulf of Mexico, where levels of the bacteria are elevated during the summer months. V. vulnificus does not change the appearance, taste, or odors of oysters or clams. The brochure outlines the symptoms of V. vulnificus infection and offers cooking tips for oysters and clams. Readers are advised to only eat oysters or clams that have been thoroughly cooked (heat destroys the bacteria), or those that have been treated and labeled as 'processed to reduce V. vulnificus to non-detectable levels.'

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Readers with sores or open wounds are also advised to never swim or wade in seawater. The brochure includes the FDA Food Safety hotline number (888-723-3366), the FDA website (www.cfsan.fda.gov), and the Interstate Shellfish Sanitation Conference (ISSC) website (www.issc.org). •

Get Hooked on Seafood Safety: Important Health Information for People with Liver Disease Source: Rockville, MD: U.S. Food and Drug Administration. 1992. 4 p. Contact: Available from U.S. Food and Drug Administration. Office of Consumer Affairs, Consumer Inquiries Section, 5600 Fishers Lane, Rockville, MD 20857. PRICE: Single copy free. Order Number: 92-2260. Summary: This brochure provides information to people with liver disease about the hazards of eating raw molluscan shellfish (oysters, mussels, clams, and whole scallops). The brochure also contains information about safe handling and consumption of seafood in general. Topics covered include risk factors for persons with serious diseases, including gastrointestinal disorders, liver disease, diabetes mellitus, or autoimmune disorders; how mollusks get contaminated; raw fish dishes; safety tips for shopping, storing, and cooking seafood; and the proper temperature at which to keep hot and cold seafood.

•

Liver Disease Source: in Kerestes-Smith, J.; Chua, G.; Sullivan, K. Guidelines for Nutritional Care. Ann Arbor, MI: Food and Nutrition Services, University of Michigan Medical Center. 1995. Chapter 56, p. 56.1-56.6. Contact: Available from Guidelines for Nutritional Care. Food and Nutrition Services, 2C227-0056, University of Michigan Hospitals, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0056. (313) 936-5199. Fax (313) 936-5195. PRICE: $79.00 including shipping and handling (as of 1996). ISBN: 0964799405. Summary: This chapter on dietary recommendations for individuals with liver disease is from a manual that outlines the impact of nutrition on promoting health and preventing and treating disease. Diseases include cholestasis, steatosis, viral hepatitis, alcoholic liver disease, cirrhosis, and hepatic encephalopathy. Included are sections detailing indications for use, contraindications, a description of the diet including a brief physiological and/or biochemical rationale, guidelines for nutritional management, nutrient adequacy, ordering procedures, and references for both health care providers and the layperson. 22 references.

•

Liver Diseases in the United States: Fact Sheet Source: Cedar Grove, NJ: American Liver Foundation. 1994. 2 p. Contact: Available from American Liver Foundation. 1425 Pompton Avenue, Cedar Grove, NJ 07009. (800) 223-0179 or (201) 256-2550. PRICE: $0.50 for single copy; $4 for 25 copies; $8 for 50 copies; $15 for 100 copies (as of 1995). Summary: This fact sheet summarizes statistical information on liver diseases in the United States. Topics include the number of Americans who have liver, bile duct, or gallbladder diseases; deaths from liver diseases; the role of alcohol abuse in liver cirrhosis; mortality due to hepatitis C and B; carriers of hepatitis B; pregnant women with hepatitis B and the implications for their children; the infectious nature of hepatitis

258 Liver Disease

B compared with AIDS; hospitalization costs for liver diseases; the estimated economic impact of hepatitis B; liver transplants; and gallbladder surgery for gallstones. •

Hepatitis A, B and C: Liver Diseases You Should Know About 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: $12 per 100, plus $2 shipping and handling (as of 1994). Summary: Viral hepatitis is a common contagious disease caused by several viruses that attack the liver. This brief brochure presents a guide to viral hepatitis, notably hepatitis A, hepatitis B, and hepatitis C (formerly called non-A, non-B hepatitis). Topics include the transmission of viral hepatitis, the symptoms of viral hepatitis, diagnostic tests used to determine hepatitis, and the differences between acute and chronic hepatitis. One chart summarizes the methods of transmission. 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 “liver disease” (or synonyms). The following was recently posted: •

American Gastroenterological Association medical position statement: nonalcoholic fatty liver disease Source: American Association for the Study of Liver Diseases - Private Nonprofit Research Organization; 2002 November; 3 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3491&nbr=2717&a mp;string=liver+AND+disease 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: •

Diseases of the Liver Summary: This web site presents an alphabetical list of liver diseases and conditions as well as links to current reports and articles on liver disease, other liver-related internet sites and books on liver Source: Educational Institution--Follow the Resource URL for More Information http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=2315

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•

259

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

•

S-Adenosyl-L-Methionine for Treatment of Depression, Osteoarthritis, and Liver Disease Summary: The objective of this report was to conduct a search of the published literature on the use of S-adenosyl- L-methionine (SAMe) for the treatment of osteoarthritis, depression, and liver disease; and, Source: Agency for Healthcare Research and Quality http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7461 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 liver disease. 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. 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

260 Liver Disease

Associations and Liver Disease The following is a list of associations that provide information on and resources relating to liver disease: •

Children's Liver Disease Foundation Telephone: 0121-212-3839 Fax: 0121-212-4300 Email: [email protected] Web Site: http://www.childliverdisease.org Background: The Children s Liver Disease Foundation (CLDF) is a voluntary organization dedicated to caring for children and families around the world who are affected by liver disease. Established in 1980 and consisting of 30 chapters, CLDF is dedicated to educating the medical profession and the general public about childhood liver disease; promoting research into early diagnosis, treatments, and cure; providing new facilities and trained staffs; and giving emotional support to children and families affected by pediatric liver disease. CLDF also publishes a newsletter, reports, and brochures; offers a referral service, a database, and a directory; and offers translations of various educational materials. Relevant area(s) of interest: Liver Disease

•

Children's Liver Disease Foundation (UK) Telephone: 0121 212 3839 Fax: 0121 212 4300 Email: [email protected] Web Site: http://www.childliverdisease.org Background: The Children's Liver Disease Foundation (UK) is a voluntary not-for-profit organization in the United Kingdom that was established in 1980. The Foundation is committed to providing emotional support to children, adolescents, and families affected by liver disease; promoting research into the causes of pediatric liver disease; creating a greater awareness of such disorders and conditions in the health care communities and the public; and promoting the development of means of early diagnosis and cure. The Children's Liver Disease Foundation is also dedicated to providing understandable information on pediatric liver disease through general informational brochures including 'A Guide to the Liver' and 'Signs and Symptoms of Liver Disease' as well as a leaflet series on specific pediatric liver diseases and conditions, such as Alagille syndrome; neonatal hepatitis; hepatitis A, B, C, and E; biliary atresia; and others. The Foundation's web site on the Internet discusses the organization's mission, goals, and services; enables interested individuals, family members, and health care professionals to make specific inquiries; and provides access to the Foundation's publication series.

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to liver disease. By consulting all of associations listed

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in this chapter, you will have nearly exhausted all sources for patient associations concerned with liver disease. 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 liver disease. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “liver disease” (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 “liver disease”. 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 “liver disease” (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 “liver disease” (or a synonym) into the search box, and click “Submit Query.”

263

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.

264 Liver Disease

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/

266 Liver Disease

•

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/

268 Liver Disease

•

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

269

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 liver disease: •

Basic Guidelines for Liver Disease Liver disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000205.htm Liver disease - resources Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002182.htm

•

Diagnostics and Tests for Liver Disease Liver function tests Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003436.htm

270 Liver Disease

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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LIVER DISEASE DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 5-Hydroxytryptophan: Precursor of serotonin used as antiepileptic and antidepressant. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Abscess: Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. [NIH] Acantholysis: Separation of the prickle cells of the stratum spinosum of the epidermis, resulting in atrophy of the prickle cell layer. It is seen in diseases such as pemphigus vulgaris (see pemphigus) and keratosis follicularis. [NIH] Acatalasia: A rare autosomal recessive disorder resulting from the absence of catalase activity. Though usually asymptomatic, a syndrome of oral ulcerations and gangrene may be present. [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] 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] Acetylcysteine: The N-acetyl derivative of cysteine. It is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates. [NIH] Acetylgalactosamine: The N-acetyl derivative of galactosamine. [NIH] Acidemia: Increased acidity of blood. [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] Acrylonitrile: A highly poisonous compound used widely in the manufacture of plastics,

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adhesives and synthetic rubber. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH] Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] 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] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adoptive Transfer: Form of passive immunization where previously sensitized immunologic agents (cells or serum) are transferred to non-immune recipients. When transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy (immunotherapy, adoptive). [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adrenoleukodystrophy: A chromosome X-linked disease. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]

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

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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] Aflatoxins: A group of closely related toxic metabolites that are designated mycotoxins. They are produced by Aspergillus flavus and A. parasiticus. Members of the group include aflatoxin B1, aflatoxin B2, aflatoxin G1, aflatoxin G2, aflatoxin M1, and aflatoxin M2. [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 Drinking: Behaviors associated with the ingesting of alcoholic beverages, including social drinking. [NIH] Aldehydes: Organic compounds containing a carbonyl group in the form -CHO. [NIH] Aldose Reductase Inhibitor: A class of drugs being studied as a way to prevent eye and nerve damage in people with diabetes. Aldose reductase is an enzyme that is normally present in the eye and in many other parts of the body. It helps change glucose (sugar) into a sugar alcohol called sorbitol. Too much sorbitol trapped in eye and nerve cells can damage these cells, leading to retinopathy and neuropathy. Drugs that prevent or slow (inhibit) the action of aldose reductase are being studied as a way to prevent or delay these complications of diabetes. [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

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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] Alkaline: Having the reactions of an alkali. [EU] Alkaline Phosphatase: An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC 3.1.3.1. [NIH] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [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] Allograft: An organ or tissue transplant between two humans. [NIH] Allopurinol: A xanthine oxidase inhibitor that decreases uric acid production. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Cell: A type of cell in the pancreas (in areas called the islets of Langerhans). Alpha cells make and release a hormone called glucagon, which raises the level of glucose (sugar) in the blood. [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-Linolenic Acid: A fatty acid that is found in plants and involved in the formation of prostaglandins. [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] Alveolitis: Inflammation of an alveolus. Called also odontobothritis. [EU] Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical

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compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino-terminal: The end of a protein or polypeptide chain that contains a free amino group (-NH2). [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] Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [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] Anaesthetic: 1. Pertaining to, characterized by, or producing anaesthesia. 2. A drug or agent that is used to abolish the sensation of pain. [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

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term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]

Anaphylactic: Pertaining to anaphylaxis. [EU] 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] Anaphylaxis: An acute hypersensitivity reaction due to exposure to a previously encountered antigen. The reaction may include rapidly progressing urticaria, respiratory distress, vascular collapse, systemic shock, and death. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgenic: Producing masculine characteristics. [EU] 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] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [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] 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] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Anode: Electrode held at a positive potential with respect to a cathode. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory

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and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [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] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Antidepressant: A drug used to treat depression. [NIH] Antiepileptic: An agent that combats epilepsy. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] 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] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU]

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Anus: The opening of the rectum to the outside of the body. [NIH] Anxiolytic: An anxiolytic or antianxiety agent. [EU] Aorta: The main trunk of the systemic arteries. [NIH] Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [NIH]

Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Aquaporins: Membrane proteins which facilitate the passage of water. They are members of the family of membrane channel proteins which includes the lens major intrinsic protein and bacterial glycerol transporters. [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] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Articular: Of or pertaining to a joint. [EU]

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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] Aspartate: A synthetic amino acid. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atrial: Pertaining to an atrium. [EU] Atrial Fibrillation: Disorder of cardiac rhythm characterized by rapid, irregular atrial impulses and ineffective atrial contractions. [NIH] 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] Autacoids: A chemically diverse group of substances produced by various tissues in the body that cause slow contraction of smooth muscle; they have other intense but varied pharmacologic activities. [NIH] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmune Hepatitis: A liver disease caused when the body's immune system destroys liver cells for no known reason. [NIH] 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] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress.

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Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Autopsy: Postmortem examination of the body. [NIH] Azithromycin: A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. [NIH] 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] 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] Barium: An element of the alkaline earth group of metals. It has an atomic symbol Ba, atomic number 56, and atomic weight 138. All of its acid-soluble salts are poisonous. [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] Beclomethasone: An anti-inflammatory, synthetic glucocorticoid. It is used topically as an anti-inflammatory agent and in aerosol form for the treatment of asthma. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Bereavement: Refers to the whole process of grieving and mourning and is associated with a deep sense of loss and sadness. [NIH]

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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 Atresia: Atresia of the biliary tract, most commonly of the extrahepatic bile ducts. [NIH]

Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biochemical reactions: In living cells, chemical reactions that help sustain life and allow cells to grow. [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]

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Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biopsy specimen: Tissue removed from the body and examined under a microscope to determine whether disease is present. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bivalent: Pertaining to a group of 2 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [NIH] Bladder: The organ that stores urine. [NIH] 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] Blister: Visible accumulations of fluid within or beneath the epidermis. [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 the blood coagulation process. [NIH] Blood Coagulation Tests: Laboratory tests for evaluating the individual's clotting mechanism. [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] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blotting and transferred to strips of nitrocellulose paper. The blots are then detected by radiolabeled antibody probes. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bone Density: The amount of mineral per square centimeter of bone. This is the definition used in clinical practice. Actual bone density would be expressed in grams per milliliter. It is

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most frequently measured by photon absorptiometry or x-ray computed tomography. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bone Remodeling: The continuous turnover of bone matrix and mineral that involves first, an increase in resorption (osteoclastic activity) and later, reactive bone formation (osteoblastic activity). The process of bone remodeling takes place in the adult skeleton at discrete foci. The process ensures the mechanical integrity of the skeleton throughout life and plays an important role in calcium homeostasis. An imbalance in the regulation of bone remodeling's two contrasting events, bone resorption and bone formation, results in many of the metabolic bone diseases, such as osteoporosis. [NIH] Bone Resorption: Bone loss due to osteoclastic activity. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] 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] 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] Budesonide: A glucocorticoid used in the management of asthma, the treatment of various skin disorders, and allergic rhinitis. [NIH] Bullous: Pertaining to or characterized by bullae. [EU] Bupivacaine: A widely used local anesthetic agent. [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

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of electricity. [NIH] Bursitis: Inflammation of a bursa, occasionally accompanied by a calcific deposit in the underlying supraspinatus tendon; the most common site is the subdeltoid bursa. [EU] 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] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal 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] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [NIH] Caloric intake: Refers to the number of calories (energy content) consumed. [NIH] Cannula: A tube for insertion into a duct or cavity; during insertion its lumen is usually occupied by a trocar. [EU] 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

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for the respiration cycle of plants and animals. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] 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] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiorespiratory: Relating to the heart and lungs and their function. [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 can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [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] Catalase: An oxidoreductase that catalyzes the conversion of hydrogen peroxide to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. EC 1.11.1.6. [NIH] Catalyse: To speed up a chemical reaction. [EU] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Causality: The relating of causes to the effects they produce. Causes are termed necessary when they must always precede an effect and sufficient when they initiate or produce an effect. Any of several factors may be associated with the potential disease causation or

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outcome, including predisposing factors, enabling factors, precipitating factors, reinforcing factors, and risk factors. [NIH] 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 made up of one or more cells. [NIH] Cell Count: A count of the number of cells of a specific kind, usually measured per unit volume of sample. [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 Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [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] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [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] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Arteries: The arteries supplying the cerebral cortex. [NIH]

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Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] 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] Chimeras: Organism that contains a mixture of genetically different cells. [NIH] Chiropractic: A system of treating bodily disorders by manipulation of the spine and other parts, based on the belief that the cause is the abnormal functioning of a nerve. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Cholangitis: Inflammation of a bile duct. [NIH] Cholecystectomy: Surgical removal of the gallbladder. [NIH] Cholecystitis: Inflammation of the gallbladder. [NIH] Cholelithiasis: Presence or formation of gallstones. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Choleretic: A choleretic agent. [EU] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla. [NIH]

Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Cholic Acid: A major primary bile acid produced in the liver and usually conjugated with glycine or taurine. It facilitates fat absorption and cholesterol excretion. [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] Chondrodysplasia Punctata: A heterogeneous group of bone dysplasias, the common character of which is stippling of the epiphyses in infancy. The group includes a severe autosomal recessive form (Chondrodysplasia punctata, rhizomelic), an autosomal dominant form (Conradi-Hunermann syndrome), and a milder X-linked form. Metabolic defects associated with impaired peroxisomes are present only in the rhizomelic form. [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] Chromium: A trace element that plays a role in glucose metabolism. It has the atomic symbol Cr, atomic number 24, and atomic weight 52. According to the Fourth Annual Report on Carcinogens (NTP85-002,1985), chromium and some of its compounds have been listed as known carcinogens. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Chymotrypsin: A serine endopeptidase secreted by the pancreas as its zymogen, chymotrypsinogen and carried in the pancreatic juice to the duodenum where it is activated by trypsin. It selectively cleaves aromatic amino acids on the carboxyl side. [NIH] 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] 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] Cleave: A double-stranded cut in DNA with a restriction endonuclease. [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]

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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]

Clonic: Pertaining to or of the nature of clonus. [EU] 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] Cobalt: A trace element that is a component of vitamin B12. It has the atomic symbol Co, atomic number 27, and atomic weight 58.93. It is used in nuclear weapons, alloys, and pigments. Deficiency in animals leads to anemia; its excess in humans can lead to erythrocytosis. [NIH] Coccidioidomycosis: An infectious disease caused by a fungus, Coccidioides immitis, that is prevalent in the western United States and is acquired by inhalation of dust containing the spores. [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] 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]

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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] 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 alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [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

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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] Computer Simulation: Computer-based representation of physical systems and phenomena such as chemical processes. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] 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] 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] Conjunctivitis: Inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH]

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Constriction: The act of constricting. [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] Continuum: An area over which the vegetation or animal population is of constantly changing composition so that homogeneous, separate communities cannot be distinguished. [NIH]

Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] 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 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 clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] 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]

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Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cosmids: Plasmids containing at least one cos (cohesive-end site) of phage lambda. They are used as cloning vehicles for the study of aberrant eukaryotic structural genes and also as genetic vectors for introducing the nucleic acid of transforming viruses into cultured cells. [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] Cowpox: A mild, eruptive skin disease of milk cows caused by cowpox virus, with lesions occurring principally on the udder and teats. Human infection may occur while milking an infected animal. [NIH] Cowpox Virus: A species of orthopoxvirus that is the etiologic agent of cowpox. It is closely related to but antigenically different from vaccina virus. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Creatine: An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. [NIH]

Creatine Kinase: A transferase that catalyzes formation of phosphocreatine from ATP + creatine. The reaction stores ATP energy as phosphocreatine. Three cytoplasmic isoenzymes have been identified in human tissues: MM from skeletal muscle, MB from myocardial tissue, and BB from nervous tissue as well as a mitochondrial isoenzyme. Macro-creatine kinase refers to creatine kinase complexed with other serum proteins. EC 2.7.3.2. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [NIH] Cryoglobulinemia: A condition characterized by the presence of abnormal or abnormal quantities of cryoglobulins in the blood. They are precipitated into the microvasculature on exposure to cold and cause restricted blood flow in exposed areas. [NIH] Cryptosporidiosis: Parasitic intestinal infection with severe diarrhea caused by a protozoan, Cryptosporidium. It occurs in both animals and humans. [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] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause

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sterility, birth defects, mutations, and cancer. [NIH] Cyst: A sac or capsule filled with fluid. [NIH] Cystathionine beta-Synthase: A multifunctional pyridoxal phosphate enzyme. In the second stage of cysteine biosynthesis it catalyzes the reaction of homocysteine with serine to form cystathionine with the elimination of water. Deficiency of this enzyme leads to hyperhomocysteinemia and homocystinuria. EC 4.2.1.22. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystic Duct: The tube that carries bile from the gallbladder into the common bile duct and the small intestine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]

Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytotoxic: Cell-killing. [NIH] Dairy Products: Raw and processed or manufactured milk and milk-derived products. These are usually from cows (bovine) but are also from goats, sheep, reindeer, and water buffalo. [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] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH]

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Decompensation: Failure of compensation; cardiac decompensation is marked by dyspnea, venous engorgement, and edema. [EU] Decongestant: An agent that reduces congestion or swelling. [EU] 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] Deoxycholic Acid: A bile acid formed by bacterial action from cholate. It is usually conjugated with glycine or taurine. Deoxycholic acid acts as a detergent to solubilize fats for intestinal absorption, is reabsorbed itself, and is used as a choleretic and detergent. [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] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Dermatitis: Any inflammation of the skin. [NIH] 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] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [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] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Dietitian: An expert in nutrition who helps people plan what and how much food to eat. [NIH]

Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are

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the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [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] 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] Dirofilaria: A genus of filarial nematodes. Various immature species have been found to infect the eyes or subcutaneous tissue in humans. [NIH] Dirofilaria immitis: A filarial parasite primarily of dogs but occurring also in foxes, wolves, and humans. The parasite is transmitted by mosquitoes. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] 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 consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] 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] Domesticated: Species in which the evolutionary process has been influenced by humans to meet their needs. [NIH] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Double-blinded: A clinical trial in which neither the medical staff nor the person knows

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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 Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated 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] Drug Toxicity: Manifestations of the adverse effects of drugs administered therapeutically or in the course of diagnostic techniques. It does not include accidental or intentional poisoning for which specific headings are available. [NIH] Duct: A tube through which body fluids pass. [NIH] 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] 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] Dystrophic: Pertaining to toxic habitats low in nutrients. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Ectopic: Pertaining to or characterized by ectopia. [EU] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Egg Yolk: Cytoplasm stored in an egg that contains nutritional reserves for the developing embryo. It is rich in polysaccharides, lipids, and proteins. [NIH] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electroencephalography: Recording of electric currents developed in the brain by means of

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electrodes applied to the scalp, to the surface of the brain, or placed within the substance of the brain. [NIH] Electrolysis: Destruction by passage of a galvanic electric current, as in disintegration of a chemical compound in solution. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] ELISA: A sensitive analytical technique in which an enzyme is complexed to an antigen or antibody. A substrate is then added which generates a color proportional to the amount of binding. This method can be adapted to a solid-phase technique. [NIH] Emboli: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] 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] Embryo Transfer: Removal of a mammalian embryo from one environment and replacement in the same or a new environment. The embryo is usually in the pre-nidation phase, i.e., a blastocyst. The process includes embryo or blastocyst transplantation or transfer after in vitro fertilization and transfer of the inner cell mass of the blastocyst. It is not used for transfer of differentiated embryonic tissue, e.g., germ layer cells. [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] Emesis: Vomiting; an act of vomiting. Also used as a word termination, as in haematemesis. [EU]

Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH]

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Empyema: Presence of pus in a hollow organ or body cavity. [NIH] Emulsions: Colloids of two immiscible liquids where either phase may be either fatty or aqueous; lipid-in-water emulsions are usually liquid, like milk or lotion and water-in-lipid emulsions tend to be creams. [NIH] Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [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] 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-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] Enhancer: Transcriptional element in the virus genome. [NIH] Enteric bacteria: Single-celled microorganisms that lack chlorophyll. Some bacteria are capable of causing human, animal, or plant diseases; others are essential in pollution control because they break down organic matter in the air and in the water. [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] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [NIH]

Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences,

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or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [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 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] Epidural block: An injection of an anesthetic drug into the space between the wall of the spinal canal and the covering of the spinal cord. [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [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]

ERCP: Endoscopic retrograde cholangiopancreatography (en-do-SKAH-pik RET-ro-grade ko-LAN-jee-o-PAN-kree-a-TAW-gra-fee). A procedure to x-ray the bile and pancreatic ducts. In this procedure, a thin, lighted tube (endoscope) is passed through the mouth and down into the first part of the small intestine (duodenum). A smaller tube (catheter) is then inserted through the endoscope into the bile and pancreatic ducts. A dye is injected through the catheter into the ducts, and an x-ray is taken. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with

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blood. [EU] 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] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [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 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] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [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] Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] 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]

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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 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] Extrarenal: Outside of the kidney. [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] Factor V: Heat- and storage-labile plasma glycoprotein which accelerates the conversion of prothrombin to thrombin in blood coagulation. Factor V accomplishes this by forming a complex with factor Xa, phospholipid, and calcium (prothrombinase complex). Deficiency of factor V leads to Owren's disease. [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] Familial polyposis: An inherited condition in which numerous polyps (tissue masses) develop on the inside walls of the colon and rectum. It increases the risk for colon cancer. [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] 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] Ferrochelatase: An enzyme widely distributed in cells and tissues. It is located in the inner mitochondrial membrane and catalyzes the formation of heme from protoporphyrin IX and ferrous ions during the terminal step in the heme biosynthetic pathway. EC 4.99.1.1. [NIH] Fetal Development: Morphologic and physiologic growth and development of the mammalian embryo or fetus. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH]

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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] 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] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filarioidea: A superfamily of nematodes of the suborder Spirurina. Its organisms possess a filiform body and a mouth surrounded by papillae. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Fish Products: Food products manufactured from fish (e.g., fish flour, fish meal). [NIH] Fistula: Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. [NIH] 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] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering,

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the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Flurbiprofen: An anti-inflammatory analgesic and antipyretic of the phenylalkynoic acid series. It has been shown to reduce bone resorption in periodontal disease by inhibiting carbonic anhydrase. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has calories. [NIH] Fructose Intolerance: An autosomal recessive fructose metabolism disorder due to deficient fructose-1-phosphate aldolase (EC 2.1.2.13) activity, resulting in accumulation of fructose-1phosphate. The accumulated fructose-1-phosphate inhibits glycogenolysis and gluconeogenesis, causing severe hypoglycemia following ingestion of fructose. Prolonged fructose ingestion in infants leads ultimately to hepatic failure and death. Patients develop a strong distaste for sweet food, and avoid a chronic course of the disease by remaining on a fructose- and sucrose-free diet. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Galactosemia: Buildup of galactose in the blood. Caused by lack of one of the enzymes needed to break down galactose into glucose. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH]

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Gallstones: The solid masses or stones made of cholesterol or bilirubin that form in the gallbladder or bile ducts. [NIH] Gamma irradiation: A type of radiation therapy that uses gamma radiation. Gamma radiation is a type of high-energy radiation that is different from x-rays. [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] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [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]

Gastroenterologist: A doctor who specializes in diagnosing and treating disorders of the 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] Gemfibrozil: A lipid-regulating agent that lowers elevated serum lipids primarily by decreasing serum triglycerides with a variable reduction in total cholesterol. These decreases occur primarily in the VLDL fraction and less frequently in the LDL fraction. Gemfibrozil increases HDL subfractions HDL2 and HDL3 as well as apolipoproteins A-I and A-II. Its

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mechanism of action has not been definitely established. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Counseling: Advising families of the risks involved pertaining to birth defects, in order that they may make an informed decision on current or future pregnancies. [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetic Vectors: Any DNA molecule capable of autonomous replication within a host cell and into which other DNA sequences can be inserted and thus amplified. Many are derived from plasmids, bacteriophages or viruses. They are used for transporting foreign genes into recipient cells. Genetic vectors possess a functional replicator site and contain genetic markers to facilitate their selective recognition. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]

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] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomeruli: Plural of glomerulus. [NIH] Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [NIH] 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

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(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] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glucuronides: Glycosides of glucuronic acid formed by the reaction of uridine diphosphate glucuronic acid with certain endogenous and exogenous substances. Their formation is important for the detoxification of drugs, steroid excretion and bilirubin metabolism to a more water-soluble compound that can be eliminated in the urine and bile. [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]

Gluten: The protein of wheat and other grains which gives to the dough its tough elastic character. [EU] Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]

Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycodeoxycholic Acid: A bile salt formed in the liver by conjugation of deoxycholate with glycine, usually as the sodium salt. It acts as a detergent to solubilize fats for absorption and is itself absorbed. It is used as a cholagogue and choleretic. [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]

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Glycogen Storage Disease: A group of inherited metabolic disorders involving the enzymes responsible for the synthesis and degradation of glycogen. In some patients, prominent liver involvement is presented. In others, more generalized storage of glycogen occurs, sometimes with prominent cardiac involvement. [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] Gonadal: Pertaining to a gonad. [EU] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] 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] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Graft Survival: The survival of a graft in a host, the factors responsible for the survival and the changes occurring within the graft during growth in the host. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Granule: A small pill made from sucrose. [EU] Granulocyte-Macrophage Colony-Stimulating Factor: An acidic glycoprotein of MW 23 kDa with internal disulfide bonds. The protein is produced in response to a number of inflammatory mediators by mesenchymal cells present in the hemopoietic environment and at peripheral sites of inflammation. GM-CSF is able to stimulate the production of neutrophilic granulocytes, macrophages, and mixed granulocyte-macrophage colonies from bone marrow cells and can stimulate the formation of eosinophil colonies from fetal liver progenitor cells. GM-CSF can also stimulate some functional activities in mature granulocytes and macrophages. [NIH] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Guinea Pigs: A common name used for the family Caviidae. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. [NIH]

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Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Haematemesis: The vomiting of blood. [EU] Haematological: Relating to haematology, that is that branch of medical science which treats of the morphology of the blood and blood-forming tissues. [EU] Haematology: The science of the blood, its nature, functions, and diseases. [NIH] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Hawthorn fruit: The fruit of the hawthorn bush. It has been used in some cultures to treat certain medical problems, including heart problems and gastrointestinal problems. [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 Policy: Decisions, usually developed by government policymakers, for determining present and future objectives pertaining to the health care system. [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [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] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] 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

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glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]

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 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 C: A form of hepatitis, similar to type B post-transfusion hepatitis, but caused by a virus which is serologically distinct from the agents of hepatitis A, B, and E, and which may persist in the blood of chronic asymptomatic carriers. Hepatitis C is parenterally transmitted and associated with transfusions and drug abuse. [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]

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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] 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] Heritability: The proportion of observed variation in a particular trait that can be attributed to inherited genetic factors in contrast to environmental ones. [NIH] Hernia: Protrusion of a loop or knuckle of an organ or tissue through an abnormal opening. [NIH]

Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes virus: A member of the herpes family of viruses. [NIH] Herpes Zoster: Acute vesicular inflammation. [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]

Heterogenic: Derived from a different source or species. Also called heterogenous. [NIH] Heterogenous: Derived from a different source or species. Also called heterogenic. [NIH] Heterotrophic: Pertaining to organisms that are consumers and dependent on other organisms for their source of energy (food). [NIH] Heterozygote: An individual having different alleles at one or more loci in homologous chromosome segments. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histamine Agonists: Drugs that bind to and activate histamine receptors. Although they have been suggested for a variety of clinical applications histamine agonists have so far been more widely used in research than therapeutically. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is

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required for the production of histamine. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [NIH]

Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homotypic: Adhesion between neutrophils. [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] 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] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] 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

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collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperaemia: An excess of blood in a part; engorgement. [EU] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercalcemia: Abnormally high level of calcium in the blood. [NIH] Hypercalciuria: Abnormally large amounts of calcium in the urine. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperemesis: Excessive vomiting. [EU] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperhomocysteinemia: An inborn error of methionone metabolism which produces an excess of homocysteine in the blood. It is often caused by a deficiency of cystathionine betasynthase and is a risk factor for coronary vascular disease. [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] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertension, Portal: Abnormally increased pressure in the portal venous system; frequently seen in cirrhosis of the liver and in other conditions which cause obstruction of the portal vein. [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] Hypesthesia: Absent or reduced sensitivity to cutaneous stimulation. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypoglycemia: Abnormally low blood sugar [NIH] Hypotension: Abnormally low blood pressure. [NIH] 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] Hypoxanthine: A purine and a reaction intermediate in the metabolism of adenosine and in the formation of nucleic acids by the salvage pathway. [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] Ileal: Related to the ileum, the lowest end of the small intestine. [NIH]

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Ileitis: Inflammation of the ileum. [EU] Ileum: The lower end of the small intestine. [NIH] Ileus: Obstruction of the intestines. [EU] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune 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] Immune Tolerance: The specific failure of a normally responsive individual to make an immune response to a known antigen. It results from previous contact with the antigen by an immunologically immature individual (fetus or neonate) or by an adult exposed to extreme high-dose or low-dose antigen, or by exposure to radiation, antimetabolites, antilymphocytic serum, etc. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] 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] Immunoblotting: Immunologic methods for isolating and quantitatively measuring immunoreactive substances. When used with immune reagents such as monoclonal antibodies, the process is known generically as western blot analysis (blotting, western). [NIH]

Immunocompetence: The ability of lymphoid cells to mount a humoral or cellular immune response when challenged by antigen. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenetics: A branch of genetics which deals with the genetic basis of the 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]

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Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] 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] Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Indolent: A type of cancer that grows slowly. [NIH] Indomethacin: A non-steroidal anti-inflammatory agent (NSAID) that inhibits the enzyme cyclooxygenase necessary for the formation of prostaglandins and other autacoids. It also inhibits the motility of polymorphonuclear leukocytes. [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,

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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]

Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]

Information Systems: Integrated set of files, procedures, and equipment for the storage, manipulation, and retrieval of information. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] 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] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant

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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-15: Cytokine that stimulates the proliferation of T-lymphocytes and shares biological activities with IL-2. IL-15 also can induce B-lymphocyte proliferation and differentiation. [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-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, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] International Normalized Ratio: System established by the World Health Organization and the International Committee on Thrombosis and Hemostasis for monitoring and reporting blood coagulation tests. Under this system, results are standardized using the International Sensitivity Index for the particular test reagent/instrument combination used. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU]

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Intracellular: Inside a cell. [NIH] Intrahepatic: Within the liver. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] 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 Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active or passive. Passive ion transport (facilitated diffusion) derives its energy from the concentration gradient of the ion itself and allows the transport of a single solute in one direction (uniport). Active ion transport is usually coupled to an energy-yielding chemical or photochemical reaction such as ATP hydrolysis. This form of primary active transport is called an ion pump. Secondary active transport utilizes the voltage and ion gradients produced by the primary transport to drive the cotransport of other ions or molecules. These may be transported in the same (symport) or opposite (antiport) direction. [NIH] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] 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] Ivermectin: A mixture of ivermectin component B1a (RN 71827-03-7) and B1b (RN 70209-813), which is a semisynthetic product from Streptomyces avermitilis. A potent macrocyclic lactone disaccharide antiparasitic agent used to prevent and treat parasite infestations in animals. The compound has activity against internal and external parasites and has been

Dictionary 319

found effective against arthropods, insects, nematodes, filarioidea, platyhelminths, and protozoa. [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] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Keto: It consists of 8 carbon atoms and within the endotoxins, it connects poysaccharide and lipid A. [NIH] Kidney Cortex: The outer zone of the kidney, beneath the capsule, consisting of kidney glomerulus; kidney tubules, distal; and kidney tubules, proximal. [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 stone: A stone that develops from crystals that form in urine and build up on the inner surfaces of the kidney, in the renal pelvis, or in the ureters. [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] Lactation: The period of the secretion of milk. [EU] 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] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] 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.

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[EU]

Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Lethargy: Abnormal drowsiness or stupor; a condition of indifference. [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] Leukopenia: A condition in which the number of leukocytes (white blood cells) in the blood is reduced. [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

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 A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] 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] Lipolysis: The hydrolysis of lipids. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH]

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Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] 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]

Lithocholic Acid: A bile acid formed from chenodeoxycholate by bacterial action, usually conjugated with glycine or taurine. It acts as a detergent to solubilize fats for absorption and is itself absorbed. It is used as cholagogue and choleretic. [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 Circulation: The circulation of blood through the vessels 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 Diseases, Alcoholic: Liver diseases associated with alcoholism. It usually refers to the coexistence of two or more subentities, i.e., alcoholic fatty liver, alcoholic hepatitis, and alcoholic liver cirrhosis, but may be the general entity when subentities are not specified. [NIH]

Liver Regeneration: Repair or renewal of hepatic tissue. [NIH] Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [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] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lower Esophageal Sphincter: The muscle between the esophagus and stomach. When a

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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 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] Lung volume: The amount of air the lungs hold. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lutein Cells: The cells of the corpus luteum which are derived from the granulosa cells and the theca cells of the Graafian follicle. [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] Lymphedema: Edema due to obstruction of lymph vessels or disorders of the lymph nodes. [NIH]

Lymphoblastic: One of the most aggressive types of non-Hodgkin lymphoma. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [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] Lymphoproliferative: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lysosomal Storage Diseases: Inborn errors of metabolism characterized by defects in specific lysosomal hydrolases and resulting in intracellular accumulation of unmetabolized substrates. [NIH]

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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] Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (magnetic resonance imaging). [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malaise: A vague feeling of bodily discomfort. [EU] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Malondialdehyde: The dialdehyde of malonic acid. [NIH] Mammary: Pertaining to the mamma, or breast. [EU] Manic: Affected with mania. [EU] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mastitis: Inflammatory disease of the breast, or mammary gland. [NIH] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [NIH]

Meconium: The thick green-to-black mucilaginous material found in the intestines of a fullterm fetus. It consists of secretions of the intestinal glands, bile pigments, fatty acids, amniotic fluid, and intrauterine debris. It constitutes the first stools passed by a newborn. [NIH]

Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH]

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MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] 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] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mephenytoin: An anticonvulsant effective in tonic-clonic epilepsy. It may cause blood dyscrasias. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [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] 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] Metabolization: The chemical process by which matter is broken down into simpler substances, said especially of food processed by the human body. [EU] Metallothionein: A low-molecular-weight (approx. 10 kD) protein occurring in the cytoplasm of kidney cortex and liver. It is rich in cysteinyl residues and contains no aromatic amino acids. Metallothionein shows high affinity for bivalent heavy metals. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the

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body to another. [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] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microsomal: Of or pertaining to microsomes : vesicular fragments of endoplasmic reticulum formed after disruption and centrifugation of cells. [EU] Microwaves: That portion of the electromagnetic spectrum lying between UHF (ultrahigh frequency) radio waves and heat (infrared) waves. Microwaves are used to generate heat, especially in some types of diathermy. They may cause heat damage to tissues. [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] Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller than a quart and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same. [NIH] Mineralocorticoid: 1. Any of the group of C21 corticosteroids, principally aldosterone,

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predominantly involved in the regulation of electrolyte and water balance through their effect on ion transport in epithelial cells of the renal tubules, resulting in retention of sodium and loss of potassium; some also possess varying degrees of glucocorticoid activity. Their secretion is regulated principally by plasma volume, serum potassium concentration and angiotensin II, and to a lesser extent by anterior pituitary ACTH. 2. Of, pertaining to, having the properties of, or resembling a mineralocorticoid. [EU] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] 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] 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] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocyte: A type of white blood cell. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monotherapy: A therapy which uses only one drug. [EU] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic.

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Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Mucilaginous: Pertaining to or secreting mucus. [NIH] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU] Mucopolysaccharidoses: Group of lysosomal storage diseases each caused by an inherited deficiency of an enzyme involved in the degradation of glycosaminoglycans (mucopolysaccharides). The diseases are progressive and often display a wide spectrum of clinical severity within one enzyme deficiency. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]

Multiple Organ Failure: A progressive condition usually characterized by combined failure of several organs such as the lungs, liver, kidney, along with some clotting mechanisms, usually postinjury or postoperative. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mushroom Poisoning: Poisoning from ingestion of mushrooms, primarily from, but not restricted to, toxic varieties. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mycotoxins: Toxins derived from bacteria or fungi. [NIH] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU]

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Myelin: The fatty substance that covers and protects nerves. [NIH] Myelodysplastic syndrome: Disease in which the bone marrow does not function normally. Also called preleukemia or smoldering leukemia. [NIH] Myeloid Cells: Cells which include the monocytes and the granulocytes. [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] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]

Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [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] 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] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH]

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Neonatal: Pertaining to the first four weeks after birth. [EU] Neonatal Hepatitis: Irritation of the liver with no known cause. Occurs in newborn babies. Symptoms include jaundice and liver cell changes. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] Nephropathy: Disease of the kidneys. [EU] Nephrosis: Descriptive histopathologic term for renal disease without an inflammatory component. [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] 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] 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] 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] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nidation: Implantation of the conceptus in the endometrium. [EU] 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 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

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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] Nitrogen Dioxide: Nitrogen oxide (NO2). A highly poisonous gas. Exposure produces inflammation of lungs that may only cause slight pain or pass unnoticed, but resulting edema several days later may cause death. (From Merck, 11th ed) It is a major atmospheric pollutant that is able to absorb UV light that does not reach the earth's surface. [NIH] Nonmalignant: Not cancerous. [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] Nucleolus: A small dense body (sub organelle) within the nucleus of eukaryotic cells, visible by phase contrast and interference microscopy in live cells throughout interphase. Contains RNA and protein and is the site of synthesis of ribosomal RNA. [NIH] Nucleoprotein: Chromosomes consist largely of nuclei acids and proteins, joined here as complexes called nucleoproteins. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] 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] Octreotide: A potent, long-acting somatostatin octapeptide analog which has a wide range of physiological actions. It inhibits growth hormone secretion, is effective in the treatment of hormone-secreting tumors from various organs, and has beneficial effects in the

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management of many pathological states including diabetes mellitus, orthostatic hypertension, hyperinsulinism, hypergastrinemia, and small bowel fistula. [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] 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] Opacity: Degree of density (area most dense taken for reading). [NIH] Opium: The air-dried exudate from the unripe seed capsule of the opium poppy, Papaver somniferum, or its variant, P. album. It contains a number of alkaloids, but only a few morphine, codeine, and papaverine - have clinical significance. Opium has been used as an analgesic, antitussive, antidiarrheal, and antispasmodic. [NIH] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] 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] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Orthostatic: Pertaining to or caused by standing erect. [EU] 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: Degeneration of articular cartilage. Primary osteoarthritis is very common in older persons, especially affecting weight-bearing joints. Articular cartilage becomes soft, frayed and thinned. [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] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH]

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Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxaliplatin: An anticancer drug that belongs to the family of drugs called platinum compounds. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]

Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative 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] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancreatic Ducts: Ducts that collect pancreatic juice from the pancreas and supply it to the duodenum. [NIH] Pancreatic Hormones: Peptide hormones secreted into the blood by cells in the Islets of Langerhans of the pancreas. The alpha cells secrete glucagon; the beta cells secrete insulin; the delta cells secrete somatostatin; and the PP cells secrete pancreatic polypeptide. [NIH] Pancreatic Insufficiency: Absence of or reduced pancreatic exocrine secretion into the duodenum and resultant poor digestion of lipids, vitamins, nitrogen, and carbohydrates. [NIH]

Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH]

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Pancreatic Polypeptide: A 36-amino acid polypeptide with physiological regulatory functions. It is secreted by pancreatic tissue. Plasma pancreatic polypeptide increases after ingestion of food, with age, and in disease states. A lack of pancreatic polypeptide in the islets of Langerhans has been associated with the obese syndrome in rats and mice. [NIH] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease; less commonly it may be associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] 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] 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] Parenteral Nutrition: The administering of nutrients for assimilation and utilization by a patient who cannot maintain adequate nutrition by enteral feeding alone. Nutrients are administered by a route other than the alimentary canal (e.g., intravenously, subcutaneously). [NIH] 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] 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] Parturition: The act or process of given birth to a child. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (=

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branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Patient Satisfaction: The degree to which the individual regards the health care service or product or the manner in which it is delivered by the provider as useful, effective, or beneficial. [NIH] Pedigree: A record of one's ancestors, offspring, siblings, and their offspring that may be used to determine the pattern of certain genes or disease inheritance within a family. [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] Pemphigus: Group of chronic blistering diseases characterized histologically by acantholysis and blister formation within the epidermis. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Pepsin A: Formed from pig pepsinogen by cleavage of one peptide bond. The enzyme is a single polypeptide chain and is inhibited by methyl 2-diaazoacetamidohexanoate. It cleaves peptides preferentially at the carbonyl linkages of phenylalanine or leucine and acts as the principal digestive enzyme of gastric juice. [NIH] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU] Peptic Ulcer: Ulcer that occurs in those portions of the alimentary tract which come into contact with gastric juice containing pepsin and acid. It occurs when the amount of acid and pepsin is sufficient to overcome the gastric mucosal barrier. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide Chain Elongation: The process whereby an amino acid is joined through a substituted amide linkage to a chain of peptides. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] 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

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defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Perineal: Pertaining to the perineum. [EU] Perineum: The area between the anus and the sex organs. [NIH] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Peripheral blood: Blood circulating throughout the body. [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 Neuropathy: Nerve damage, usually affecting the feet and legs; causing pain, numbness, or a tingling feeling. Also called "somatic neuropathy" or "distal sensory polyneuropathy." [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] 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] 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] Peroxisomal Disorders: A heterogeneous group of inherited metabolic disorders marked by absent or dysfunctional peroxisomes. Peroxisomal enzymatic abnormalities may be single or multiple. Biosynthetic peroxisomal pathways are compromised, including the ability to synthesize ether lipids and to oxidize long-chain fatty acid precursors. Diseases in this category include Zellweger syndrome; infantile Refsum disease; rhizomelic chondrodysplasia (chondrodysplasia punctata, rhizomelic); hyperpipecolic acidemia; neonatal adrenoleukodystrophy; and adrenoleukodystrophy (X-linked). Neurologic dysfunction is a prominent feature of most peroxisomal disorders. [NIH] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH]

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Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Phalloidine: Very toxic polypeptide isolated mainly from Amanita phalloides (Agaricaceae) or death cup; causes fatal liver, kidney, and CNS damage in mushroom poisoning; used in the study of liver damage. [NIH] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] 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] Phenylephrine: An alpha-adrenergic agonist used as a mydriatic, nasal decongestant, and cardiotonic agent. [NIH] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] 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] Photosensitivity: An abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280400 mm. There are two main types : photoallergy and photoxicity. [EU] 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]

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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 Diseases: Diseases of plants. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] 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] Plasma Volume: Volume of plasma in the circulation. It is usually measured by indicator dilution techniques. [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 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]

Platinum Compounds: Inorganic compounds which contain platinum as the central atom. [NIH]

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Platyhelminths: A phylum of acoelomate, bilaterally symmetrical flatworms, without a definite anus. It includes three classes: Cestoda, Turbellaria, and Trematoda. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polyarteritis Nodosa: A form of necrotizing vasculitis involving small- and medium-sized arteries. The signs and symptoms result from infarction and scarring of the affected organ system. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polyp: A growth that protrudes from a mucous membrane. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] 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]

Porphyria Cutanea Tarda: A form of hepatic porphyria (porphyria, hepatic) characterized by photosensitivity resulting in bullae that rupture easily to form shallow ulcers. This condition occurs in two forms: a sporadic, nonfamilial form that begins in middle age and has normal amounts of uroporphyrinogen decarboxylase with diminished activity in the liver; and a familial form in which there is an autosomal dominant inherited deficiency of uroporphyrinogen decarboxylase in the liver and red blood cells. [NIH] Porphyria, Hepatic: Porphyria in which the liver is the site where excess formation of

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porphyrin or its precursors is found. Acute intermittent porphyria and porphyria cutanea tarda are types of hepatic porphyria. [NIH] Porphyrins: A group of compounds containing the porphin structure, four pyrrole rings connected by methine bridges in a cyclic configuration to which a variety of side chains are attached. The nature of the side chain is indicated by a prefix, as uroporphyrin, hematoporphyrin, etc. The porphyrins, in combination with iron, form the heme component in biologically significant compounds such as hemoglobin and myoglobin. [NIH] Portal 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] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Postoperative Period: The period following a surgical operation. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] 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] Preceptorship: Practical experience in medical and health-related services that occurs as part of an educational program wherein the professionally-trained student works outside the academic environment under the supervision of an established professional in the particular field. [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] 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

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symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Preleukemia: Conditions in which the abnormalities in the peripheral blood or bone marrow represent the early manifestations of acute leukemia, but in which the changes are not of sufficient magnitude or specificity to permit a diagnosis of acute leukemia by the usual clinical criteria. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Priapism: Persistent abnormal erection of the penis, usually without sexual desire, and accompanied by pain and tenderness. It is seen in diseases and injuries of the spinal cord, and may be caused by vesical calculus and certain injuries to the penis. [EU] Primary Biliary Cirrhosis: A chronic liver disease. Slowly destroys the bile ducts in the liver. This prevents release of bile. Long-term irritation of the liver may cause scarring and cirrhosis in later stages of the disease. [NIH] Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Procollagen: A biosynthetic precursor of collagen containing additional amino acid sequences at the amino-terminal ends of the three polypeptide chains. Protocollagen, a precursor of procollagen consists of procollagen peptide chains in which proline and lysine have not yet been hydroxylated. [NIH] Progeny: The offspring produced in any generation. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Progressive disease: Cancer that is increasing in scope or severity. [NIH] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should

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fertilization occur. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Prospective 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] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] 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]

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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] 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] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Pruritus: An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. [NIH] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] 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

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and animals. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary 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] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] 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] 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] Radio Waves: That portion of the electromagnetic spectrum beyond the microwaves, with wavelengths as high as 30 KM. They are used in communications, including television. Short Wave or HF (high frequency), UHF (ultrahigh frequency) and VHF (very high frequency) waves are used in citizen's band communication. [NIH] Radioactive: Giving off radiation. [NIH]

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Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] 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] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Reconstitution: 1. A type of regeneration in which a new organ forms by the rearrangement of tissues rather than from new formation at an injured surface. 2. The restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] 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

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erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] 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] 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 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] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] 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] Research Support: Financial support of research activities. [NIH] Resected: Surgical removal of part of an organ. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Resolving: The ability of the eye or of a lens to make small objects that are close together, separately visible; thus revealing the structure of an object. [NIH]

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Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] 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] Resuscitation: The restoration to life or consciousness of one apparently dead; it includes such measures as artificial respiration and cardiac massage. [EU] 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] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retrograde: 1. Moving backward or against the usual direction of flow. 2. Degenerating, deteriorating, or catabolic. [EU] Retrospective: Looking back at events that have already taken place. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [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] 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]

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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] 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] 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] 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] Ristocetin: An antibiotic mixture of two components, A and B, obtained from Nocardia lurida (or the same substance produced by any other means). It is no longer used clinically because of its toxicity. It causes platelet agglutination and blood coagulation and is used to assay those functions in vitro. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rubber: A high-molecular-weight polymeric elastomer derived from the milk juice (latex) of Hevea brasiliensis and other trees. It is a substance that can be stretched at room temperature to atleast twice its original length and after releasing the stress, retractrapidly, and recover its original dimensions fully. Synthetic rubber is made from many different chemicals, including styrene, acrylonitrile, ethylene, propylene, and isoprene. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Satellite: Applied to a vein which closely accompanies an artery for some distance; in cytogenetics, a chromosomal agent separated by a secondary constriction from the main body of the chromosome. [NIH] Saturated fat: A type of fat found in greatest amounts in foods from animals, such as fatty cuts of meat, poultry with the skin, whole-milk dairy products, lard, and in some vegetable oils, including coconut, palm kernel, and palm oils. Saturated fat raises blood cholesterol more than anything else eaten. On a Step I Diet, no more than 8 to 10 percent of total calories should come from saturated fat, and in the Step II Diet, less than 7 percent of the day's total calories should come from saturated fat. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or

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computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Schematic: Representative or schematic eye computed from the average of a large number of human eye measurements by Allvar Gullstrand. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Seafood: Marine fish and shellfish used as food or suitable for food. (Webster, 3d ed) shellfish and fish products are more specific types of seafood. [NIH] Sebaceous: Gland that secretes sebum. [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] 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] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] 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] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH]

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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] 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] 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 in atrophic rhinitis of pigs. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Shunt: A surgically created diversion of fluid (e.g., blood or cerebrospinal fluid) from one area of the body to another area of the body. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter)

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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] 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] 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] 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] Smoldering leukemia: Disease in which the bone marrow does not function normally. Also called preleukemia or myelodysplastic syndrome. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

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] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatostatin: A polypeptide hormone produced in the hypothalamus, and other tissues

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and organs. It inhibits the release of human growth hormone, and also modulates important physiological functions of the kidney, pancreas, and gastrointestinal tract. Somatostatin receptors are widely expressed throughout the body. Somatostatin also acts as a neurotransmitter in the central and peripheral nervous systems. [NIH] Sorbitol: A polyhydric alcohol with about half the sweetness of sucrose. Sorbitol occurs naturally and is also produced synthetically from glucose. It was formerly used as a diuretic and may still be used as a laxative and in irrigating solutions for some surgical procedures. It is also used in many manufacturing processes, as a pharmaceutical aid, and in several research applications. [NIH] Soybean Oil: Oil from soybean or soybean plant. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] 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] Splanchnic Circulation: The circulation of blood through the vessels supplying the abdominal viscera. [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] 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] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Spores: The reproductive elements of lower organisms, such as protozoa, fungi, and cryptogamic plants. [NIH] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

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] Stem cell transplantation: A method of replacing immature blood-forming cells that were

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destroyed by cancer treatment. The stem cells are given to the person after treatment to help the bone marrow recover and continue producing healthy blood cells. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] 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] 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] 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] Stupor: Partial or nearly complete unconsciousness, manifested by the subject's responding only to vigorous stimulation. Also, in psychiatry, a disorder marked by reduced responsiveness. [EU] Styrene: A colorless, toxic liquid with a strong aromatic odor. It is used to make rubbers, polymers and copolymers, and polystyrene plastics. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subcapsular: Situated below a capsule. [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] 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.

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[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] 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] Superinfection: A frequent complication of drug therapy for microbial infection. It may result from opportunistic colonization following immunosuppression by the primary pathogen and can be influenced by the time interval between infections, microbial physiology, or host resistance. Experimental challenge and in vitro models are sometimes used in virulence and infectivity studies. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] 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] 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] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatic treatment: Therapy that eases symptoms without addressing the cause of disease. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Synovial: Of pertaining to, or secreting synovia. [EU] Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease

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marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] 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] Tendinitis: Inflammation of tendons and of tendon-muscle attachments. [EU] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] 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] Thoracic: Having to do with the chest. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [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]

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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]

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] Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thromboxanes: Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]

Thymidine Phosphorylase: The enzyme catalyzing the transfer of 2-deoxy-D-ribose from thymidine to orthophosphate, thereby liberating thymidine. EC 2.4.2.4. [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] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Thyrotoxicosis: The clinical syndrome that reflects the response of the peripheral tissues to an excess of thyroid hormone. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Ticks: Blood-sucking arachnids of the order Acarina. [NIH] Tin: A trace element that is required in bone formation. It has the atomic symbol Sn, atomic number 50, and atomic weight 118.71. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Banks: Centers for acquiring, characterizing, and storing organs or tissue for future use. [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

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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] Tonic: 1. Producing and restoring the normal tone. 2. Characterized by continuous tension. 3. A term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU] Tonicity: The normal state of muscular tension. [NIH] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Toxoplasmosis: The acquired form of infection by Toxoplasma gondii in animals and man. [NIH]

Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] 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] Transdermal: Entering through the dermis, or skin, as in administration of a drug applied to the skin in ointment or patch form. [EU] 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]

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Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] 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 protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Trees: Woody, usually tall, perennial higher plants (Angiosperms, Gymnosperms, and some Pterophyta) having usually a main stem and numerous branches. [NIH] Triad: Trivalent. [NIH] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Troglitazone: A drug used in diabetes treatment that is being studied for its effect on reducing the risk of cancer cell growth in fat tissue. [NIH] Troleandomycin: A macrolide antibiotic that is similar to erythromycin. [NIH] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] 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

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appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [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] 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] 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] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] 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]

Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Dictionary 359

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] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urokinase: A drug that dissolves blood clots or prevents them from forming. [NIH] Uroporphyrinogen Decarboxylase: One of the enzymes active in heme biosynthesis. It catalyzes the decarboxylation of uroporphyrinogen III to coproporphyrinogen III by the conversion of four acetic acid groups to four methyl groups. EC 4.1.1.37. [NIH] 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] 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] Vaccinia Virus: The type species of Orthopoxvirus, related to cowpox virus, but whose true origin is unknown. It has been used as a live vaccine against smallpox. It is also used as a vector for inserting foreign DNA into animals. Rabbitpox virus is a subspecies of vaccinia virus. [NIH] Vancomycin: Antibacterial obtained from Streptomyces orientalis. It is a glycopeptide related to ristocetin that inhibits bacterial cell wall assembly and is toxic to kidneys and the inner ear. [NIH] Varices: Stretched veins such as those that form in the esophagus from cirrhosis. [NIH] Variola: A generalized virus infection with a vesicular rash. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasoactive Intestinal Peptide: A highly basic, single-chain polypeptide isolated from the intestinal mucosa. It has a wide range of biological actions affecting the cardiovascular, gastrointestinal, and respiratory systems. It is also found in several parts of the central and peripheral nervous systems and is a neurotransmitter. [NIH] 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] Venous: Of or pertaining to the veins. [EU]

360 Liver Disease

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] Villous: Of a surface, covered with villi. [NIH] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Hepatitis: Hepatitis caused by a virus. Five different viruses (A, B, C, D, and E) most commonly cause this form of hepatitis. Other rare viruses may also cause hepatitis. [NIH] 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] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] 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] 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 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] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the

Dictionary 361

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] 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] Vulgaris: An affection of the skin, especially of the face, the back and the chest, due to chronic inflammation of the sebaceous glands and the hair follicles. [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] Weight-Bearing: The physical state of supporting an applied load. This often refers to the weight-bearing bones or joints that support the body's weight, especially those in the spine, hip, knee, and foot. [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] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] 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 autosomal recessive trait, causes xanthinuria. EC 1.1.3.22. [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] 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

362 Liver Disease

axonal degeneration resulting in peripheral neuropathy. [NIH] Zidovudine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. 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, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIVinduced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. [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]

363

INDEX 5 5-Hydroxytryptophan, 136, 271 A Abdomen, 12, 151, 175, 250, 255, 271, 283, 300, 317, 321, 331, 332, 335, 351, 352, 354, 360 Abdominal, 4, 11, 116, 133, 198, 205, 216, 271, 286, 332, 333, 335, 351, 358 Abdominal Pain, 216, 271, 335, 358 Aberrant, 190, 271, 293 Abscess, 271, 348 Acantholysis, 271, 334 Acatalasia, 271, 285 Acceptor, 271, 320, 332, 356, 357 Acetaldehyde, 156, 229, 271 Acetaminophen, 28, 205, 216, 271 Acetylcholine, 271, 287, 330 Acetylcysteine, 9, 271 Acetylgalactosamine, 157, 271, 308 Acidemia, 271, 335 Acidosis, 106, 271 Acrylonitrile, 271, 347 Actin, 45, 59, 272 Acute lymphoblastic leukemia, 112, 272 Acute lymphocytic leukemia, 272 Adaptability, 272, 286 Adduct, 156, 272 Adenine, 272, 343 Adenocarcinoma, 272, 310 Adenosine, 14, 272, 284, 313, 336 Adenovirus, 33, 272 Adipose Tissue, 56, 272 Adjustment, 185, 272 Adolescence, 185, 272 Adoptive Transfer, 36, 183, 272 Adrenal Cortex, 272, 273, 292, 340 Adrenal Glands, 272, 275 Adrenergic, 272, 336 Adrenoleukodystrophy, 272, 335 Adverse Effect, 10, 129, 206, 259, 272, 297, 349 Aerobic, 272, 326 Aerosol, 272, 280 Affinity, 64, 157, 165, 167, 195, 197, 272, 273, 320, 324, 350 Aflatoxins, 31, 273 Age of Onset, 273, 358 Agonist, 273, 336

Airway, 198, 273 Alanine, 56, 101, 119, 136, 253, 273 Alanine Transaminase, 56, 273 Albumin, 214, 215, 253, 273, 337 Alcohol Drinking, 118, 273 Aldehydes, 273, 361 Aldose Reductase Inhibitor, 178, 273 Aldosterone, 204, 273, 325 Alertness, 273, 284 Algorithms, 74, 274, 282 Alimentary, 81, 113, 114, 117, 274, 333, 334 Alkaline, 57, 214, 215, 253, 271, 274, 275, 280, 284 Alkaline Phosphatase, 57, 214, 215, 253, 274 Alkaloid, 274, 289, 326 Alkylating Agents, 200, 274 Alleles, 60, 88, 274, 311 Allergen, 274, 348 Allergic Rhinitis, 198, 274, 283 Allograft, 43, 145, 274 Allopurinol, 201, 274 Alopecia, 274, 293 Alpha Cell, 274, 332 Alpha Particles, 274, 343 Alpha-1, 87, 216, 221, 274 Alpha-Linolenic Acid, 159, 274 Alternative medicine, 226, 274 Alveolitis, 162, 274 Ameliorated, 64, 274 Ameliorating, 33, 162, 164, 197, 274 Amine, 274, 311 Amino Acid Sequence, 163, 166, 275, 277, 306, 340 Amino-terminal, 275, 340 Ammonia, 275, 358 Amnestic, 275, 325 Amniotic Fluid, 275, 323 Amplification, 62, 86, 115, 275 Ampulla, 275, 287, 299 Amputation, 185, 275 Amyloid, 181, 275 Amyloidosis, 217, 275 Anaesthesia, 116, 275, 315 Anaesthetic, 116, 275 Anal, 192, 275, 300, 303, 321 Analgesic, 271, 275, 304, 326, 331 Analog, 275, 319, 330

364 Liver Disease

Analogous, 275, 356 Analytes, 250, 253, 275 Anaphylactic, 175, 276 Anaphylatoxins, 276, 290 Anaphylaxis, 276 Anatomical, 276, 279, 296, 315, 333, 348 Androgenic, 78, 276 Anemia, 212, 245, 276, 289, 304, 362 Anesthesia, 79, 206, 207, 212, 273, 276, 325 Anesthetics, 215, 276 Aneurysm, 276, 359 Angina, 177, 276 Angina Pectoris, 177, 276 Anginal, 276, 329 Angiogenesis, 162, 187, 276 Angiotensinogen, 276, 345 Animal model, 18, 19, 21, 42, 43, 46, 49, 59, 61, 65, 67, 71, 183, 276 Anions, 57, 273, 276, 318, 349, 353 Annealing, 276, 338 Anode, 276 Anorexia, 10, 276, 358 Antagonism, 277, 284 Antibacterial, 277, 351, 359 Antibiotic, 177, 178, 253, 277, 280, 288, 301, 347, 351, 354, 357 Anticoagulant, 167, 277, 342, 361 Anticonvulsant, 277, 324 Antidepressant, 271, 277 Antiepileptic, 271, 277 Antigen-Antibody Complex, 277, 290 Anti-infective, 277, 312, 318 Anti-inflammatory, 183, 198, 217, 271, 277, 280, 292, 304, 306, 315, 333, 340 Antimetabolite, 277, 347 Antineoplastic, 274, 277, 292, 293 Antineoplastic Agents, 274, 277, 293 Antioxidant, 10, 52, 81, 182, 277, 332, 350 Antipyretic, 271, 277, 304 Antiviral, 9, 16, 20, 62, 74, 149, 161, 200, 271, 277, 317, 347 Anus, 275, 278, 283, 335, 338, 344 Anxiolytic, 278, 325 Aorta, 278, 286, 360 Aplastic anemia, 164, 165, 168, 169, 278 Apolipoproteins, 278, 305, 321 Apoptosis, 42, 58, 71, 81, 83, 165, 168, 169, 170, 278, 285 Aquaporins, 120, 278 Aqueous, 157, 278, 280, 294, 299, 312, 320 Arachidonic Acid, 159, 160, 198, 204, 278, 320, 341

Arginine, 136, 201, 204, 276, 278, 329, 357 Aromatic, 278, 288, 324, 352 Arrhythmia, 193, 278, 360 Arterial, 117, 177, 204, 278, 286, 287, 311, 313, 342, 354 Arteries, 151, 175, 201, 214, 278, 282, 286, 292, 321, 325, 328, 338, 355 Arteriolar, 278, 283, 302 Arterioles, 278, 282, 325, 328 Arteriolosclerosis, 278 Arteriosclerosis, 184, 278 Arteriovenous, 278, 325 Articular, 278, 331 Ascites, 66, 113, 174, 203, 205, 207, 214, 215, 256, 279 Ascitic Fluid, 204, 279 Aspartate, 11, 119, 279 Assay, 37, 57, 61, 65, 97, 165, 167, 168, 169, 174, 186, 279, 314, 347 Asymptomatic, 35, 227, 253, 271, 279, 310, 333 Ataxia, 245, 279, 354 Atrial, 204, 279, 361 Atrial Fibrillation, 279, 361 Atrium, 279, 360 Atrophy, 245, 271, 279 Attenuated, 23, 43, 279, 296 Attenuation, 23, 113, 279 Atypical, 41, 195, 279 Autacoids, 279, 315 Autoantibodies, 4, 50, 88, 195, 279 Autoantigens, 86, 279 Autodigestion, 279, 333 Autoimmune disease, 50, 173, 204, 279, 327 Autoimmune Hepatitis, 6, 77, 173, 195, 200, 204, 205, 216, 218, 279, 310 Autoimmunity, 50, 102, 107, 109, 164, 165, 190, 204, 279 Autologous, 79, 146, 279 Autonomic, 271, 279, 335, 353 Autonomic Nervous System, 279, 335, 353 Autopsy, 120, 280 Azithromycin, 177, 178, 280 B Bactericidal, 195, 280, 301 Bacteriophage, 280, 356 Bacteriostatic, 280, 301 Bacterium, 280, 291 Barium, 168, 280 Basal Ganglia, 279, 280 Basal Ganglia Diseases, 279, 280

Index 365

Base, 21, 28, 29, 63, 89, 187, 272, 280, 295, 306, 319, 358 Basement Membrane, 26, 280, 302, 319 Basophils, 280, 308, 320 Beclomethasone, 200, 280 Benign, 12, 35, 133, 255, 278, 280, 309, 329, 344 Bereavement, 219, 280 Beta-pleated, 275, 281 Beta-Thromboglobulin, 281, 317 Bewilderment, 281, 291 Bile Acids, 23, 57, 58, 72, 101, 166, 173, 174, 181, 184, 192, 207, 281, 305, 352, 354 Bile Acids and Salts, 192, 281 Bile Ducts, 17, 72, 205, 281, 305, 340 Bile Pigments, 281, 319, 323 Biliary Atresia, 8, 107, 152, 260, 281 Biliary Tract, 8, 49, 205, 281, 333 Bilirubin, 3, 72, 176, 212, 213, 214, 215, 228, 253, 273, 281, 305, 307, 313 Binding Sites, 168, 281 Bioavailability, 10, 147, 148, 159, 281 Biochemical reactions, 156, 281 Biological response modifier, 281, 317 Biological therapy, 281, 308 Biological Transport, 281, 295 Biomarkers, 29, 281 Biopsy, 4, 8, 11, 12, 13, 20, 22, 24, 28, 43, 46, 59, 60, 64, 66, 68, 79, 87, 222, 227, 228, 241, 250, 255, 282 Biopsy specimen, 59, 282 Biosynthesis, 14, 184, 278, 282, 294, 349, 359 Biotechnology, 75, 76, 161, 212, 226, 239, 244, 245, 246, 282 Bivalent, 282, 324 Bladder, 282, 327, 341, 358, 359 Blastocyst, 282, 291, 298 Blister, 282, 334 Blood Coagulation, 79, 111, 167, 191, 282, 284, 302, 317, 347, 355 Blood Coagulation Factors, 282 Blood Coagulation Tests, 282, 317 Blood Glucose, 12, 185, 240, 282, 309, 316 Blood Platelets, 282, 337, 349, 355 Blood pressure, 151, 197, 201, 256, 282, 285, 302, 313, 326, 329, 350 Blood transfusion, 171, 282 Blot, 64, 282, 314 Blotting, Western, 282, 314 Body Fluids, 281, 282, 284, 297, 350, 358 Body Mass Index, 61, 282, 332

Bone Density, 152, 153, 282 Bone Marrow, 32, 53, 272, 278, 283, 301, 308, 314, 322, 328, 340, 350, 352, 362 Bone Marrow Cells, 283, 308 Bone Marrow Transplantation, 33, 283 Bone Remodeling, 81, 283 Bone Resorption, 283, 304 Bone scan, 283, 347 Bowel, 134, 195, 275, 283, 295, 316, 317, 319, 331, 335, 358 Bowel Movement, 283, 295 Brachytherapy, 283, 317, 318, 343 Bradykinin, 283, 330, 337 Branch, 27, 209, 229, 240, 267, 283, 309, 310, 314, 322, 334, 343, 351, 354 Breakdown, 161, 283, 295, 305 Bronchi, 283, 356 Bronchial, 198, 283, 311 Budesonide, 157, 283 Bullous, 216, 283 Bupivacaine, 88, 283 Burns, 201, 283 Burns, Electric, 283 Bursitis, 198, 284 Bypass, 217, 284, 328 C Cachexia, 184, 284 Caffeine, 28, 284, 343 Calcification, 278, 284 Calcium, 23, 33, 167, 177, 193, 240, 283, 284, 290, 302, 313, 328, 329, 342, 350, 360 Calcium blocker, 177, 284 Calcium channel blocker, 284, 360 Callus, 284, 298 Caloric intake, 255, 284 Cannula, 284, 333 Capsid, 164, 284, 330, 360 Capsules, 201, 284, 305 Carbimazole, 172, 284 Carbohydrate, 49, 89, 119, 167, 176, 217, 284, 292, 307, 338 Carbon Dioxide, 284, 294, 303, 305, 346 Carcinogen, 272, 285 Carcinogenesis, 47, 95, 180, 198, 285 Carcinogenic, 274, 285, 316, 341, 352 Cardiac, 57, 193, 253, 279, 284, 285, 295, 305, 308, 325, 328, 346, 352 Cardiomyopathy, 181, 285 Cardiorespiratory, 285, 325 Cardiotonic, 285, 336 Cardiovascular, 54, 164, 165, 168, 169, 179, 207, 285, 320, 349, 359

366 Liver Disease

Cardiovascular disease, 164, 165, 168, 169, 179, 285 Carrier Proteins, 191, 285, 337 Case report, 77, 94, 104, 222, 285, 288 Case series, 44, 285, 288 Case-Control Studies, 63, 285, 300 Caspase, 42, 285 Catabolism, 159, 285 Catalase, 196, 271, 285 Catalyse, 285, 356 Cations, 285, 318 Causal, 45, 285, 300, 310, 349 Causality, 44, 285 Cause of Death, 14, 17, 23, 61, 146, 174, 286 Celiac Artery, 286, 310 Celiac Disease, 87, 114, 219, 226, 286 Cell Count, 22, 286 Cell Death, 20, 53, 58, 92, 156, 165, 168, 169, 170, 190, 278, 286, 328 Cell Differentiation, 286, 350 Cell Division, 245, 280, 286, 308, 326, 337 Cell membrane, 158, 281, 285, 286, 295, 318, 336 Cell motility, 286, 311 Cell proliferation, 70, 165, 191, 278, 286, 350 Cell Respiration, 286, 326, 346 Cell Size, 286, 304 Cell Survival, 52, 286, 308 Cell Transplantation, 47, 48, 149, 286 Cellular Structures, 286, 326 Centrifugation, 286, 325 Cerebellar, 164, 165, 279, 286, 345 Cerebellum, 286, 345 Cerebral, 201, 279, 280, 286, 287, 301 Cerebral Arteries, 201, 286 Cerebrospinal, 287, 349 Cerebrospinal fluid, 287, 349 Cerebrovascular, 280, 285, 287, 354 Cerebrum, 286, 287, 358 Character, 276, 287, 288, 295, 307 Chemokines, 40, 62, 69, 71, 83, 101, 287 Chemotactic Factors, 287, 290 Chenodeoxycholic Acid, 174, 184, 287, 359 Chimeras, 19, 287 Chiropractic, 5, 287 Chlorophyll, 287, 299, 304 Cholangitis, 4, 54, 157, 181, 184, 195, 200, 204, 205, 216, 218, 251, 287 Cholecystectomy, 222, 287 Cholecystitis, 205, 287

Cholelithiasis, 180, 205, 287 Cholera, 287, 349 Choleretic, 184, 287, 295, 307, 321, 359 Cholestasis, 8, 23, 57, 58, 64, 69, 130, 146, 147, 152, 181, 182, 184, 215, 216, 256, 257, 287 Cholesterol, 17, 33, 127, 134, 144, 166, 174, 180, 190, 191, 228, 281, 287, 288, 292, 305, 313, 321, 347, 352 Cholesterol Esters, 17, 190, 287, 321 Cholic Acid, 174, 287 Choline, 125, 147, 287 Chondrodysplasia Punctata, 288, 335 Choroid, 288, 346 Chromatin, 278, 288 Chromium, 212, 288 Chromosomal, 275, 288, 346, 347 Chromosome, 34, 272, 288, 291, 311, 320, 347 Chronic Disease, 47, 240, 255, 284, 288, 289 Chronic renal, 162, 288, 338, 358 Chylomicrons, 288, 321 Chymotrypsin, 170, 288 CIS, 57, 288, 346 Clamp, 66, 288 Clarithromycin, 177, 178, 288 Cleave, 170, 288 Clinical Medicine, 23, 186, 288, 339 Clinical study, 288, 292 Clinical trial, 13, 14, 42, 54, 60, 61, 72, 145, 153, 181, 239, 241, 288, 292, 296, 327, 342, 344 Clone, 19, 289 Clonic, 289, 324 Cloning, 25, 34, 162, 164, 179, 282, 289, 293 Coagulation, 81, 124, 167, 213, 282, 289, 310, 337, 355, 361 Cobalt, 124, 289 Coccidioidomycosis, 101, 289 Coenzyme, 174, 289 Cofactor, 19, 289, 342, 355 Cohort Studies, 289, 300 Colchicine, 289, 358 Colitis, 54, 135, 195, 289 Collagen, 14, 16, 18, 45, 59, 181, 200, 280, 289, 303, 305, 337, 340, 341 Collagen disease, 181, 289 Collapse, 276, 283, 289 Colloidal, 273, 290, 298, 349 Colorectal, 255, 290 Combination Therapy, 4, 9, 74, 192, 290 Common Bile Duct, 23, 290, 294

Index 367

Comorbidity, 10, 22, 30, 290 Complement, 5, 25, 42, 72, 185, 196, 276, 290, 306, 337, 348 Complementary and alternative medicine, 118, 129, 130, 132, 141, 216, 290 Complementary medicine, 63, 130, 290 Complete remission, 290, 345 Computational Biology, 25, 239, 244, 290 Computed tomography, 283, 291, 347 Computer Simulation, 22, 30, 291 Computerized axial tomography, 291, 348 Computerized tomography, 11, 152, 291 Conception, 215, 291, 302, 352 Confounding, 56, 76, 291 Confusion, 65, 214, 215, 241, 255, 291, 296, 358 Conjugated, 174, 281, 287, 291, 294, 295, 321 Conjugation, 176, 291, 307 Conjunctiva, 291 Conjunctivitis, 198, 291 Connective Tissue, 14, 79, 181, 283, 289, 291, 303, 305, 322, 324, 346, 353 Connective Tissue Cells, 291 Consciousness, 275, 291, 296, 310, 346 Constipation, 291, 335 Constriction, 292, 318, 347 Consultation, 21, 292 Contamination, 292, 310, 311 Continuum, 23, 28, 292 Contraindications, ii, 257, 292 Control group, 37, 59, 66, 292, 340 Controlled clinical trial, 74, 292 Coordination, 286, 292, 327 Coronary, 177, 185, 276, 285, 292, 313, 325, 328 Coronary Arteriosclerosis, 292, 328 Coronary Circulation, 276, 292 Coronary heart disease, 285, 292 Coronary Thrombosis, 292, 325, 328 Cortex, 279, 286, 292, 301, 345 Cortical, 292, 301, 348, 354 Corticosteroid, 292, 340 Cortisol, 197, 273, 292 Cortisone, 197, 293, 340 Cosmids, 24, 293 Coumarins, 293, 342 Cowpox, 293, 359 Cowpox Virus, 293, 359 Cranial, 286, 293, 309, 329, 331, 335 Creatine, 57, 293

Creatine Kinase, 57, 293 Creatinine, 3, 293, 358 Cross-Sectional Studies, 293, 300 Cryoglobulinemia, 102, 215, 293 Cryptosporidiosis, 280, 293 Cues, 53, 293 Cultured cells, 293 Curative, 53, 293, 329, 354 Cutaneous, 216, 293, 313, 322, 336, 359 Cyclic, 134, 284, 293, 308, 330, 339, 341 Cyclophosphamide, 200, 293 Cyst, 34, 294 Cystathionine beta-Synthase, 294, 313 Cysteine, 169, 170, 271, 287, 294, 353 Cystic Duct, 290, 294 Cystine, 294 Cytochrome, 32, 58, 60, 66, 83, 85, 95, 96, 294 Cytokine, 20, 37, 39, 40, 44, 46, 48, 51, 59, 69, 71, 124, 161, 294, 317 Cytomegalovirus, 54, 76, 294 Cytoplasm, 195, 278, 280, 286, 294, 297, 300, 308, 324, 347 Cytotoxic, 43, 51, 72, 86, 124, 145, 163, 187, 294, 344, 350 D Dairy Products, 294, 347 Data Collection, 15, 130, 294 Databases, Bibliographic, 239, 294 Deamination, 188, 294, 358 Decarboxylation, 294, 311, 343, 359 Decompensation, 7, 28, 29, 86, 99, 172, 295 Decongestant, 295, 336 Degenerative, 158, 165, 168, 169, 181, 193, 295, 310, 346 Deletion, 190, 197, 278, 295 Denaturation, 295, 338 Density, 25, 81, 82, 190, 196, 229, 282, 286, 295, 304, 321, 331 Deoxycholic Acid, 174, 193, 295 Depolarization, 295, 350 Depressive Disorder, 295, 321 Deprivation, 165, 201, 295 Dermatitis, 86, 198, 295 Detoxification, 176, 188, 295, 307 Deuterium, 295, 312 Diabetes Mellitus, 13, 125, 132, 199, 217, 229, 257, 295, 307, 310, 331 Diagnostic Imaging, 228, 295 Diagnostic procedure, 155, 227, 295 Dialyzer, 295, 309 Diastolic, 295, 313

368 Liver Disease

Dietitian, 255, 295 Diffusion, 86, 124, 281, 295, 296, 316, 318 Digestion, 171, 191, 274, 281, 283, 295, 297, 317, 321, 332, 334, 352 Digestive system, 154, 295, 305, 327 Digestive tract, 20, 295, 350 Dihydrotestosterone, 296, 345 Dihydroxy, 180, 273, 296 Dilatation, 52, 276, 296, 311, 340, 359 Dilatation, Pathologic, 296, 359 Dilation, 283, 296, 359 Dilution, 173, 296, 337 Direct, iii, 6, 7, 10, 24, 27, 46, 57, 71, 167, 173, 199, 231, 288, 296, 345 Dirofilaria, 175, 296 Dirofilaria immitis, 175, 296 Disease Progression, 6, 15, 20, 22, 24, 28, 35, 37, 38, 42, 43, 51, 65, 241, 296, 360 Disinfectant, 296, 301 Disorientation, 291, 296 Disparity, 48, 70, 161, 296 Disposition, 27, 296 Dissociation, 167, 273, 296 Dissociative Disorders, 296 Distal, 296, 305, 319, 335, 342 Diuresis, 284, 296 Domesticated, 296, 308 Dose-dependent, 216, 296, 362 Double-blinded, 68, 72, 296 Drive, ii, vi, 3, 5, 6, 7, 8, 11, 13, 16, 123, 204, 205, 215, 216, 217, 257, 297, 318 Drug Interactions, 206, 217, 234, 297 Drug Tolerance, 297, 356 Drug Toxicity, 149, 297 Duct, 5, 17, 58, 69, 72, 73, 255, 257, 275, 284, 287, 290, 297, 301, 347 Duodenum, 281, 288, 297, 299, 300, 310, 332, 348, 352 Dyes, 275, 280, 297, 304 Dyspepsia, 212, 297 Dysplasia, 96, 245, 297 Dyspnea, 295, 297, 343 Dystrophic, 218, 297 Dystrophy, 245, 297 E Ectopic, 170, 297 Edema, 162, 295, 297, 319, 322, 328, 330, 358 Effector, 51, 62, 163, 170, 271, 290, 297 Effector cell, 163, 297 Efficacy, 5, 9, 15, 19, 33, 65, 68, 89, 90, 125, 130, 132, 150, 170, 177, 194, 211, 230, 297

Egg Yolk, 196, 297 Elasticity, 278, 292, 297 Elastin, 289, 297 Elective, 115, 297 Electrocoagulation, 289, 297 Electroencephalography, 113, 297 Electrolysis, 276, 285, 298 Electrolyte, 273, 292, 298, 326, 339, 350, 358 Electrons, 277, 280, 298, 318, 323, 332, 343, 344 Electrophoresis, 195, 298 Elementary Particles, 298, 323, 329, 342 ELISA, 173, 174, 298 Emboli, 111, 298, 361 Embolism, 298, 343, 361 Embolization, 111, 298, 361 Embolus, 298, 315 Embryo, 49, 282, 286, 297, 298, 302, 315 Embryo Transfer, 49, 298 Embryogenesis, 160, 165, 168, 169, 298 Emesis, 205, 298 Emphysema, 53, 78, 222, 298 Empirical, 8, 298 Empyema, 91, 299 Emulsions, 201, 299 Encephalopathy, 13, 124, 214, 215, 255, 299 Endemic, 4, 38, 287, 299, 310, 351 Endocrine System, 299, 329 Endoscope, 299, 300 Endoscopic, 222, 250, 299, 300, 325 Endoscopy, 4, 104, 255, 299 Endothelial cell, 26, 52, 73, 165, 168, 169, 197, 299, 303, 317, 355 Endothelium, 299, 329 Endothelium-derived, 299, 329 Endotoxemia, 124, 299 Endotoxic, 299, 320 Endotoxin, 25, 71, 90, 151, 174, 299, 358 End-stage renal, 241, 288, 299, 338 Enhancer, 45, 76, 299 Enteric bacteria, 174, 299 Enterohepatic, 57, 174, 299 Enterohepatic Circulation, 174, 299 Enteropeptidase, 299, 357 Environmental Exposure, 299, 331 Environmental Health, 151, 238, 240, 299 Enzymatic, 57, 159, 213, 284, 290, 300, 311, 335, 338, 346 Enzyme Inhibitors, 300, 337 Eosinophil, 300, 308

Index 369

Epidemic, 31, 300, 351 Epidemiologic Studies, 86, 300 Epidemiological, 21, 37, 45, 213, 300 Epidermal, 199, 300, 319, 324 Epidermal Growth Factor, 199, 300 Epidermis, 271, 282, 300, 319, 334 Epidural, 15, 88, 300 Epidural block, 88, 300 Epigastric, 300, 332 Epithelial, 64, 272, 281, 300, 311, 319, 326 Epithelial Cells, 64, 300, 311, 319, 326 Epithelium, 33, 53, 64, 280, 299, 300, 305 Epitope, 85, 300 ERCP, 250, 300 Erection, 300, 340 Erythrocytes, 10, 32, 201, 276, 283, 301, 310, 345, 348 Erythromycin, 177, 178, 280, 288, 301, 357 Erythropoietin, 117, 301 Esophageal, 7, 55, 301, 305 Esophageal Varices, 7, 301 Esophagitis, 99, 301, 305 Esophagus, 94, 295, 296, 301, 305, 321, 336, 345, 352, 359 Essential Tremor, 245, 301 Estrogen, 120, 301, 340 Estrogen receptor, 120, 301 Ethanol, 10, 15, 22, 26, 32, 36, 40, 45, 52, 96, 103, 111, 124, 156, 195, 200, 217, 301 Ether, 301, 335 Eukaryotic Cells, 301, 315, 330, 331 Evoke, 301, 352 Excitation, 301, 303 Excitatory, 301, 307 Exhaustion, 11, 277, 301 Exocrine, 301, 332 Exogenous, 52, 60, 64, 188, 301, 307, 341, 358 Extensor, 301, 342 External-beam radiation, 301, 318, 343 Extracellular, 162, 194, 204, 275, 291, 302, 303, 350 Extracellular Matrix, 162, 291, 302, 303 Extracellular Space, 162, 302 Extraction, 55, 302 Extrarenal, 34, 42, 302 Eye Infections, 272, 302 F Factor V, 119, 302 Failure to Thrive, 256, 302 Familial polyposis, 180, 302 Family Planning, 239, 302

Fatigue, 12, 92, 208, 302, 309 Fatty acids, 35, 49, 159, 273, 302, 307, 320, 323, 341 Fatty Liver, Alcoholic, 229, 302, 321 Feces, 192, 291, 302 Felodipine, 177, 302 Ferritin, 11, 37, 302 Ferrochelatase, 32, 93, 302 Fetal Development, 197, 302 Fetus, 49, 301, 302, 314, 323, 340 Fibrin, 282, 303, 335, 355 Fibrinogen, 95, 303, 337, 342, 355 Fibroblast Growth Factor, 187, 199, 303 Fibroblasts, 170, 173, 187, 291, 303, 317 Filarioidea, 303, 319 Filtration, 171, 303 Fish Products, 303, 348 Fistula, 303, 331 Fixation, 303, 348 Flatus, 303, 305 Flavivirus, 19, 164, 303, 361 Flow Cytometry, 19, 303 Fluorescence, 33, 192, 195, 303, 304 Fluorescent Dyes, 303, 304 Flurbiprofen, 28, 304 Folate, 93, 103, 124, 304 Fold, 31, 35, 68, 146, 304, 324, 331 Folic Acid, 126, 232, 304 Forearm, 282, 304 Fructose, 217, 304 Fructose Intolerance, 217, 304 Fungi, 171, 195, 291, 302, 304, 325, 327, 351, 361 Fungus, 289, 304 G Galactosemia, 217, 252, 304 Gallbladder, 174, 218, 257, 271, 281, 287, 294, 295, 304, 305, 310 Gallstones, 92, 205, 208, 209, 258, 281, 287, 305, 359 Gamma irradiation, 64, 305 Gamma Rays, 305, 343, 344 Ganglia, 271, 280, 305, 329, 335, 353 Gangrenous, 305, 349 Gas, 52, 176, 178, 275, 284, 295, 303, 305, 312, 329, 330, 346, 353 Gas exchange, 52, 305, 346 Gastric, 55, 192, 217, 279, 286, 300, 305, 311, 334 Gastric Juices, 305, 334 Gastric Mucosa, 305, 334 Gastrin, 305, 312

370 Liver Disease

Gastroenterologist, 31, 148, 305 Gastroesophageal Reflux, 205, 215, 305 Gastroesophageal Reflux Disease, 205, 215, 305 Gastrointestinal tract, 20, 158, 180, 192, 206, 216, 217, 301, 305, 320, 349, 351, 358 Gelatin, 305, 307 Gemfibrozil, 9, 305 Gene, 7, 11, 20, 21, 23, 24, 26, 29, 31, 32, 33, 34, 36, 42, 47, 49, 51, 52, 53, 57, 60, 63, 69, 77, 93, 95, 103, 105, 115, 131, 143, 145, 157, 161, 164, 165, 170, 179, 187, 190, 197, 201, 212, 226, 246, 247, 272, 274, 282, 306, 317, 331, 357 Gene Expression, 20, 21, 23, 24, 26, 29, 36, 49, 52, 58, 63, 115, 187, 201, 246, 306 Genetic Code, 306, 330 Genetic Counseling, 166, 306 Genetic Engineering, 47, 282, 289, 306 Genetic testing, 11, 306, 338 Genetic Vectors, 293, 306 Genetics, 27, 45, 47, 50, 51, 89, 96, 104, 107, 146, 222, 229, 291, 306, 314, 326 Genomics, 164, 179, 306 Genotype, 7, 22, 34, 35, 37, 49, 55, 61, 67, 74, 96, 306, 336 Germ Cells, 306, 331, 350, 354 Gestation, 306, 335 Ginseng, 170, 171, 194, 306 Gland, 171, 272, 293, 306, 322, 323, 332, 337, 341, 348, 352, 355 Glomerular, 306, 345 Glomeruli, 306 Glomerulonephritis, 80, 306 Glomerulus, 306, 319, 329 Glucocorticoid, 197, 280, 283, 306, 326, 340 Gluconeogenesis, 304, 307 Glucose Intolerance, 23, 217, 295, 307 Glucose tolerance, 307 Glucose Tolerance Test, 307 Glucuronic Acid, 162, 307 Glucuronides, 307 Glutamate, 273, 307 Glutamic Acid, 137, 168, 304, 307, 341 Gluten, 87, 286, 307 Glycerol, 278, 307, 336 Glycerophospholipids, 307, 336 Glycine, 137, 174, 184, 281, 287, 295, 307, 321, 349 Glycodeoxycholic Acid, 193, 307 Glycogen, 188, 191, 217, 252, 307, 308 Glycogen Storage Disease, 217, 252, 308

Glycoprotein, 183, 301, 302, 303, 308, 319, 327, 355, 358 Glycosaminoglycans, 308, 327 Gonadal, 308, 352 Governing Board, 308, 339 Grade, 68, 175, 300, 308 Graft, 5, 43, 65, 106, 308, 312, 315, 328 Graft Rejection, 308, 315 Graft Survival, 65, 106, 308 Gram-negative, 299, 308 Granule, 308, 347 Granulocyte-Macrophage ColonyStimulating Factor, 89, 308 Granulocytes, 195, 308, 320, 328, 350, 361 Growth factors, 69, 161, 165, 187, 199, 308 Guanylate Cyclase, 78, 201, 308, 330 Guinea Pigs, 156, 308 H Habitual, 118, 287, 309 Haematemesis, 298, 309 Haematological, 102, 309 Haematology, 309 Hair follicles, 309, 361 Haptens, 273, 309 Hawthorn fruit, 170, 171, 194, 309 Headache, 284, 309 Health Education, 12, 309 Health Policy, 13, 30, 54, 309 Health Services, 29, 31, 309 Health Status, 6, 30, 309 Heart attack, 285, 309 Heart failure, 120, 205, 309, 343 Hematopoiesis, 161, 309 Hematopoietic Stem Cells, 33, 309 Heme, 60, 281, 294, 302, 309, 338, 339, 359 Hemochromatosis, 11, 31, 60, 102, 205, 216, 218, 228, 309 Hemodialysis, 113, 117, 295, 309, 319 Hemodynamics, 84, 88, 309 Hemoglobin, 276, 301, 309, 310, 339 Hemoglobinuria, 245, 310 Hemolysis, 49, 310 Hemorrhage, 73, 214, 215, 297, 309, 310, 328, 352 Hemostasis, 117, 167, 222, 310, 317, 349 Hepatic Artery, 149, 150, 310 Hepatic Encephalopathy, 82, 113, 205, 255, 257, 310 Hepatic Veins, 99, 310 Hepatitis A, 28, 31, 35, 46, 58, 98, 100, 163, 171, 178, 194, 196, 199, 200, 212, 229, 232, 241, 242, 256, 258, 310

Index 371

Hepatitis B, 9, 36, 98, 150, 171, 172, 180, 194, 214, 227, 232, 256, 310 Hepatitis D, 149, 150, 171, 194, 310 Hepatitis Delta Virus, 149, 150, 310 Hepatitis Viruses, 187, 310 Hepatitis, Chronic, 28, 310 Hepatobiliary, 8, 23, 57, 63, 69, 205, 207, 217, 310 Hepatocellular carcinoma, 6, 15, 23, 28, 31, 35, 36, 37, 38, 40, 41, 48, 51, 54, 59, 62, 70, 79, 86, 88, 96, 99, 104, 110, 112, 113, 115, 117, 160, 163, 167, 186, 187, 256, 310 Hepatocyte, 11, 20, 35, 40, 41, 51, 53, 58, 62, 66, 71, 81, 113, 161, 183, 191, 287, 311 Hepatocyte Growth Factor, 41, 113, 311 Hepatologist, 55, 311 Hepatopulmonary Syndrome, 52, 311 Hepatorenal Syndrome, 13, 80, 204, 205, 311 Hepatotoxic, 53, 63, 117, 311 Hepatotoxicity, 63, 71, 79, 215, 311 Hepatovirus, 310, 311 Hereditary, 11, 69, 102, 105, 217, 311, 335, 346 Heredity, 306, 311 Heritability, 73, 311 Hernia, 106, 311 Herpes, 99, 134, 135, 145, 311 Herpes virus, 145, 311 Herpes Zoster, 134, 135, 311 Heterogeneity, 37, 273, 311 Heterogenic, 311 Heterogenous, 195, 311 Heterotrophic, 304, 311 Heterozygote, 49, 311 Histamine, 199, 276, 311, 312 Histamine Agonists, 199, 311 Histidine, 138, 311 Histology, 8, 9, 26, 48, 52, 72, 101, 105, 113, 149, 217, 312, 333 Homeostasis, 34, 51, 101, 165, 168, 169, 170, 191, 193, 204, 283, 312 Homodimer, 312, 357 Homogeneous, 193, 195, 278, 292, 312 Homologous, 19, 169, 187, 274, 282, 311, 312, 348, 353 Homotypic, 26, 312 Hormonal, 279, 292, 312 Humoral, 86, 308, 312, 314 Humour, 312 Hybrid, 25, 156, 289, 312 Hybridization, 25, 312, 326

Hybridomas, 312, 317 Hydrogen Peroxide, 202, 285, 312, 320, 353 Hydrolysis, 312, 318, 320, 336, 338, 342, 357 Hydrophilic, 181, 312 Hydrophobic, 72, 181, 307, 312, 321 Hydroxylysine, 289, 312 Hydroxyproline, 289, 313 Hyperaemia, 291, 313 Hyperbilirubinemia, 313, 319 Hypercalcemia, 193, 313 Hypercalciuria, 193, 313 Hypercholesterolemia, 134, 166, 217, 313 Hyperemesis, 215, 313 Hyperglycemia, 217, 313 Hyperhomocysteinemia, 87, 294, 313 Hyperlipidemia, 9, 13, 16, 34, 54, 184, 228, 313 Hyperplasia, 41, 133, 313 Hypersensitivity, 57, 181, 274, 276, 300, 313, 320, 347, 348 Hypertension, Portal, 205, 313 Hypertrophy, 313 Hypesthesia, 313, 329 Hypnotic, 313, 325 Hypoglycemia, 134, 185, 217, 304, 313 Hypotension, 164, 165, 313 Hypothalamus, 280, 313, 337, 350 Hypoxanthine, 313, 361 Hypoxemia, 52, 313 Hypoxia, 202, 313, 354 I Id, 126, 132, 251, 258, 259, 266, 268, 313 Idiopathic, 44, 46, 313 Ileal, 57, 101, 166, 217, 313 Ileitis, 191, 314 Ileum, 166, 174, 313, 314 Ileus, 7, 314 Imidazole, 284, 311, 314 Immune function, 56, 147, 196, 314, 357 Immune Sera, 314 Immune Tolerance, 50, 314 Immunity, 18, 36, 43, 60, 159, 169, 201, 273, 314, 322, 357 Immunization, 163, 242, 255, 256, 272, 314, 315, 348, 349 Immunoassay, 44, 57, 167, 314 Immunoblotting, 195, 314 Immunocompetence, 160, 314 Immunodeficiency, 16, 24, 37, 39, 41, 48, 55, 60, 70, 109, 245, 314

372 Liver Disease

Immunofluorescence, 195, 314 Immunogenetics, 62, 314 Immunogenic, 156, 163, 314, 320 Immunoglobulin, 4, 277, 314, 326 Immunohistochemistry, 64, 314 Immunologic, 5, 40, 43, 50, 56, 181, 241, 272, 287, 314, 323, 344, 362 Immunology, 27, 65, 70, 85, 86, 88, 97, 102, 187, 209, 213, 273, 304, 315 Immunosuppressant, 274, 315 Immunosuppressive, 4, 18, 59, 65, 72, 160, 293, 306, 315 Immunosuppressive therapy, 4, 315 Immunotherapy, 146, 272, 281, 315 Impairment, 81, 184, 185, 201, 203, 279, 281, 287, 302, 315, 324 Implant radiation, 315, 317, 318, 343 Implantation, 291, 315, 329 In situ, 21, 25, 69, 112, 315 In Situ Hybridization, 21, 25, 69, 315 In vitro, 18, 24, 25, 26, 53, 62, 64, 70, 71, 73, 97, 156, 170, 185, 298, 315, 338, 347, 353, 355 In vivo, 19, 24, 26, 32, 33, 45, 52, 53, 60, 62, 70, 71, 73, 77, 161, 183, 185, 315, 320, 332, 355 Incision, 315, 318 Incompetence, 305, 315 Incubated, 64, 315 Incubation, 23, 40, 315 Incubation period, 40, 315 Indicative, 206, 315, 333, 359 Indolent, 66, 67, 315 Indomethacin, 26, 315 Induction, 25, 50, 120, 315, 340 Infancy, 210, 288, 315 Infantile, 315, 335 Infarction, 57, 315, 338, 345 Infiltration, 50, 156, 200, 306, 316 Inflammation, 8, 12, 15, 20, 21, 39, 51, 59, 72, 133, 164, 165, 168, 169, 171, 175, 176, 179, 190, 194, 200, 214, 215, 221, 273, 274, 277, 284, 287, 289, 291, 295, 301, 302, 303, 305, 308, 310, 311, 314, 316, 320, 328, 329, 330, 333, 335, 343, 346, 347, 354, 358, 359, 361 Inflammatory bowel disease, 183, 190, 195, 205, 215, 216, 316 Information Systems, 30, 316 Informed Consent, 148, 316 Infusion, 52, 114, 149, 150, 152, 316, 328, 357

Ingestion, 37, 129, 171, 174, 256, 304, 307, 316, 327, 333, 338 Inhalation, 116, 272, 289, 316, 338 Initiation, 38, 47, 51, 180, 316, 356 Inlay, 316, 346 Inner ear, 316, 359 Inotropic, 302, 316 Insight, 8, 10, 31, 52, 62, 69, 316 Insulator, 316, 327 Insulin, 8, 12, 34, 45, 66, 67, 92, 131, 184, 185, 198, 217, 228, 307, 316, 332, 358 Insulin-dependent diabetes mellitus, 185, 316 Insulin-like, 199, 316 Intensive Care, 205, 206, 207, 316 Interferon, 9, 15, 18, 38, 40, 42, 43, 46, 48, 61, 74, 89, 91, 117, 161, 172, 183, 232, 241, 317, 322 Interferon-alpha, 43, 46, 317 Interleukin-1, 18, 44, 96, 168, 169, 170, 183, 317 Interleukin-10, 18, 44, 317 Interleukin-15, 183, 317 Interleukin-2, 317 Interleukin-6, 28, 44, 317 Interleukin-8, 71, 317 Intermittent, 217, 317, 339 Internal Medicine, 16, 27, 34, 37, 39, 49, 51, 60, 66, 71, 74, 83, 109, 119, 173, 305, 317 Internal radiation, 317, 318, 343 International Normalized Ratio, 3, 317 Interstitial, 283, 302, 317, 318, 329, 345 Intestinal, 21, 28, 67, 174, 188, 190, 286, 287, 293, 295, 299, 307, 317, 323, 359 Intestine, 53, 166, 174, 198, 281, 283, 299, 317, 319 Intoxication, 317, 361 Intracellular, 58, 187, 194, 284, 316, 318, 322, 330, 339, 341, 349, 360 Intrahepatic, 8, 18, 19, 20, 39, 59, 62, 66, 67, 90, 99, 184, 215, 318 Intramuscular, 177, 318, 333 Intravenous, 15, 28, 58, 124, 177, 316, 318, 333 Intrinsic, 273, 278, 280, 311, 318 Invasive, 11, 41, 48, 102, 162, 175, 314, 318, 323 Involuntary, 280, 301, 318, 328 Iodine, 318, 325 Ion Channels, 193, 318 Ion Transport, 17, 57, 318, 326 Ionizing, 274, 299, 318, 344

Index 373

Ions, 167, 168, 280, 296, 298, 302, 312, 318, 342 Irradiation, 318 Ischemia, 162, 164, 165, 168, 169, 201, 279, 318, 328, 345 Isoenzyme, 57, 293, 318 Ivermectin, 175, 318 J Jaundice, 4, 174, 176, 190, 204, 205, 215, 216, 218, 228, 252, 253, 256, 311, 313, 319, 329 Joint, 82, 107, 278, 319, 353, 354 K Kb, 238, 319 Keratinocytes, 317, 319 Keto, 197, 319, 356 Kidney Cortex, 319, 324 Kidney Failure, 299, 319 Kidney stone, 319, 359 Kinetic, 38, 222, 318, 319 L Labile, 290, 302, 319 Lactation, 33, 319, 340 Laminin, 280, 319 Lamivudine, 9, 86, 89, 90, 319 Large Intestine, 295, 296, 317, 319, 344, 350 Latency, 145, 319 Latent, 145, 319, 340 Lavage, 45, 319 Laxative, 287, 319, 351 Lens, 278, 320, 345, 361 Lesion, 320, 321, 358 Lethal, 17, 41, 42, 51, 73, 280, 320 Lethargy, 175, 320 Leucocyte, 274, 300, 320, 322 Leukemia, 33, 245, 320, 340 Leukocytes, 280, 283, 287, 308, 315, 317, 320, 335, 358 Leukopenia, 320, 362 Leukotrienes, 278, 320 Library Services, 266, 320 Life cycle, 304, 320 Ligament, 320, 341 Ligands, 17, 157, 184, 210, 320 Ligation, 23, 255, 320 Linkage, 34, 116, 320, 334 Lipid A, 45, 174, 320 Lipid Peroxidation, 17, 26, 59, 66, 196, 320, 332 Lipid Peroxides, 66, 320 Lipolysis, 66, 320 Lipophilic, 158, 320

Lipopolysaccharide, 45, 71, 308, 320 Lipoprotein, 45, 80, 189, 190, 196, 308, 321, 360 Lithium, 172, 321 Lithocholic Acid, 174, 321 Liver cancer, 6, 21, 38, 39, 68, 85, 95, 171, 176, 180, 194, 196, 214, 222, 228, 256, 321 Liver Circulation, 204, 321 Liver Cirrhosis, 15, 99, 116, 135, 162, 171, 176, 194, 198, 257, 311, 321 Liver Diseases, Alcoholic, 176, 321 Liver Regeneration, 48, 191, 321 Liver scan, 321, 347 Localization, 25, 69, 112, 191, 314, 321 Localized, 69, 194, 275, 303, 316, 319, 321, 337, 358 Longitudinal study, 55, 109, 114, 321 Loop, 17, 311, 321 Low-density lipoprotein, 321 Lower Esophageal Sphincter, 305, 321 Luciferase, 57, 322 Lumen, 166, 284, 322 Lung volume, 229, 322 Lupus, 322, 354 Lutein Cells, 322, 340 Lymph, 64, 214, 215, 299, 312, 322, 352 Lymph node, 64, 322 Lymphatic, 299, 316, 322, 324, 350, 351, 355 Lymphatic system, 322, 350, 351, 355 Lymphedema, 69, 322 Lymphoblastic, 322 Lymphoblasts, 272, 322 Lymphocyte, 19, 145, 163, 277, 317, 322, 323 Lymphocytic, 49, 111, 322 Lymphoid, 277, 314, 320, 322 Lymphokines, 72, 322, 323 Lymphoma, 245, 322 Lymphoproliferative, 145, 322 Lysine, 156, 312, 322, 340, 357 Lysosomal Storage Diseases, 322, 327 Lytic, 323, 349 M Macrophage, 9, 17, 20, 70, 200, 308, 317, 323 Macrophage Activation, 20, 323 Magnetic Resonance Imaging, 11, 151, 152, 323, 348 Magnetic Resonance Spectroscopy, 68, 77, 323 Malabsorption, 135, 159, 216, 245, 286, 323

374 Liver Disease

Malaise, 12, 323 Malignancy, 31, 129, 216, 323 Malignant, 35, 95, 105, 245, 255, 272, 277, 278, 321, 323, 329, 344, 354 Malnutrition, 56, 159, 217, 273, 279, 284, 323, 327 Malondialdehyde, 156, 323 Mammary, 162, 187, 323 Manic, 321, 323 Manifest, 216, 323 Mastitis, 134, 323, 349 Meat, 323, 347 Meconium, 7, 323 Medial, 278, 323 Mediate, 65, 76, 173, 323 Mediator, 45, 70, 201, 317, 323, 337, 349 Medical Staff, 296, 323 MEDLINE, 239, 244, 245, 324 Melanocytes, 324 Melanoma, 245, 324 Memory, 276, 324 Meninges, 286, 324 Mental Disorders, 154, 324, 342 Mental Health, iv, 14, 31, 154, 238, 243, 324, 343 Mental Processes, 296, 324, 342 Mephenytoin, 28, 324 Mercury, 303, 324 Mesenchymal, 300, 308, 324 Mesenteric, 324, 339 Meta-Analysis, 96, 131, 324 Metabolic disorder, 73, 184, 229, 256, 308, 324, 335 Metabolite, 10, 181, 200, 324 Metabolization, 176, 324 Metallothionein, 98, 324 Metastasis, 324 Metastatic, 94, 105, 111, 324 Methimazole, 172, 284, 325 Methionine, 80, 93, 114, 130, 132, 259, 325, 353 MI, 104, 120, 131, 168, 169, 172, 257, 270, 325 Microbe, 325, 356 Microbiology, 105, 121, 187, 279, 325 Microcirculation, 16, 321, 325 Microgram, 198, 325 Microorganism, 289, 325, 333, 361 Microscopy, 16, 58, 66, 195, 280, 325, 330 Microsomal, 4, 10, 35, 85, 196, 325 Microwaves, 325, 343 Midazolam, 28, 325

Migration, 73, 75, 97, 161, 162, 323, 325 Milk Thistle, 129, 139, 140, 188, 259, 325, 350 Milligram, 325 Milliliter, 282, 325 Mineralocorticoid, 197, 325 Mitochondria, 58, 66, 326, 328, 331 Mitochondrial Swelling, 326, 328 Mitosis, 278, 326 Mobility, 37, 57, 326 Mobilization, 35, 326 Modeling, 24, 30, 143, 326 Modification, 8, 28, 52, 167, 191, 306, 326, 343, 361, 362 Molecular Probes, 14, 326 Monitor, 16, 77, 88, 152, 185, 228, 293, 326, 330 Monoclonal, 156, 312, 314, 318, 326, 343 Monoclonal antibodies, 314, 326 Monocyte, 71, 200, 326 Mononuclear, 18, 37, 59, 163, 326, 358 Monotherapy, 9, 74, 101, 326 Morphine, 28, 326, 328, 331 Morphological, 298, 304, 324, 327 Morphology, 21, 25, 309, 323, 327 Motility, 193, 205, 315, 327, 349 Mucilaginous, 323, 327 Mucolytic, 271, 327 Mucopolysaccharidoses, 217, 327 Mucosa, 286, 305, 322, 327, 340, 359 Mucositis, 327, 355 Mucus, 327, 358 Multicenter study, 65, 327 Multiple Organ Failure, 198, 327 Multiple sclerosis, 164, 165, 183, 327 Muscle Fibers, 327 Muscular Atrophy, 245, 327 Muscular Dystrophies, 297, 327 Mushroom Poisoning, 327, 336 Mutagenesis, 24, 327 Mutagenic, 274, 327 Mutagens, 327 Mycotoxins, 273, 327 Mydriatic, 296, 327, 336 Myelin, 327, 328 Myelodysplastic syndrome, 164, 165, 168, 169, 328, 350 Myeloid Cells, 195, 328 Myocardial infarction, 164, 165, 168, 169, 185, 281, 292, 325, 328, 361 Myocardial Ischemia, 162, 276, 328 Myocardial Reperfusion, 328, 345

Index 375

Myocardial Reperfusion Injury, 328, 345 Myocarditis, 181, 328 Myocardium, 181, 276, 325, 328 Myotonic Dystrophy, 245, 328 N Narcotic, 271, 326, 328 NCI, 1, 38, 152, 153, 237, 288, 328 Necrosis, 58, 156, 158, 278, 310, 315, 325, 328, 345 Neonatal, 50, 58, 107, 260, 329, 335 Neonatal Hepatitis, 260, 329 Neoplasia, 47, 245, 329 Neoplasm, 180, 329, 358 Neoplastic, 131, 312, 322, 329 Nephritis, 198, 329 Nephropathy, 185, 244, 319, 329 Nephrosis, 311, 329 Nerve, 272, 273, 276, 279, 287, 323, 327, 329, 331, 335, 339, 346, 348, 352, 357 Nervous System, 179, 193, 213, 245, 255, 271, 273, 279, 284, 286, 305, 307, 309, 320, 323, 327, 329, 331, 335, 349, 353 Neural, 33, 275, 312, 329 Neuritis, 214, 329 Neuroendocrine, 17, 329 Neuronal, 86, 92, 124, 194, 329 Neurons, 301, 305, 329, 353 Neuropathy, 273, 329, 335 Neutrons, 274, 318, 329, 343 Neutrophil, 75, 97, 201, 256, 329 Niacin, 126, 216, 233, 329, 357 Nidation, 298, 329 Nifedipine, 177, 329 Nitric Oxide, 52, 58, 73, 78, 90, 201, 204, 329 Nitrogen, 186, 202, 274, 293, 303, 330, 332, 357 Nitrogen Dioxide, 202, 330 Nonmalignant, 86, 330 Nuclear, 17, 184, 191, 195, 222, 223, 280, 289, 291, 298, 301, 305, 328, 330 Nuclei, 274, 291, 298, 306, 323, 326, 329, 330, 331, 342 Nucleic Acid Hybridization, 312, 330 Nucleocapsid, 50, 330 Nucleolus, 330, 347 Nucleoprotein, 50, 310, 330 Nucleus, 278, 280, 288, 293, 294, 295, 298, 301, 305, 326, 329, 330, 342, 352, 354 Nutritional Status, 9, 120, 330 O Observational study, 76, 330

Octreotide, 81, 103, 131, 330 Ointments, 331, 333 Omentum, 310, 331 Oncogene, 41, 187, 245, 311, 331 Opacity, 295, 331 Opium, 326, 331 Opportunistic Infections, 22, 41, 331 Optic Nerve, 331, 346 Organ Culture, 331, 355 Organ Transplantation, 30, 65, 106, 331 Organelles, 286, 294, 324, 331 Orthostatic, 331 Osmotic, 273, 326, 331, 349 Osteoarthritis, 130, 135, 164, 165, 183, 259, 331 Osteoporosis, 97, 110, 114, 164, 165, 168, 169, 197, 210, 215, 229, 283, 331 Outpatient, 26, 45, 146, 331 Ovary, 197, 331, 332 Overexpress, 16, 332 Overweight, 125, 228, 332 Ovum, 306, 320, 332, 340, 362 Oxaliplatin, 152, 332 Oxidants, 32, 110, 332 Oxidation, 10, 49, 66, 176, 196, 271, 277, 294, 320, 325, 332 Oxidation-Reduction, 332 Oxidative Stress, 7, 8, 13, 20, 25, 32, 49, 51, 58, 66, 113, 131, 199, 209, 228, 332 Oxygenation, 311, 313, 332 P Palliative, 332, 354 Pancreatic, 49, 135, 185, 205, 216, 240, 245, 288, 300, 305, 332, 333 Pancreatic cancer, 245, 332 Pancreatic Ducts, 300, 332 Pancreatic Hormones, 240, 332 Pancreatic Insufficiency, 135, 205, 332 Pancreatic Juice, 288, 305, 332 Pancreatic Polypeptide, 332, 333 Pancreatitis, 198, 205, 333 Paracentesis, 204, 333 Paraffin, 41, 333 Parasite, 47, 296, 318, 333 Parasitic, 172, 173, 175, 293, 333 Parenchyma, 34, 53, 333 Parenteral, 16, 18, 56, 76, 147, 217, 333 Parenteral Nutrition, 147, 217, 333 Paresis, 329, 333 Paresthesias, 329, 333 Paroxysmal, 245, 276, 333 Partial remission, 333, 345

376 Liver Disease

Particle, 190, 333, 356, 360 Parturition, 333, 340 Patch, 17, 79, 333, 356 Pathogen, 315, 333, 353 Pathologic, 4, 110, 271, 278, 282, 292, 313, 333, 334, 342, 346 Pathologic Processes, 278, 334 Pathophysiology, 17, 19, 33, 42, 47, 69, 83, 206, 211, 215, 216, 217, 221, 334 Patient Education, 254, 264, 266, 270, 334 Patient Satisfaction, 255, 334 Pedigree, 50, 334 Peer Review, 123, 241, 334 Pelvic, 334, 341 Pemphigus, 216, 271, 334 Penis, 334, 340 Pepsin, 334, 348 Pepsin A, 334 Peptic, 205, 334 Peptic Ulcer, 205, 334 Peptide, 56, 157, 163, 199, 204, 288, 299, 303, 332, 334, 337, 338, 340, 341, 342 Peptide Chain Elongation, 288, 334 Perception, 64, 334, 348 Perfusion, 27, 32, 313, 334, 355 Pericardium, 334, 354 Perinatal, 50, 57, 68, 334 Perineal, 216, 335 Perineum, 335 Periodontal disease, 304, 335 Peripheral blood, 33, 37, 59, 99, 111, 163, 174, 317, 335, 340 Peripheral Nervous System, 335, 351, 352, 359 Peripheral Neuropathy, 185, 335, 362 Peritoneal, 216, 217, 279, 335 Peritoneal Cavity, 279, 335 Peritoneum, 331, 335 Peritonitis, 135, 204, 205, 335 Peroxidase, 320, 325, 335 Peroxisomal Disorders, 33, 335 Petroleum, 333, 335 PH, 47, 106, 115, 116, 182, 283, 335 Phagocyte, 332, 335 Phagocytosis, 111, 188, 191, 336 Phalloidine, 158, 336 Pharmacodynamic, 10, 336 Pharmacokinetic, 10, 28, 66, 158, 336 Pharmacologic, 48, 103, 276, 279, 336, 355, 356 Pharynx, 305, 336

Phenotype, 11, 26, 33, 34, 49, 64, 164, 170, 179, 336 Phenyl, 177, 197, 336 Phenylephrine, 197, 336 Phorbol, 69, 336 Phospholipases, 336, 350 Phospholipids, 158, 160, 302, 321, 336 Phosphorus, 77, 284, 336 Phosphorylated, 289, 336 Phosphorylation, 23, 66, 336 Photocoagulation, 289, 336 Photosensitivity, 32, 336, 338 Physical Examination, 152, 255, 336 Physiologic, 23, 129, 273, 282, 295, 302, 336, 341, 344, 346 Physiology, 9, 27, 51, 73, 89, 204, 214, 215, 221, 305, 336, 353 Pigment, 281, 324, 337 Pilot study, 54, 60, 64, 68, 100, 337 Pituitary Gland, 292, 303, 337 Plant Diseases, 299, 337 Plants, 274, 285, 287, 306, 307, 327, 337, 338, 347, 351, 356, 357 Plasma cells, 200, 277, 337 Plasma protein, 53, 167, 188, 273, 337, 342, 349 Plasma Volume, 326, 337 Platelet Activation, 337, 350 Platelet Aggregation, 201, 276, 330, 337, 355 Platelet Factor 4, 317, 337 Platelet-Derived Growth Factor, 199, 337 Platelets, 49, 281, 330, 337, 355 Platinum, 321, 332, 337 Platinum Compounds, 332, 337 Platyhelminths, 319, 338 Poisoning, 297, 317, 324, 327, 338 Polyarteritis Nodosa, 214, 338 Polycystic, 34, 42, 50, 84, 96, 104, 105, 106, 165, 168, 169, 222, 244, 245, 338 Polymerase, 19, 24, 170, 187, 338 Polymerase Chain Reaction, 187, 338 Polymers, 192, 338, 342, 352 Polymorphism, 7, 77, 103, 117, 338 Polyp, 180, 338 Polyposis, 338 Polysaccharide, 162, 277, 338, 342 Polyunsaturated fat, 18, 159, 338, 355 Porphyria, 60, 217, 338 Porphyria Cutanea Tarda, 217, 338, 339 Porphyria, Hepatic, 338 Porphyrins, 338, 339

Index 377

Portal Vein, 73, 111, 174, 256, 313, 339 Portosystemic Shunt, 90, 339 Posterior, 275, 279, 286, 288, 332, 339 Postmenopausal, 331, 339 Postnatal, 57, 339, 352 Postoperative, 115, 204, 205, 216, 327, 339 Postoperative Period, 216, 339 Postsynaptic, 339, 350 Post-translational, 167, 339 Potassium, 120, 193, 273, 326, 339 Potentiate, 35, 339 Potentiation, 339, 350 Practice Guidelines, 243, 258, 339 Preceptorship, 30, 339 Precipitating Factors, 286, 339 Precursor, 164, 167, 271, 276, 278, 287, 293, 297, 300, 339, 340, 342, 357, 359 Predisposition, 118, 340 Prednisolone, 4, 158, 340 Prednisone, 200, 340 Preleukemia, 328, 340, 350 Prenatal, 298, 340 Priapism, 201, 340 Primary Biliary Cirrhosis, 6, 63, 72, 77, 82, 147, 157, 173, 181, 184, 200, 204, 205, 216, 218, 340 Primary endpoint, 46, 55, 340 Probe, 14, 340 Procollagen, 112, 340 Progeny, 291, 340 Progesterone, 340, 352 Progression, 5, 6, 12, 18, 20, 22, 23, 25, 29, 31, 37, 38, 39, 40, 41, 42, 43, 44, 48, 51, 54, 55, 56, 58, 59, 61, 65, 71, 72, 101, 102, 115, 149, 276, 340 Progressive disease, 21, 174, 340 Prolactin, 57, 340 Proline, 289, 313, 340, 341 Promoter, 32, 45, 57, 76, 341 Prone, 10, 341 Prophylaxis, 22, 204, 215, 240, 341, 359, 361 Proportional, 298, 341 Prospective Studies, 31, 63, 341 Prospective study, 11, 148, 321, 341 Prostaglandin, 48, 341, 355 Prostaglandins A, 315, 341 Prostate, 133, 162, 245, 281, 341, 358 Protease, 168, 169, 290, 341 Protein Binding, 341, 356 Protein C, 35, 159, 273, 275, 278, 280, 302, 321, 342, 358, 360

Protein Conformation, 275, 342 Protein S, 212, 245, 246, 282, 288, 301, 306, 342, 347, 354 Proteoglycans, 280, 342 Proteolytic, 53, 167, 170, 274, 290, 299, 303, 342 Prothrombin, 167, 302, 342, 355 Prothrombin Time, 167, 342 Protocol, 15, 18, 146, 342 Protons, 274, 312, 318, 323, 342, 343 Protozoa, 171, 195, 291, 319, 325, 342, 351 Proximal, 296, 319, 342, 348 Pruritus, 64, 72, 146, 147, 214, 215, 342, 358 Psoriasis, 63, 198, 342 Psychiatric, 48, 70, 324, 342 Psychiatry, 303, 342, 352 Psychic, 342, 348 Psychology, 296, 342 Public Health, 13, 19, 27, 29, 30, 38, 42, 44, 61, 94, 240, 243, 343 Public Policy, 239, 343 Publishing, 4, 10, 75, 218, 219, 343 Pulmonary, 46, 52, 53, 241, 282, 292, 311, 319, 320, 343, 346, 360, 361 Pulmonary Artery, 282, 343, 360 Pulmonary Embolism, 343, 361 Pulmonary Fibrosis, 46, 343 Pulse, 326, 343 Purines, 343, 349, 361 Pyridoxal, 294, 343, 356 Pyruvate Dehydrogenase Complex, 50, 64, 343 Q Quality of Life, 5, 6, 15, 22, 30, 46, 54, 55, 64, 130, 343 R Race, 13, 29, 70, 74, 325, 343 Radiation therapy, 88, 301, 305, 317, 318, 343 Radio Waves, 151, 325, 343 Radioactive, 157, 212, 283, 312, 315, 317, 318, 321, 326, 330, 343, 344, 348 Radioimmunotherapy, 344 Radiolabeled, 282, 318, 343, 344 Radiological, 11, 250, 344 Radiology, 97, 113, 118, 250, 251, 344 Radiotherapy, 88, 113, 283, 318, 343, 344 Randomized, 9, 37, 42, 54, 66, 68, 72, 97, 146, 297, 344 Reabsorption, 299, 344 Reactive Oxygen Species, 58, 111, 199, 344 Reagent, 24, 166, 317, 322, 344, 354

378 Liver Disease

Receptor, 14, 17, 23, 35, 41, 47, 50, 60, 69, 71, 73, 118, 157, 184, 193, 277, 311, 344, 349, 350 Recombinant, 9, 32, 33, 70, 89, 91, 119, 162, 164, 165, 168, 169, 179, 232, 344, 359 Recombination, 291, 344 Reconstitution, 18, 344 Rectal, 148, 344 Rectum, 180, 278, 283, 290, 295, 296, 302, 303, 305, 316, 319, 341, 344 Recur, 8, 13, 344 Recurrence, 15, 115, 344 Red blood cells, 301, 338, 344, 347 Red Nucleus, 279, 345 Reductase, 33, 196, 273, 345 Refer, 1, 290, 303, 304, 311, 321, 329, 344, 345 Reflux, 305, 345 Refraction, 345, 351 Refractory, 66, 204, 297, 345 Regeneration, 21, 41, 47, 303, 344, 345 Regimen, 10, 72, 297, 345 Regurgitation, 305, 345 Relapse, 9, 74, 345 Remission, 4, 344, 345 Renal Circulation, 204, 345 Renal failure, 82, 162, 204, 311, 345 Renin, 204, 276, 345 Reperfusion, 164, 165, 168, 169, 201, 328, 345 Reperfusion Injury, 164, 165, 168, 169, 201, 345 Replicon, 24, 345 Research Support, 31, 345 Resected, 41, 345 Resection, 104, 115, 345 Resolving, 13, 36, 345 Resorption, 283, 344, 346 Respiration, 285, 326, 346 Respiratory Paralysis, 271, 346 Respiratory System, 346, 359 Response rate, 38, 43, 172, 346 Restoration, 9, 328, 344, 345, 346, 361 Resuscitation, 73, 346 Retina, 187, 288, 320, 331, 346, 347, 361 Retinal, 296, 331, 346 Retinoblastoma, 245, 346 Retinopathy, 185, 273, 336, 346 Retrograde, 250, 300, 346 Retrospective, 38, 60, 346 Retroviral vector, 33, 346 Retrovirus, 33, 64, 346

Rheumatism, 346 Rheumatoid, 33, 162, 164, 165, 168, 169, 182, 198, 289, 332, 346, 347 Rheumatoid arthritis, 33, 162, 164, 165, 168, 169, 182, 198, 289, 347 Rhinitis, 347, 349 Ribavirin, 18, 38, 46, 48, 61, 74, 347 Ribose, 170, 272, 347, 355 Ribosome, 19, 347, 357 Risk patient, 42, 347 Ristocetin, 347, 359 Rod, 280, 288, 299, 347 Rubber, 255, 272, 347 S Saliva, 347 Salivary, 145, 294, 295, 332, 347, 352 Salivary glands, 294, 295, 347 Saponins, 347, 352 Satellite, 310, 347 Saturated fat, 125, 347 Scans, 152, 347 Schematic, 193, 348 Schizoid, 348, 361 Schizophrenia, 348, 361 Schizotypal Personality Disorder, 348, 361 Sclerosis, 164, 165, 245, 278, 289, 327, 348 Screening, 7, 11, 30, 35, 37, 38, 110, 114, 166, 179, 185, 189, 191, 222, 240, 288, 348 Seafood, 208, 257, 348 Sebaceous, 348, 361 Secretin, 17, 348 Secretory, 17, 45, 348 Sedative, 325, 348 Seizures, 146, 333, 348 Semen, 341, 348 Semisynthetic, 288, 318, 348 Senile, 208, 331, 348 Sensitization, 71, 348 Sepsis, 151, 164, 165, 168, 169, 201, 241, 348 Septal, 72, 113, 348 Septic, 164, 165, 168, 169, 349 Septicaemia, 349 Sequence Homology, 193, 349 Sequencing, 24, 29, 38, 55, 63, 187, 338, 349 Serine, 288, 294, 349, 357 Seroconversion, 117, 349 Serologic, 38, 44, 64, 314, 349 Serotonin, 271, 349, 357 Serotypes, 32, 349 Serous, 279, 299, 349

Index 379

Serum, 3, 10, 11, 28, 30, 35, 36, 37, 38, 46, 55, 56, 63, 64, 72, 79, 80, 90, 100, 115, 144, 153, 167, 173, 174, 180, 189, 190, 191, 192, 196, 197, 213, 272, 273, 276, 290, 293, 305, 314, 321, 326, 335, 344, 349, 358 Serum Albumin, 10, 173, 349 Sex Characteristics, 272, 349, 354 Sex Determination, 245, 349 Shock, 69, 73, 164, 165, 168, 169, 175, 201, 276, 299, 349, 357 Shunt, 251, 255, 349 Side effect, 46, 103, 131, 152, 158, 160, 161, 200, 231, 272, 281, 293, 349, 356, 361 Signal Transduction, 40, 74, 349 Signs and Symptoms, 260, 338, 345, 350, 358 Silymarin, 131, 158, 188, 325, 350 Skeletal, 214, 288, 293, 327, 350 Skeleton, 272, 283, 319, 341, 350 Small intestine, 166, 171, 281, 287, 288, 294, 297, 300, 312, 313, 314, 317, 350, 357 Smallpox, 350, 359 Smoldering leukemia, 328, 350 Smooth muscle, 45, 59, 73, 199, 201, 276, 279, 284, 291, 302, 311, 327, 350, 352 Social Environment, 343, 350 Sodium, 9, 166, 167, 193, 255, 273, 307, 326, 344, 350 Soft tissue, 283, 350 Solid tumor, 276, 350 Solvent, 301, 307, 331, 350 Soma, 350 Somatic, 47, 272, 298, 312, 326, 335, 350, 354 Somatostatin, 81, 330, 332, 350 Sorbitol, 273, 351 Soybean Oil, 338, 351 Specialist, 261, 296, 351 Species, 19, 37, 151, 175, 199, 201, 286, 289, 293, 296, 303, 308, 311, 312, 325, 326, 331, 333, 343, 344, 349, 351, 352, 357, 359, 360, 361 Specificity, 36, 51, 166, 273, 340, 351, 356 Spectrum, 8, 12, 13, 21, 34, 43, 59, 63, 67, 83, 84, 110, 189, 256, 325, 327, 343, 351 Sperm, 288, 351, 358 Spinal cord, 286, 287, 300, 324, 329, 335, 340, 346, 351, 353 Splanchnic Circulation, 27, 204, 351 Spleen, 102, 250, 275, 294, 322, 351 Splenic Vein, 339, 351

Sporadic, 338, 346, 351 Spores, 289, 351 Staging, 117, 347, 351 Steatosis, 8, 11, 12, 13, 26, 34, 44, 45, 67, 81, 147, 217, 257, 302, 351 Steel, 288, 351 Stellate, 14, 17, 20, 26, 45, 46, 59, 200, 351 Stem cell transplantation, 150, 351 Stem Cells, 33, 53, 150, 301, 352 Sterility, 294, 352 Steroid, 107, 197, 281, 292, 293, 307, 347, 352 Stimulant, 284, 311, 352 Stimulus, 200, 297, 301, 317, 318, 319, 333, 352, 354 Strand, 338, 352 Stress, 10, 20, 32, 52, 59, 73, 110, 125, 191, 196, 199, 279, 292, 332, 340, 347, 352 Stroke, 154, 164, 165, 168, 169, 193, 201, 238, 252, 285, 352 Stroma, 333, 352 Stupor, 320, 328, 352 Styrene, 347, 352 Subacute, 316, 352 Subcapsular, 104, 352 Subclinical, 180, 316, 348, 352 Subcutaneous, 177, 296, 297, 305, 333, 352 Submaxillary, 300, 352 Subspecies, 351, 352, 359 Substance P, 301, 324, 344, 347, 348, 352 Substrate, 167, 170, 173, 298, 300, 353 Suction, 303, 353 Sulfur, 198, 319, 325, 353 Superinfection, 99, 353 Superoxide, 32, 117, 202, 353 Superoxide Dismutase, 117, 353 Supplementation, 29, 33, 160, 353 Support group, 218, 219, 353 Suppression, 16, 56, 292, 353, 362 Survival Rate, 66, 353 Sympathetic Nervous System, 204, 279, 353 Symphysis, 341, 353 Symptomatic, 37, 130, 183, 333, 353 Symptomatic treatment, 183, 353 Synaptic, 350, 353 Synergistic, 340, 353 Synovial, 183, 353 Systemic disease, 181, 205, 353 Systemic lupus erythematosus, 118, 289, 353 Systolic, 313, 354

380 Liver Disease

T Taurine, 174, 184, 281, 287, 295, 321, 354 Telangiectasia, 105, 245, 354 Telomerase, 112, 354 Tendinitis, 198, 354 Teratogenic, 274, 354 Terminator, 354, 361, 362 Testis, 187, 354 Testosterone, 345, 354 Tetracycline, 40, 354 Thalamic, 279, 354 Thalamic Diseases, 279, 354 Therapeutics, 14, 44, 81, 113, 114, 117, 186, 234, 354 Thermal, 296, 329, 338, 354 Thigh, 198, 354 Thioacetamide, 26, 354 Thoracic, 15, 354, 361 Thorax, 271, 354 Threshold, 313, 354 Thrombin, 167, 302, 303, 337, 342, 355 Thrombocytes, 337, 355 Thrombocytopenia, 119, 355 Thrombomodulin, 117, 342, 355 Thromboplastin, 342, 355 Thrombosis, 79, 111, 117, 281, 317, 342, 352, 355 Thromboxanes, 278, 355 Thrombus, 292, 315, 328, 337, 355, 360 Thymidine, 115, 355 Thymidine Phosphorylase, 115, 355 Thymus, 314, 322, 355 Thyroid, 33, 215, 217, 318, 325, 355 Thyroid Hormones, 325, 355 Thyrotoxicosis, 217, 355 Thyroxine, 273, 355 Ticks, 303, 355 Tin, 124, 335, 337, 355 Tissue, 12, 16, 28, 32, 33, 35, 37, 41, 43, 44, 45, 49, 53, 55, 56, 57, 59, 62, 63, 67, 70, 75, 81, 99, 117, 151, 160, 162, 165, 168, 169, 174, 187, 188, 199, 201, 272, 273, 274, 276, 277, 279, 280, 281, 282, 283, 287, 289, 291, 293, 296, 297, 298, 300, 302, 303, 304, 305, 308, 311, 313, 314, 316, 317, 320, 321, 322, 323, 324, 327, 328, 329, 331, 333, 334, 335, 337, 338, 342, 345, 346, 349, 350, 352, 354, 355, 356, 357, 358, 361 Tissue Banks, 63, 355 Tissue Culture, 151, 355 Tissue Distribution, 56, 355

Tolerance, 46, 50, 272, 307, 356 Tomography, 38, 86, 323, 356 Tonic, 285, 324, 356 Tonicity, 310, 356 Topical, 301, 312, 333, 356 Torsion, 316, 356 Toxicology, 240, 356 Toxins, 188, 191, 192, 215, 277, 307, 316, 326, 327, 344, 356 Toxoplasmosis, 280, 356 Trace element, 288, 289, 355, 356 Trachea, 283, 336, 355, 356 Traction, 288, 356 Transaminase, 213, 356 Transcriptase, 319, 346, 354, 356, 361 Transcription Factors, 184, 356 Transdermal, 177, 356 Transduction, 17, 40, 349, 356 Transfection, 35, 57, 282, 356 Transfer Factor, 314, 357 Transferases, 7, 357 Transforming Growth Factor beta, 112, 199, 357 Transfusion, 21, 91, 111, 151, 152, 163, 310, 357 Translation, 301, 357 Translational, 21, 25, 28, 71, 357 Translocation, 58, 288, 301, 357 Transmitter, 271, 318, 323, 357 Trauma, 69, 280, 301, 309, 328, 333, 354, 357 Trees, 347, 357 Triad, 311, 357 Triglyceride, 34, 357 Troglitazone, 9, 357 Troleandomycin, 177, 178, 357 Trypsin, 170, 288, 299, 357 Tryptophan, 289, 349, 357 Tuberculosis, 63, 292, 322, 357 Tuberous Sclerosis, 245, 357 Tubulin, 156, 358 Tumor marker, 281, 358 Tumor Necrosis Factor, 18, 28, 68, 71, 76, 173, 190, 358 Tumour, 120, 358 Type 2 diabetes, 45, 120, 358 U Ulcer, 334, 358 Ulceration, 185, 358 Ulcerative colitis, 180, 183, 195, 219, 316, 358 Ultrasonography, 4, 7, 11, 88, 117, 213, 358

Index 381

Unconscious, 276, 313, 358 Uraemia, 333, 358 Urea, 89, 188, 358 Uremia, 319, 345, 358 Urethra, 334, 341, 358, 359 Uric, 92, 274, 343, 359 Urinary, 358, 359, 361 Urine, 90, 152, 171, 176, 181, 282, 293, 296, 300, 307, 310, 313, 319, 358, 359 Urokinase, 41, 359 Uroporphyrinogen Decarboxylase, 60, 338, 359 Ursodeoxycholic Acid, 9, 12, 54, 72, 101, 104, 147, 157, 174, 180, 359 V Vaccination, 64, 98, 119, 227, 242, 359 Vaccine, 50, 91, 147, 150, 232, 256, 342, 359 Vaccinia, 163, 359 Vaccinia Virus, 163, 359 Vancomycin, 148, 359 Varices, 55, 359 Variola, 359 Vasculitis, 333, 338, 359 Vasoactive, 17, 74, 359 Vasoactive Intestinal Peptide, 17, 359 Vasodilatation, 52, 359 Vasodilation, 173, 201, 204, 359 Vasodilator, 283, 311, 328, 329, 359 Vector, 18, 356, 359, 361 Vein, 152, 276, 278, 318, 330, 339, 347, 351, 359, 360 Venous, 278, 281, 295, 313, 342, 359, 360, 361 Venous Thrombosis, 281, 360, 361 Ventricle, 175, 313, 343, 354, 360 Ventricular, 181, 328, 360 Venules, 282, 325, 360 Verapamil, 177, 360 Vesicular, 311, 325, 350, 359, 360 Veterinary Medicine, 239, 360 Villous, 286, 360 Vinblastine, 358, 360 Vincristine, 358, 360

Viral, 4, 5, 8, 9, 15, 16, 20, 21, 22, 31, 32, 35, 36, 37, 39, 43, 45, 47, 50, 55, 59, 60, 61, 62, 64, 65, 66, 68, 74, 76, 84, 91, 94, 96, 101, 116, 117, 120, 129, 135, 149, 150, 151, 163, 164, 165, 168, 169, 170, 172, 173, 181, 183, 185, 187, 194, 200, 201, 205, 206, 211, 212, 215, 216, 217, 228, 241, 257, 258, 271, 284, 310, 346, 356, 360, 361, 362 Viral Load, 9, 15, 22, 39, 55, 360 Viral vector, 32, 360 Viremia, 39, 43, 76, 121, 360 Virion, 310, 330, 360 Virulence, 61, 279, 353, 356, 360 Virus Replication, 99, 183, 360 Viscera, 350, 351, 360 Viscosity, 271, 360 Vitreous Body, 346, 360 Vitro, 26, 35, 53, 64, 75, 361 Vivo, 14, 26, 33, 45, 53, 73, 100, 361 Vulgaris, 216, 271, 361 W Warfarin, 167, 361 Weight Gain, 147, 302, 361 Weight-Bearing, 230, 331, 361 White blood cell, 147, 151, 256, 272, 277, 315, 320, 322, 323, 326, 327, 329, 337, 361 Windpipe, 336, 355, 361 Withdrawal, 4, 133, 361 Wound Healing, 162, 303, 361 X Xanthine, 122, 201, 274, 361 Xanthine Oxidase, 201, 274, 361 Xenograft, 276, 361 X-ray, 152, 283, 291, 300, 304, 305, 318, 330, 343, 344, 348, 361 Y Yeasts, 304, 336, 361 Yellow Fever, 164, 303, 361 Yellow Fever Virus, 164, 303, 361 Z Zalcitabine, 319, 361 Zidovudine, 148, 362 Zygote, 291, 362 Zymogen, 288, 342, 362

382 Liver Disease

Index 383

384 Liver Disease