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

CHOLESTASIS A 3-IN-1 MEDICAL REFERENCE Medical Dictionary Bibliography & Annotated Research Guide TO I NTERNET R EFEREN...

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CHOLESTASIS A 3-IN-1 MEDICAL REFERENCE Medical Dictionary Bibliography & Annotated Research Guide TO I NTERNET

R EFERENCES

CHOLESTASIS 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., 1960Cholestasis: 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: 0-497-00236-1 1. Cholestasis-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 cholestasis. 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 CHOLESTASIS ............................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Cholestasis..................................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 37 The National Library of Medicine: PubMed ................................................................................ 38 CHAPTER 2. NUTRITION AND CHOLESTASIS .................................................................................. 83 Overview...................................................................................................................................... 83 Finding Nutrition Studies on Cholestasis ................................................................................... 83 Federal Resources on Nutrition ................................................................................................... 85 Additional Web Resources ........................................................................................................... 86 CHAPTER 3. ALTERNATIVE MEDICINE AND CHOLESTASIS ............................................................ 87 Overview...................................................................................................................................... 87 The Combined Health Information Database............................................................................... 87 National Center for Complementary and Alternative Medicine.................................................. 88 Additional Web Resources ........................................................................................................... 95 General References ....................................................................................................................... 96 CHAPTER 4. PATENTS ON CHOLESTASIS ......................................................................................... 99 Overview...................................................................................................................................... 99 Patents on Cholestasis.................................................................................................................. 99 Patent Applications on Cholestasis............................................................................................ 102 Keeping Current ........................................................................................................................ 105 CHAPTER 5. BOOKS ON CHOLESTASIS .......................................................................................... 107 Overview.................................................................................................................................... 107 Book Summaries: Federal Agencies............................................................................................ 107 Book Summaries: Online Booksellers......................................................................................... 111 Chapters on Cholestasis ............................................................................................................. 111 CHAPTER 6. MULTIMEDIA ON CHOLESTASIS ................................................................................ 113 Overview.................................................................................................................................... 113 Video Recordings ....................................................................................................................... 113 CHAPTER 7. PERIODICALS AND NEWS ON CHOLESTASIS ............................................................. 115 Overview.................................................................................................................................... 115 News Services and Press Releases.............................................................................................. 115 Newsletter Articles .................................................................................................................... 117 Academic Periodicals covering Cholestasis................................................................................ 117 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 119 Overview.................................................................................................................................... 119 U.S. Pharmacopeia..................................................................................................................... 119 Commercial Databases ............................................................................................................... 120 Researching Orphan Drugs ....................................................................................................... 120 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 125 Overview.................................................................................................................................... 125 NIH Guidelines.......................................................................................................................... 125 NIH Databases........................................................................................................................... 127 Other Commercial Databases..................................................................................................... 129 APPENDIX B. PATIENT RESOURCES ............................................................................................... 131 Overview.................................................................................................................................... 131 Patient Guideline Sources.......................................................................................................... 131 Finding Associations.................................................................................................................. 134

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APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 137 Overview.................................................................................................................................... 137 Preparation................................................................................................................................. 137 Finding a Local Medical Library................................................................................................ 137 Medical Libraries in the U.S. and Canada ................................................................................. 137 ONLINE GLOSSARIES................................................................................................................ 143 Online Dictionary Directories ................................................................................................... 144 CHOLESTASIS DICTIONARY .................................................................................................. 145 INDEX .............................................................................................................................................. 205

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

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

Jaundice and Cholestasis: Some Common and Uncommon Causes Source: Postgraduate Medicine. 90(4): 65, 68, 70-71. September 15, 1991. Summary: This article discusses jaundice and cholestasis, focusing on common and uncommon causes of the two conditions. The author notes that there is variability in presentation of cholestasis, and jaundice may be intrahepatic or extrahepatic and acute or chronic. Some intrahepatic causes of cholestatic jaundice seen on medical wards include viral hepatitis, sepsis, postoperative mechanism, Hodgkin's disease, and use of certain drugs. Chronic cholestatic syndromes may result from primary biliary cirrhosis, primary sclerosing cholangitis, and sarcoidosis, among others. The author concludes that individual patients often do not conform to textbook definitions, and the diagnosis of cholestatic jaundice remains elusive. 10 references. (AA-M).

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Review: Intrahepatic Cholestasis. A Puzzling Disorder of Pregnancy Source: Journal of Gastroenterology and Hepatology. 13(3): 211-216. March 1997. Contact: Available from Blackwell Science Pty Ltd. P.O. Box 378, Carlton, Victoria 3053, Australia. Phone: 61 3 9347 0300; Fax: 61 3 9347 5001; E-mail: [email protected]. Web site: http://www.blacksci.co.uk. Summary: This article provides information about intrahepatic cholestasis of pregnancy, a puzzling disorder characterized by skin pruritus and a biochemical cholestasis of mild to moderate severity appearing mainly during the third trimester and disappearing after delivery. It recurs in 40 to 60 percent of future pregnancies. The intensity of pruritus (itching) and the laboratory alterations (increased serum bile salts and transminases in almost all patients, hyperbilirubinemia in 20 percent of patients) fluctuate during one pregnancy and also vary in subsequent affected pregnancies. The disease has no meaningful consequences for the mother; in contrast, it is associated with an increased risk of fetal distress, causing premature deliveries and stillbirths. Cholestasis of pregnancy has been recognized in most countries and ethnic groups but its prevalence is higher in Chile (14 percent of deliveries in 1975 and approximately 4 percent in 1995) and in Sweden than in other countries. The cause is unknown. Sex hormones, mainly estrogen and progesterone, appear to be involved in its pathogenesis. An interplay between a genetic metabolic predisposition and some environmental factor(s) is apparently relevant. Clinical and experimental studies suggest that a marginal selenium deficiency could be a dietary pathogenic factor. Some drugs attenuate pruritus and improve maternal cholestasis, but not the fetal prognosis. Urosdeoxycholic acid (UDCA) administration provides a significant improvement in maternal pruritus and in the biochemical abnormalities, with no adverse effects in the mother or child. 59 references. (AA-M).

Federally Funded Research on Cholestasis The U.S. Government supports a variety of research studies relating to cholestasis. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to cholestasis. 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 cholestasis. The following is typical of the type of information found when searching the CRISP database for cholestasis:

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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).

Studies

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Project Title: ABC-TRANSPORTER BINDING PROTEINS AND TRAFFICKING Principal Investigator & Institution: Ortiz, Daniel F.; Physiology; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): The ABC (ATP-Binding-Cassette)-type proteins SPGP and MDR3 are essential for bile formation. SPGP mediates ATP-dependent transport of conjugated bile acids across the canalicular membrane and MDR3 is a phospholipid flippase that mediates transfer of phosphatidylcholine to bile. The transporters, which reside primarily in the canalicular membrane, can be recruited or removed from the apical domain in response to signals such as bile acids, cAMP or changes in osmolarity. Mobilization and targeting of the transporters to and from the canalicular membrane is probably mediated by association with proteins that link SPGP and MDR3 to sorting and trafficking networks. However, outside of the interaction between CFTR and NHERF, which is essential for polarized sorting of the chloride channel, little is known about proteins that bind and regulate trafficking of ABCtransporters. We have identified two proteins that specifically bind MDR3 and SPGP. GST-pulldowns from liver homogenates, FRET analyses and co-immunoprecipitation of transporters with associated proteins, confirmed the validity of these interactions. The goal of the proposed research is to study the role of these binding proteins in regulation of SPGP trafficking in polarized cells. Experiments in Aim 1 will use immunofluorescence microscopy and FRET to establish the sites in hepatocytes where SPGP interacts with binding partners, and the effect of stimuli which induce SPGP recruitment to, or retrieval from, the canalicular membrane. Aim 2 focuses on determining the function of the interacting proteins vis-a-vis SPGP trafficking. The specific amino acid motifs in SPGP which mediate its association with interacting proteins will be identified using yeast two hybrid assays. These moieties will be mutated with the objective of generating mutant transporters that do not bind interacting proteins. Trafficking of the SPGP mutants will be studied in polarized cell model systems to determine the function of the association with the interacting proteins. Mutations which cause abnormal trafficking of canalicular ABC-transporters have been associated with cholestasis of pregnancy and Dubin-Johnson syndrome. Therefore, elucidating the pathways that govern transfer and recruitment of ABC-transporters to the apical membrane, and identifying proteins which control these processes, will provide critical insight into mechanisms underlying cholestasis and suggest targets for therapeutic drug design. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ALIMENTARY TRACT LIPIDS IN HEALTH AND DISEASE Principal Investigator & Institution: Carey, Martin C.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-JUL-1985; Project End 31-MAR-2004 Summary: Bile formation and secretion control homeostatic mechanisms for eliminating cholesterol and tetrapyrrole molecules form the organism as well as absorption of dietary fat. Bile dysfunction causes several common diseases, including gallstones and cholestasis. This proposal employs biophysical rationale and physical-chemical methodology to further molecular understanding of the physical biochemistry of bile, its formation, secretion and functions. The PI and colleagues will design and study appropriate model systems and correlate the results with pathophysiological phenomena pertaining to the function and dysfunction of native systems. They will use

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I)novel flurocholesterol methodology, cryoelectron microscopy and electron energy-loss spectroscopy to elucidate physical-chemical pathways whereby cholesterol molecules are transferred from blood to liver cell and bile, ii) characterize interactions of bile salt molecules with sphingomyelin in micellar solutions and at interfaces related to cholesterol secretion, absorption and apoptosis, iii) determine the physical-chemical origin and pathophysiology of lipoprotein X in bile secretory failure, iv) define how phosphatidylcholine, cholesterol and calcium influence the physical- chemical state of natural conjugated bilrubins in model (bilrubin ditaurate) and native biles employing analytical ultracentrifugation and spectrophotometric techniques, v) measure the metastable and equilibrium solubilities of unconjugated bilirubin in modelbiles utilizing potentiometric titration and dissolution and correlate the information pathophysiologically with pigment-stone biles, vi) discover whether humans with ~black~ pigment gallstones have dysfunctional mutations of the ileal bile acid transporter gene. These objectives are designed to advance our understanding of physical chemistry of bile as ell as normal and abnormal movements of cholesterol and billirubin to and from the liver and alimentary tract. The systematic project should lead to new targets and strategies for prevention of pigment and cholesterol gallstone diseases as well as lipid transport abnormalities sin cholestasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: BILE ACID MODULATION OF BILE DUCT SECRETION AND GROWTH Principal Investigator & Institution: Lesage, Gene D.; Professor; Internal Medicine; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 30-JUN-2005 Summary: The Principal Investigator proposes to examine the effect of bile acids on cholangiocyte biology, based on the premise that chronic liver diseases with prominent cholestasis may be the result of injury directed towards the epithelial cells lining the biliary tree (cholangiocytes). Increased cholangiocyte secretion and proliferation are hallmarks of bile duct injury, and appear to be adaptive responses to injury. This occurs in the presence of elevated local levels of bile acids. With the recent discovery of the apical bile acid transporter (ABAT) in cholangiocytes, the question arises as to how bile acids modify cholangiocyte biology. The hypothesis is proposed that bile acids are internalized and affect intracellular signaling. The studies will determine the transcriptional regulation, translocation, and activity of ABAT in cholangiocytes; the potential for ABAT promoting the "chole-hepatic shunt" for uptake of bile acids from bile back into the circulation within the liver will also be examined. The effect of bile acids on intracellular PKC, Ca++ and ERK signaling pathways will be determined. The differential effects of endogenous bile acids vs. therapeutic bile acids also will be examined. These studies will provide a better understanding of how bile acids interact with cholangiocytes, and hence may improve understanding of the cholangiocyte adaptation to injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BILIARY ATRESIA CLINICAL RESEARCH CONSORTIUM Principal Investigator & Institution: Rosenthal, Philip J.; Associate Professor; Pediatrics; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-MAY-2007

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Summary: (provided by applicant): Two forms of biliary atresia have been recognized. The embryonic or fetal type is often associated with congenital malformations suggesting the insult occurs prenatally. The more common perinatal type usually presents at 4-8 weeks of life. Because the disease occurs so early in the perinatal period, a genetic factor being causal or contributory must be considered. Previous data has been conflicting; there are case reports of biliary atresia occurring in families and HLA identical twins that are discordant for biliary atresia. In one study, HLA-B 12 was found more commonly then expected in children with biliary atresia. HLA-Cw4/7 has also been increased in children with biliary atresia and in adults with primary sclerosing cholangitis. However, all these studies suffer from the small number of subjects and single-center studies. The etiologic mechanism(s) for biliary atresia remain enigmatic. By analyzing HLA types in a large cohort of children with biliary atresia and neonatal hepatitis, determination of any genetic predisposition to these disorders should be accelerated. Biliary atresia remains the leading indication for pediatric liver transplantation in the United States. Recently, the Pediatric Liver Disease Severity Score (PELD) was proposed to improve organ allocation for children in need of liver transplants. The major limitation of the PELD score is that it has not been prospectively validated. However, the PELD score is based on only a few variables that can be objectively assessed and are reproducible. No individual center has sufficient patients with biliary atresia or neonatal hepatitis to ascertain whether the PELD score can predict outcomes prospectively. This proposal brings together a unique consortium of investigators and resources within the State of California with a plan for a participating Clinical Center in the Biliary Atresia Clinical Research Consortium. Our research plan describes the establishment of a large multicomponent Clinical Center patient database that would contribute to the proposed multicenter Biliary Atresia Clinical Research Consortium. These include tertiary care referral specialty clinics at a large university medical center and an HMO patient population. We propose to identify patients with biliary atresia and neonatal hepatitis from these sources, to allow participation in the Consortium. Secondly, we propose two research protocols that would use the Biliary Atresia Clinical Research Consortium to explore a possible etiologic relationship between HLA type and biliary atresia and allow a prospective evaluation of the PELD score. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: BILIARY ATRESIA CLINICAL RESEARCH CONSORTIUM Principal Investigator & Institution: Shepherd, Ross W.; Pediatrics; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-MAY-2007 Summary: (provided by applicant): The creation of a multi-center collaborative consortium provides an unprecedented opportunity to improve the lives of children with neonatal liver disease. This Clinical Center application from four pediatric medical centers describes the collective clinical expertise, collaborative research experience, and outstanding institutional core facilities needed to be productive contributing members to this consortium. This application proposes participation in the consortium in three ways: 1. Clinical Data Collection: A uniform, concise data form and electronic collection system will be developed to manage clinical data. Relevant clinical data and tissue specimens will be contributed to the Consortium. The two research programs and four clinical programs collaborating in this proposal can contribute data from approximately 25 new patients with biliary atresia (BA)/year and 12 patients with neonatal hepatitis (NH)/yr. 2. Short-term study: Using available and accumulated specimens, we will

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study the pathogenesis, natural history, and clinical correlates of hepatic fibrogenesis in patients with biliary atresia and NH. A variation of the Knodell hepatic fibrosis scale will be used to determine the extent of hepatic fibrosis at the time of the Kasai procedure. Immunohistochemical and in situ hybridization techniques will be used to quantify the expression of specific molecular markers of hepatic fibrosis and inflammation. The severity of fibrosis or specific staining patterns will be correllated with patient diagnosis and response to the Kasai procedure. 3. Long-term study: To identify patterns of protein and gene expression that are unique to biliary atresia or that predict response to the Kasai procedure, gene expression profiles will be determined in wedge liver biopsies as well as in hepatocytes and biliary epithelial cells isolated by laser capture microdissection (LCM). Modern proteomic techniques will also be applied to serum samples to identify proteins synthesized and released by the injured liver. Similar to the genetic profile, the pattern of proteins will be correlated with clinical data to identify patterns of serum proteins that are disease specific or predict prognosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: BIOAVAILABILITY OF URSOCARB VS ACTIGALL IN CHRONIC CHOLESTATIC LIVER DISEASE Principal Investigator & Institution: Balistreri, William F.; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2003 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHOLESTASIS IN NEONATES RECEIVING PARENTERAL AMINO ACID SOLUTION Principal Investigator & Institution: Snyder, John; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLINICAL CENTER FOR BILIARY ATRESIA: ETIOPATHOGENESIS A* Principal Investigator & Institution: Bezerra, Jorge A.; Associate Professor of Pediatrics; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-MAY-2007 Summary: (provided by applicant): We propose to develop a Biliary Atresia Clinical Center to perform translational research focused on diagnosis, pathogenesis, and novel therapeutic modalities for biliary atresia and neonatal hepatitis. These disorders are the main causes of neonatal cholestasis, with biliary atresia accounting for -50% of the indications for liver transplantation in children. The application is a logical extension of the long-standing mission of the applicant Center to provide exceptional care to any child with liver disease through comprehensive care and research. To pursue this mission, a clinical service focused exclusively on pediatric liver disease was created in 1985; since, then, we have served as a referral center for regional medical groups and institutions. We also performed clinical and patient-directed laboratory research to define specific causes of neonatal hepatitis and to explore novel therapeutic modalities

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for affected infants. Recently, we applied functional genomics to identify immunologic pathways that may regulate pathogenesis of biliary atresia. Despite these accomplishments, we recognize that further advances will depend directly on the access to a large patient population in a prospective manner for adequately powered studies. Therefore, we set two goals for the applicant Center: 1) to establish and maintain the infrastructure of a Clinical Center that will work in collaboration with other centers of the Biliary Atresia Clinical Research Consortium, and 2) to actively use the resources provided by the consortium to carry out studies on children with biliary atresia and neonatal hepatitis. To accomplish these goals, we propose an administrative structure jointly shared by medical and surgical faculty of the Center, a network of regional collaborators that will assure access to patients, and a database to gather clinical and laboratory information based on the natural history of biliary atresia. Using a model of translational research that is focused on the child with biliary atresia, we propose two studies to be carried with the approval by the Research Consortium. The first is a shortterm study applying basic science technology to further defines the pathogenesis of this disease. The second is a 3-year open-label randomized study to establish the efficacy of corticosteroids in improving biliary flow following surgical portoenterostomy in infants with biliary atresia. Execution of these studies and access to a critical amount of clinical information and serum/tissues will facilitate research and generate hypotheses on pathogenesis and optimal treatment for children with biliary atresia and neonatal hepatitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: CLINICAL CENTER--BILIARY ATRESIA CLINICAL RESEARCH CONS* Principal Investigator & Institution: Whitington, Peter F.; Professor of Pediatrics and Medicine; Children's Memorial Hospital (Chicago) Chicago, Il 606143394 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-MAY-2007 Summary: (provided by applicant): The long-term objective of this proposal is to contribute to the Biliary Atresia Research Consortium to assure its success in improving the understanding of the etiology, pathogenesis, and disease mechanisms of biliary atresia and improving the clinical care, diagnosis and management of affected children. This is an important project because biliary atresia affects about 600 children each year in the US. Its cause is unknown. There are no good studies regarding early diagnosis or screening strategies, which are needed to improve patient care. The medical and surgical care of affected children is sub-optimal. Biliary atresia is the number one indication for pediatric liver transplantation, accounting for about 50% of cases in the US. The cost of care of this relatively rare disease is exorbitant. Better understanding of the disease should lead to improved care, better outcomes and reduced cost of care. The specific aims of this proposal are #1 To participate fully as a clinical center in the Biliary Atresia Clinical Research Consortium. This entails participation in the development of the functions of the consortium, including determining data to be collected, projects to be undertaken and how information is to be disseminated; #2 To identify and enter into the consortium database all or nearly all of the cases of biliary atresia in the upper midwest region over the five year period of the grant to determine the incidence of the disease and important epidemiological characteristics, such as racial/ethnic, socioeconomic and gender differences in incidence, secular trends, and temporal relationship to identifiable viral epidemics; #3 To examine prognostic indicators in a select cohort of biliary atresia patients.; and #4 To examine the hypothesis that biliary atresia is a viral-induced, immune mediated disease.

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

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 2002; 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--CELL CULTURE Principal Investigator & Institution: Lu, Shelly Chi-Loo.; Professor of Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002 Summary: (Taken from the application) The original cell culture core due to the large variety of services has been subdivided into two subcores, the Parenchymal Liver Cell Subcore and the Non-parenchymal Liver Cell Subcore last year. 1. Parenchymal Liver Subcore. This core was established in the beginning of the fourth year of the current funding cycle. The objectives are to 1. provide services needed by a large number of independently funded investigators to improve research efficiency by sharing resources and lowering costs, and 2. foster an environment for interdisciplinary collaboration and

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research. 2. Non-parenchymal Liver Cell Subcore. The primary objectives of this subcore are to promote research on non-parenchymal liver cell biology by providing specialized services for isolation of rat non-parenchymal cells and to stimulate collaboration among the center and non-center investigators on and off campus. The subcore will provide normal rat Kupffer cells, hepatic stellate cells, and sinusoidal endothelial cells to investigators. It will isolate the cells from various rat models of liver injury, including that induced by ethanol, carbon tetrachloride or cholestasis. It will also provide consultation on techniques involved in non-parenchymal liver cell isolation and culture. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: CYTOKINE REGULATION OF LIVER GROWTH HORMONE SIGNALING Principal Investigator & Institution: Denson, Lee Armistead.; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2005 Summary: (provided by applicant): Children with cholestatic liver diseases including extrahepatic biliary atresia (EHBA) exhibit an acquired growth hormone (GH) resistance, in which GH secretion is normal, but hepatic expression of the GH receptor (GHR) and synthesis of anabolic target genes including IGF-I is reduced. Consequences include poor linear growth, muscle wasting, and increased post-transplant morbidity and mortality. The molecular basis for impaired GH signaling in obstructive cholestasis is not known. We hypothesize that down regulation of the GHR by TNFalpha and up regulation of Suppressors of Cytokine Signaling 3 (SOCS-3) by IL-6 may combine to reduce GH signaling in this setting. We will test this hypothesis in the following aims: Aim 1: Characterize cytokine regulation of liver Ghr and Socs-3 gene expression. Cytokine response elements in the mouse Socs-3 promoter will be identified by examining regulation of gene promoter reporter constructs in cultured hepatocytes. We will then determine whether TNFalpha down regulates Ghr expression via Sp1/Sp3 dephosphorylation leading to reduced DNA binding affinity, and whether IL-6 up regulates Socs-3 expression by increasing STAT3 phosphorylation and nuclear abundance. These data will identify mechanisms by which cytokines regulate target genes involved in GH signaling via alterations in transcription factor phosphorylation. Aim 2: Identify mechanisms of GH resistance in obstructive cholestasis. Our preliminary studies have demonstrated that bile duct ligated (BDL) mice exhibit GH resistance which reproduces that observed in children with EHBA. This is associated with hepatic up regulation of TNFalpha and IL-6, down regulation of the Ghr, and up regulation of Socs-3. Abundance of these proteins relative to GH activation of STAT5 will be examined in sham, pair fed, and BDL wild type (WT), TNF receptor 1 (TNFR1) null, and IL-6 null mice. These data will determine whether disruption of TNFalpha or IL-6 signaling will restore GH action in obstructive cholestasis. These findings will have implications for therapeutic strategies to ameliorate acquired GH resistance in diseases complicated by liver inflammation, including chronic cholestatic liver diseases Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEGRADATION OF ABC TRANSPORTERS IN GENETIC LIVER DISEASE Principal Investigator & Institution: Wang, Li; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2004; Project Start 01-MAR-2004; Project End 28-FEB-2007

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Summary: (provided by applicant): The candidate has two years post-doctoral and three years research-scientist experience, and is currently being proposed for an Assistant Professor appointment at School of Medicine of Yale University. This application for a mentored K01 award is submitted with the goal of providing the candidate with the further training experience to function as an independent investigator working in the field of liver cell biology. The project's long-term objectives are to understand the mechanisms that underlie the degradation of hepatic transporters in a number of hereditary diseases including cholestasis. This is a prerequisite for developing novel stratagies to overcome the bile secretion defect in hereditary cholestasis and such stratagies may also apply to other genetic diseases such as cystic fibrosis. We and others have demonstrated that in hereditary cholestasis and Dubin-Johnson syndrome genetic mutations lead to the intracellular retention and subsequent degradation of the bile salt export pump (BSEP) and the multidrug resistance protein 2 (MRP2) by proteasomes. This leads to the hypothesis that endoplasmic reticulum-associated protein degradation (ERAD) and ubiquitination enzymes are responsible for the degradation of the BSEP and MRP2 in these disorders. The preliminary data demonstrates that a novel ubiquitin ligase targets one mutant of BSEP to degradation. The candidate proposes to I) Characterize the different cellular pathways in the degradation of the BSEP mutants in hereditary cholestasis. II) Determine the ubiqutin ligase(s) that target BSEP mutants to degradation. III) Examine the ERAD-specific ubiquitin conjugating enzymes in the degradation of the BSEP mutants. IV) Establish whether the primary ubiquitin ligase responsible for the ERAD of BSEP also targets the mutants of other ABC transporters such as MRP2 and CFTR protein in Dubin-Johnson syndrome and cystic firbosis. The Section of Digestive Diseases and Department of Molecular Biophysics and Biochemistry at Yale University are ideal for carrying out such studies because of the quality of their faculty, their experience as mentors and the core facility at the Yale Liver Center. The School of Medicine has pledged protected time for the candidate during this further training period prior to functioning as an independent investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: DEVELOPMENTAL PHARMACOLOGY OF HEPATIC OCT1 Principal Investigator & Institution: Green, Richard M.; Medicine; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 21-SEP-2000; Project End 30-JUN-2005 Summary: (Adapted from the applicant's Description): Hepatic metabolism and secretion of endobiotic and xenobiotic substances are essential functions of the liver, and hepatobiliary secretion into bile is the major excretory route for numerous pharmacologic agents. Many commonly used drugs are Type I organic cation amines, which are transported into the liver via a transport protein termed Oct1. In humans, Oct1 is expressed almost exclusively in the liver, further indicating the importance of the liver for the elimination of Type I organic cationic drugs. Although Type I organic cationic drugs are pharmacologic agents that are commonly used in both premature infants as well as neonatal and pediatric populations, little is known about the developmental expression of Oct1 in normal physiology or in pathophysiological states; and the mechanisms of gene regulation of Oct1 remain virtually unexplored. Therefore, the objectives of this project are to employ murine models and human liver tissue samples to examine the developmental regulation of Oct1, and determine the mechanisms of gene regulation during the ontogenic expression of this essential hepatic transporter. The investigators will initially employ murine models to further characterize the kinetics of hepatic Type I organic cation uptake and expression of

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mouse Oct1 in normal development, and determine the pharmacologic effect of these changes in experimental pathophysiological states, as well as in models with reduced hepatic Oct1 expression. They will clone the mouse Oct1 promoter and employ 5'deletional analysis to study the transcriptional gene regulation of murine Oct1. Subsequently they will determine the mechanisms of gene regulation of human Oct1 in normal development and pediatric disease states. Finally, they will develop transgenic mice that employ Oct1 promoter-reporter gene constructs to determine the cis-acting regulatory elements that are essential for the ontogenic expression of Oct1. These studies will have direct implications on our understanding of the physiology, developmental pharmacology, and mechanisms of regulation of the hepatic Oct1 transporter. This knowledge will be critical for the development of rational pharmacologic and therapeutic approaches of the many organic cationic drugs used in the neonatal and pediatric population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: DISORDERS OF PORPHYRIN METABOLISM Principal Investigator & Institution: Kushner, James P.; Professor of Medicine; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ETIOLOGY OF INHERITED INTRAHEPATIC CHOLESTASIS Principal Investigator & Institution: Labrecque, Douglas R.; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002 Summary: Subjects with inherited intrahepatic cholestasis are being studied to determine the genetic mode of transmission, the degree to which associated findings are linked to inheritance of the liver disease and to determine in what ways bile formation or secretion is altered. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EVALUATION OF MINIMALLY INVASIVE SURGERY Principal Investigator & Institution: Rogers, Stanley J.; Surgery; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Major advances have been made over the past decade developing minimallyinvasive endoscopic, surgical and radiographic procedures in an attempt to decrease mortality, morbidity, hospital stay and overall health care costs in treating patients with abdominal disorders. The treatment of these common gastrointestinal disorders needs to be studied in randomized controlled clinical trials. Given my training and experience in surgical endoscopy and minimally invasive surgery (laparoscopy), I propose studying in the context of randomized controlled clinical trials three distinct areas of gastrointestinal disease in which major advances have occurred employing laparoscopy, endoscopy and interventional radiological techniques. The three principal projects for this mentored clinical research are the following: 1. Randomized controlled clinical trial of laparoscopic cholecystectomy with laparoscopic common bile duct exploration versus endoscopic retrograde cholangiopancreatography with sphincterotomy followed by

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laparoscopic cholecystectomy for patients with common bile duct stone disease. 2. Laparoscopic anti-reflux surgery versus long-term administration of proton pump inhibitors (lanzoprasole) for moderate to severe gastroesophageal reflux disease. 3. Intra-arterial chemoembolization alone versus intra-arterial chemoembolization plus laparoscopic, ultrasound-guided radiofrequency ablation for non-resectable hepatocellular carcinoma. All three protocols involve minimally invasive surgery and other therapies studied in a prospective randomized controlled fashion. While the technical expertise, equipment and facilities used to perform these procedures have been developed around the world, few randomized controlled clinical trials exist that critically examine outcome parameters for a sufficient period of time to document efficacy, safety, improved survival and overall cost benefits in the treatment of these disorders. These three trials will allow such an evaluation of minimally invasive procedures used to treat patients with common gastrointestinal disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: GABAPENTIN THERAPY FOR THE PRURITUS OF CHOLESTASIS Principal Investigator & Institution: Bergasa, Nora V.; Medicine; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 15-FEB-2001; Project End 31-JAN-2004 Summary: 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 can be so severe that it can be an indication for liver transplantation, ever in the face of good hepatic function. Accordingly, the provision of satisfactory treatment for this symptom is needed. Pruritus is a nociceptive stimulus that elicits the reflect act of scratching. Because the perception of nociception can be altered by drugs that mediate antinociception, this type of drugs may be of value in the treatment of pruritus. Recent data from animal and clinical studies suggest that gabapentin mediates antinociception/analgesia. The specific aim of this study is to compare the effect of gabapentin to that of placebo on the pruritus of cholestasis. Adult patients with pruritus secondary to liver disease will be studied, in a single blind, randomized, placebo controlled trial. Because pruritus is a perception, it cannot be objectively quantitated. In contrast, the behavioral manifestation of the pruritus of cholestasis, scratching activity, can be objectively quantitated. The primary end point of this study is scratching activity. Scratching activity will be measured by a stem designed specifically to record this behavior. The potential outcome of this study is the identification of an effective form of therapy for the pruritus of cholestasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HEPATIC DRUG ELIMINATION IN PREGNANCY Principal Investigator & Institution: Vore, Mary E.; Professor and Director; Toxicology; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 30-SEP-1979; Project End 31-MAY-2006 Summary: (provided by applicant): This proposal focuses on the effects of estradiol and its metabolites on the function and expression of Mrp2 (ABCC2), the ABC transporter that mediates the biliary excretion of glucuronide and glutathione conjugates from the hepatocyte into bile. The proposal builds on our findings that 1) Mrp2-mediated transport of estradiol-17Beta-(Beta-D-glucuronide) (E217G) is essential for its cholestatic activity, 2) E217G causes endocytic retrieval of Mrp2 from the canalicular membrane that coincides with decreased bile flow, and 3) expression of Mrp2 protein, but not Mrp2

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mRNA, is decreased in pregnancy. Aim 1 will test the hypothesis that transport of cholestatic E217G and the choleretic estradiol-3-glucuronide (E23G) by rat Mrp2 and human MRP2 is mediated by overlapping but non-identical substrate binding sites. We will use an Mrp2/MRP2 baculovirus expression system in Sf9 cells and probe the substrate binding sites of E217G vs E23G. We will also determine if women with intrahepatic cholestasis of pregnancy have polymorphisms in MRP2 that alter their transport of E217G vs E23G. Aim 2 will test the hypotheses that A) E217G causes endocytic retrieval of Mrp2 and other transporters critical to bile formation from the canalicular membrane leading to inhibition of flow, and B) agents that protect against cholestasis do so by either inhibiting Mrp2 transport of E217G or prevention of transporter retrieval. We will use confocal immunomicroscopy to monitor endocytic retrieval of transporters from and their exocytic insertion into the canalicular membrane. Aim 3 will characterize the changes in Mrp2 expression in pregnancy and test the hypotheses that A) estrogens mediate the decreased hepatic Mrp2 expression in pregnancy, B) Mrp2 is subject to transcript-specific translational control conferred by regulatory elements in the 5' or 3' untranslated regions of Mrp2 mRNA and C) pregnancy and estrogens increase the degradation of Mpr2 protein. We will use polysomal distribution analysis of Mrp2 mRNA, translation assays in HepG2 cells and determine the degradation half-life of Mrp2 protein in control, pregnant, and estrogentreated rats. Significance: Characterization of the mechanisms by which estrogens decrease Mrp2/MRP2 function and expression can lead to 1) improved drug therapy for women in pregnancy, 2) development of therapeutic measures to increase MRP2 function in cholestatic liver disease, and 3) methods to screen for cholestatic toxicity in drugs under development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: HEPATIC ENGRAFTMENT OF MARROW CELLS IN MICE AND HUMANS Principal Investigator & Institution: Theise, Neil D.; Associate Professor; Pathology; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JAN-2003 Summary: (provided by applicant): Identification of biopotent hepatic stem cells, able to regenerate both hepatocytes and cholangioctyes, could be of key therapeutic importance in the development of artificial livers, techniques of liver cell transplantation, and for use as target cells in gene therapies. Recent work indicates that the bone marrow of rodents harbors hepatic stem cells. The short-term goal of this project is to determine the kinetics of hepatic engraftment of bone marrow cells in mice by stimulating hepatic engraftment via different models of hepatic injury. CD34+lin- male, beta-galactosidase positive marrow cells, previously shown to accomplish such engraftment, will be transplanted into female, beta-galactosidase negative mice. Fluorescence in situ hybridization for Y-chromosome and histochemical staining for cytoplasmic betegalactosidase will identify hepatocytes and cholangiocytes of bone marrow origin. Hepatic engraftment of marrow cells will be quantitatively and topographically evaluated in different models of hepatic regeneration including: without any source of hepatic injury (c-kit deficient mutant mice); requiring no radiation, low dose radiation or myeloablative radiation; well characterized toxic injuries of specific cell compartments (perivenular and periportal hepatocytes, biliary epithelium); and pan-organ hypertrophy after partial hepatectomy. The long term aim is to determine if this hepatic engraftment is functional. The most reproducible models from the first phase of work will be applied to correction of genetic defects in hepatocytes, in particular, hepatocyte

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apical and basolateral secretory defects. Specifically, correction of hepatocyte secretory defects will be tested by transplanting: female transgenic mice expressive of human abnormal (PiZ) a-1-antitrypsin (A1AT) with marrow from male mice expressive of human normal (PiM) A1AT (basolateral defect); female mdr2 knockout mice, mimicking human Progressive Familial Intrahepatic Cholestasis, with bone marrow from male transgenic mice expressive of human MDR3 (apical defect). Finally, evidence of hepatic engraftment of marrow cells in humans will be sought by examining clinical (biopsy and autopsy) specimens from female recipients of therapeutic bone marrow transplants from male donors to determine applicability of these studies for treatment of human diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: HGF AND CAMP MEDIATED SURVIVAL FROM HEPATOCYTE APOPTOSIS Principal Investigator & Institution: Leveille-Webster, Cynthia R.; None; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 30-AUG-2004 Summary: (provided by applicant): The long-range goal of the proposed studies is to identify therapeutic strategies to slow the progression of cell injury in cholestatic liver disease. Cholestasis, the slowing of bile flow, accompanies viral, immunologic and toxic liver disease. A major form of liver cell death during cholestasis is apoptosis. Hepatocyte apoptosis in cholestatic disease is due, in part, to the retention of endogenous cytotoxic compounds normally excreted in bile. Among these retained hepatoxins are bile acids. Since bile acids induce apoptosis in hepatocytes, it is likely that they contribute to ongoing pathology in cholestatic hepatic disorders. The objective of these studies is to delineate the cellular mechanisms involved in bile acid induced hepatocyte apoptosis. The specific aims are targeted to determine the mechanisms involved in the anti-apoptotic effect of two compounds, cyclic AMP and hepatocyte growth factor. The studies are conducted in primary cultures of rat hepatocytes and will look at post-translational events controlled by the cytoprotective agents, particularly protein phosphorylation. They will examine the role of the lipid kinase, phosphoinositide-3 kinase, in the anti-apoptotic action of cAMP and HGF since previous studies have demonstrated that the survival effect of both agents is prevented when this kinase is inhibited. A second aim of these studies is to investigate how the substrata to which hepatocytes attach is capable of modulating the cell death response. Attachment to certain extracellular matrices, such as fibronectin or collagen, decreases the sensitivity of hepatocytes to bile acid induced apoptosis. This protection is correlated with the ability of the hepatocytes to spread on the matrix. Experiments will be conducted to determine if this spreading is necessary and sufficient for the protective effect and if so what are the cellular mechanisms that promotes both spreading and survival. Since the extracellular matrix composition of the liver is modified in cholestatic disease, elucidation of the mechanisms involved in matrix induced hepatocyte survival may have implications in the design of treatment protocols in chronic liver disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HORMONAL REGULATION OF BILE FLOW Principal Investigator & Institution: Simon, Francis R.; Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-AUG-1978; Project End 30-JUN-2005

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Summary: (Adapted from the Applicant's Abstract): Hepatic bile secretion is divided into bile salt dependent and independent processes. Canalicular bile flow results from coordinately regulated transport processes located at the sinusoidal sodium/taurocholate transporter and bile canalicular domains of hepatocytes. The applicant and his collaborators have examined the hormonal regulation of the canalicular multidrug resistance associated proteins. The long-range goal of the applicant's laboratory has been to characterize the hormonal regulation of membrane transporters involved in bile formation and to examine the alterations that are involved in the pathogenesis of cholestasis. Studies from the applicant's laboratory indicate that estrogens alter the liver specific expression of the sodium/taurocholate transporter through alterations in secretion of growth hormone. On the other hand, although the multidrug resistance protein is regulated by growth hormone, estrogens alter its expression by posttranslational mechanisms. The first aim is to examine the liverspecific expression and growth hormone regulation of the sodium/taurocholate transporter. The applicant will determine whether it is controlled by the interaction of liver specific transcription factors which may be regulated by growth hormone. The human sodium/taurocholate transporter gene has been cloned, and the applicant will characterize the transcription factors involved in its regulation using transfection assays, analysis of protein-protein interactions and mutation of putative domains. The second aim is to determine the specific molecular and cellular processes regulating hepatic multidrug-resistance protein 2 at the transcriptional and posttranslational level by pituitary hormones and estrogens, respectively. The applicant will characterize the human promoter, determine the effect of estrogens on its trafficking itinerary and examine the role of putative phosphorylation sites and protein binding domains on posttranslational regulation using intact rats, cell culture models and adenovirus transfections in rats. Taken together, these studies will provide an understanding of the hormonal control of the molecular and cellular events regulating sinusoidal and canalicular transporters that are involved in formation of bile flow and the alterations involved in the pathogenesis of cholestasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: IL-6 AND HEPATIC DYSFUNCTION IN SEPSIS Principal Investigator & Institution: Deutschman, Clifford S.; Professor; Anesthesia; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: ( Applicant's abstract.) Sepsis and the related Systemic Inflammatory Response Syndrome (SIRS) and Multiple Organ Dysfunction Syndrome (MODS) are important causes of death and disability in surgical or injured patients, although the exact cause of death is often obscure. These disorders are complex, involve a number of molecular mediators and effect most organs. Little is understood, however, about the manner in which organ dysfunction develops in these diseases. One important organ that is damaged in sepsis/SIRS/MODS is the lever. Intra-abdominal fecal contamination causes SIRS/MODS-like abnormalities in the liver of rodents. In this study we will examine one proposed mechanism that we believe contributes to the development of liver dysfunction in sepsis /SIRS/MODS. We have shown that intra-abdominal fecal contamination causes an early down regulation of transcription in this organ. This change affects many genes, including some encoding molecules that 1) transfer bile acids out of liver cells and into the biliary system and 2) allow liver cells to burn fat. We propose that the inflammatory cytokine IL-6 mediates some aspects of decreased gene expression, leading to liver cells that cannot excrete bile salts or burn fat. A build-up of

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bile salts and fat in liver cells "poisons" them so that they die. When enough liver cells die, liver dysfunction develops. The role played by IL-6 in this proposed mechanism of hepatic dysfunction will be studied in the setting of normal IL-6 levels, IL-6 absence, IL6 excess and IL-6 repletion after depletion. Several specific measures will be studied. These include 1) transcription of the bile acid transporters Ntcp and Mrp2 and the ratelimiting enzyme in fat oxidation, CPTII, to be determined using transcription elongation analysis, 2) activation of two hepatic nuclear proteins, C/EBPalpha and HNF-1alpha, that modulate transcription of Ntcp, Mrp2 and CPTII and 3) the development of cholestasis (bile trapping in cells) and steatosis (fat trapping in cells) as indicated by microscopic examination of fixed liver sections. In addition, we will mimic IL-6 levels in sepsis in normal mice by 1) administering intravenous IL-6 and 2) injecting a virus that is taken up by the liver and produces high intrahepatic levels of IL-6. We will then study transcription, transcription factor activation, cholestasis and steatosis. These studies should provide key information on the role played by an important inflammatory mediator, IL-6, in the complex series of events that results in the hepatic dysfunction of SIRS/MODS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: IMPROVED LIVER FUNCTION AND REGENERATION WITH A20 Principal Investigator & Institution: Ferran, Christiane; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Necrosis and apoptosis of hepatocytes are critical pathologic features associated with liver injury. Hepatocyte apoptosis is a feature of viral hepatitis, ischemic liver injury, sepsis, cholestasis, and a result of exposure to hepatotoxic substances such as ethanol, acetaminophen and cytostatic drugs. Massive hepatocyte apoptosis and necrosis result in fulminant hepatic failure (FHF). Only 14% of patients diagnosed with FHF recover with medical therapy. Orthotopic liver transplantation (OLT) has dramatically improved the fate of these patients (49% undergo OLT), yet 37% die while awaiting OLT. This gloomy picture is balanced by the unique capacity of the liver to regenerate. Hepatocyte replication leads to a full recovery of liver function and mass 1-2 weeks following surgical, viral or chemical hepatic loss. We propose that protecting hepatocytes from apoptosis and promoting their proliferation are two strategies that could beneficially impact FHF. Our preliminary data demonstrate that A20 promotes hepatocyte proliferation and is anti-apoptotic. A20 is part of the physiologic response of hepatocytes to injury. A20 is upregulated in hepatocytes by pro-inflammatory stimuli including TNF and LPS and functions to protect from TNF mediated apoptosis. Gene transfer of A20 to mice livers protects from lethality in the galactosamine and LPS (D-gal/LPS) model of toxic FHF. Adenovirus mediated expression of A20 in livers of BALB/c mice yields an 89% survival rate following administration of D-gal/LPS as compared to 15-20% in control mice. Mice expressing A20 maintain normal liver function as assessed by prothrombin time while controls suffer from a severe bleeding diathesis. Expression of A20 in the liver protects from lethality associated with a subtotal (87%) liver resection (LR). In this model, resection of 87% of the liver mass results in 100% lethality. In contrast, >60% of mice expressing A20 survive the 87% LR and demonstrate increased regenerative capacity as assessed by the number of PCNA (proliferating cell nuclear antigen) positive nuclei in the liver. These results qualify A20 as a critical gene involved in accelerating liver regeneration and promoting hepatocyte survival and function, even when facing extreme metabolic demands. These encouraging results prompted the submission of this

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proposal. Our specific aims are i) to dissect, in vitro, the molecular basis of the (1) antiapoptotic and (2) pro-proliferative function of A20 in hepatocytes and ii) to confirm that liver directed gene therapy using A20 will beneficially impact upon toxic, FAS-mediated and surgical experimental models of FHF. From a basic science standpoint, the in vitro work proposed will address the effect of A20 upon transcription factors and expression of genes involved in apoptosis, activation and proliferation of hepatocytes. This should unveil many unknowns in our understanding of hepatocyte biology and could lead to the discovery of novel therapeutic targets. From a therapeutic standpoint, validation of the beneficial effect of A20 in the murine in vivo models of FHF should set the basis for extending this approach to models of FHF in non human primates and potentially to clinical applications. The generation of novel safer and tissue specific viral vectors for gene transfer and the development of non-viral means of protein delivery to cells will facilitate clinical translation of A20 based therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: LASER RESEARCH/EDUCATION

SCANNING

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MICROSCOPE

Principal Investigator & Institution: Nathanson, Michael H.; Professor and Chief; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003 Summary: (provided by applicant): This proposal seeks to acquire a point-scanning confocal fluorescence microscope for the Center for Cell Imaging at Yale University School of Medicine. The ongoing renaissance in the use of light microscopy for cell and molecular biology and physiology has been driven in large part by the development of specific fluorescent probes of cell structure and function, coupled with confocal fluorescence microscope systems that extend our abilities to visualize and quantitate such probes in cells and tissues. Laser scanning confocal microscopy, because of its ability to "optically section" cells and tissues, provides a tool with the spatial resolution needed to define structure in live and fixed cells alike, along with the temporal resolution to follow dynamic processes in living cells. Specific projects that would take immediate advantage of this equipment include regulation of osteoclast function and bone resorption, MHC transport in dendritic cells, establishment of polarity in epithelia and neurons, molecular basis for bile secretion and cholestasis, regulation of oogenesis, and subcellular mechanisms of calcium signaling. Although our facility already has a confocal microscope and a two photon microscope, these are so heavily used that an additional confocal microscope now is needed to assure that our investigators will continue to have adequate access to state-of-the-art imaging techniques. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: MECHANISM OF ACTIVATION OF THE JNK PATHWAY BY BILE ACIDS Principal Investigator & Institution: Gupta, Seema; Microbiology and Immunology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2007 Summary: (provided by applicant): The studies in this proposal address the specific role that signaling pathways play in regulation of bile acid biosynthetic enzymes, specifically the enzyme cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the neutral pathway of bile acid biosynthesis. Recent findings from our laboratory provide

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strong evidence that activation of the c-Jun N-terminal Kinase (JNK) pathway by bile acids plays a pivotal role in regulation of CYP7A1 in primary rat hepatocytes. However, the molecular events by which bile acids activate this pathway have not yet been fully elucidated, but may have important implications in the pathogenesis of hypercholesterolemia and cholestatic liver diseases. It is proposed that interplay of ceramide and FAS within outer membrane lipid rafts is capable of regulating CYP7A1 through JNK activation. The objectives of this application are to (1) determine the mechanism(s) of activation of the JNK pathway by bile acids by defining the role of the FAS receptor in the activation of JNK in primary hepatocytes, (2) investigate the involvement of sphingomyelinases and ceramide in activation of the FAS receptor by bile acids, (3) determine whether the mechanism(s) of in vitro regulation of CYP7A1 by bile acids also apply in vivo, using FAS and acidic sphingomyelinase knock-out mice. An integrative approach combining kinase assays, ceramide measurements, fluorescence imaging, serum lipid analysis, and other molecular biology techniques will be applied to the proposed studies. Studies will be performed at Virginia Commonwealth University's-Medical College of Virginia Campus. The Department of Microbiology and Immunology and the Liver Centre at VCU are fully committed to support this research endeavor and to further develop the candidate's research career by providing the protected time, resources, and continuing research educational opportunities. This will enable the candidate to achieve her long term career goals of forming a fundamental understanding of bile acid-mediated signaling to serve as a basis for the development of effective therapies to reduce serum cholesterol levels and limit cholestasis-associated liver damage, and to develop an independent and successful research career. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: MECHANISM OF CANALICULAR BILE FORMATION AND CHOLESTASIS Principal Investigator & Institution: Anwer, M. Sawkat.; Distinguished Professor & Chairman; Biomedical Sciences; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2002; Project Start 01-JUL-1983; Project End 30-JUN-2004 Summary: The long-term objective of the present proposal is to more clearly define cellular mechanisms involved in hepatic solute transport and bile formation. Solute transport from blood to bile is an important function of the liver, with accumulation of (otherwise excreted) endogenous and exogenous solutes in blood being a common feature of cholestasis. The major focus of this proposal will be to define the role of phosphoinositide-3-OH kinase (PII3K), protein kinase B (PKB), mitogen activate protein kinase (MAPK) and protein phosphatases (PP2A and PP2B) in hepatic bile acid transport from blood to bile. Sinusoidal Na+/taurocholate (TC) co-transport is mediated via Na/TC co-transport peptide (ntcp), and canalicular ATP-dependent bile acid transport is mediated via a sister P-glycoprotein (spgp). The following hypothesis will be tested: 1) The short term regulation of Na+/TC co-transport by cAMP involves translocation of ntcp to the sinusoidal membrane; the translocation require PI3K/PKB activity, involves vesicular transport and is facilitated by dephosphorylation, a process stimulated by PP2A and PP2B, and inhibited by MAPK, and 2) PI3K and MAPK stimulate canalicular ATP-dependent bile acid transport by translocating spgp to the canalicular membrane. Effects of various activators and inhibitors of kinases and phosphatases on sinusoidal and canalicular bile acid transport will be studied in isolated perfused rat livers, rat hepatocytes and plasma membrane vesicles using established techniques. The effectiveness of various inhibitors and activators will be assessed by

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determining the activity of PI3K, PKB, MAPK and PPA2/2B. MDCK cells stably transfected with wild- type and mutant ntcp will be used to determine the role of phosphorylation in translocation and transport activity. Transporter translocation will be evaluated by determining transporter mass in plasma membranes isolated from hepatocytes/livers treated with various activators/inhibitors. Suggestive evidence for the involvement of a kinase/phosphatase will be obtained through transport studies in hepatocytes/perfused livers using known inhibitors and activators. Direct modification of the transporter will be assessed by determining transport activity and transporter mass and phosphorylation in membrane vesicles treated with specific kinases/phosphatases. Collectively, proposed studies should provide further insight into cellular mechanisms involved in the regulation of hepatic bile acid transport. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: MECHANISMS OF BILE SECRETION AND CHOLESTASIS Principal Investigator & Institution: Boyer, James L.; Professor; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 01-SEP-1978; Project End 30-JUN-2008 Summary: (provided by applicant): Bile secretion is a major function of the liver which is frequently impaired in diseases of the liver resulting in the syndrome of cholestasis. The long term objectives of this grant (since 1973) have been to characterize the basic transport mechanisms in hepatocytes and bile duct epithelial cells (cholangiocytes) that determine the secretion of bile and to define, at the cellular and molecular level, alternations in these mechanisms that result in cholestatic liver disease. Thus the specific aims of this proposal are: 1) to understand the molecular mechanisms for transcriptional regulation of membrane transporters in liver, kidney and intestine that are important determinants of bile formation and that undergo adaptive regulation in cholestatic liver injury. In particular we will examine the role of nuclear transcription factors in adaptive responses of several ABC transporters, Mrp2, Mrp3 and Bsep and the influence of cytokines on this process. Mechanisms of transcriptional regulation of the human MRP3 promoter will be sought as well as the effects of cholestasis on the expression of organic cation transporters (Octs) and Mrp4 in liver, kidney and intestine and the ameliorating effects of ursodeoxycholic acid. By understanding the mechanisms of these adaptive changes, ways may be found to diminish cholestatic liver injury; (2) to characterize posttranscriptional mechanisms of regulation of the expression of canalicular ABC transporters. Utilizing a series of Bsep-GFP mutants that cause PFIC-II in children, we will determine if chemical chaperones can correct defects in targeting of these mutants to apical domains when expressed in MDCK cells using confocal microscopy. The effects of agonists and inhibitors on post-transcriptional Bsep-GFP targeting will also be examined. The role of "tethering" proteins (ezrin, radixin, EKARP, EBP50) in the targeting of Mrp2, Bsep and Mdr1 to the canalicular domain in hepatocytes will also be examined; (3) caracterization of transport mechanisms in cholangiocytes. The effects of gender and estrogens on the role of these tethering proteins will also be compared in cyclic AMP mediated secretion in cholangiocytes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF LIVER CELL INJURY Principal Investigator & Institution: Gores, Gregory J.; Professor of Medicine; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 30-SEP-1992; Project End 31-MAR-2005

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Summary: The overall objective of this proposal is to understand the cellular mechanisms by which bile salts, which accumulate in the liver during cholestasis, modulate hepatocyte apoptosis. The central hypothesis proposed is that hydrophobic hepatotoxic bile salts induce hepatocyte apoptosis by a Fas-dependent mechanism while more hydrophilic bile salts inhibit apoptosis by actively stimulating a phosphoinositide 3-kinase (PI3K)-dependent survival pathway. The proposal will use complementary molecular, biochemical, and cell biological approaches to ascertain how bile salts modulate apoptotic effector processes in three specific aims. Specific aim one will test the hypothesis that toxic bile salts induce hepatocyte apoptosis by a Fas-dependent process resulting in a) Fas oligomerization independent of Fas ligand; and b) formation of a death-inducing signaling complex (DISC) with caspase 8 activation. Specific aim two will test the hypothesis that toxic bile salts increase plasma membrane Fas receptors: a) by a mechanism dependent upon a redistribution of pre-existing cytoplasmic Fas to the plasma membrane via a microtubule-dependent transport pathway; and b) resulting in a mechanism of apoptosis dependent upon intracellular Fas translocation to the cell surface. Specific aim three will test the hypothesis that non toxic, hydrophilic bile salts directly signal cell survival pathways by a PI3K-dependent mechanism resulting in: a) activation of anti-apoptotic atypical protein kinase c isoforms; and b) inhibition of apoptosis by atypical PKC-dependent activation of nuclear factor kappa B (NF-kappa B) and/or caspase phosphorylation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: MOLECULAR ALAGILLE SYNDROME

&

PHENOTYPIC

CHARACTERIZATION

OF

Principal Investigator & Institution: Spinner, Nancy B.; Associate Professor of Human Genetics In; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: MOLECULAR ANALYSIS OF TIGHT JUNCTIONS IN LIVER AND GUT Principal Investigator & Institution: Anderson, James Melvin.; Professor and Chair; Cellular/Molecular Physiology; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 01-FEB-1992; Project End 30-JUN-2008 Summary: (provided by applicant): The long-range goal of this project is to understand the molecular basis for regulating paracellular transport of solutes across the tight junctions of epithelia in the gastrointestinal tract and liver. Barrier characteristics of tight junctions vary widely among cell types in terms of electrical resistance, solute flux and ionic charge selectivity. When the barrier is disrupted by pathogenic factors in different tissues (inflammation, specific bacterial toxins, drugs, etc.) transport is arrested leading to diarrhea, cholestasis, or enhanced entry of antigens and microbes. Presently the molecular basis for the barrier, its variable properties and regulation are poorly understood. In the proposed studies we will pursue the hypothesis that a newly described family of transmembrane proteins called the claudins are responsible for forming the barrier and its selectivity properties. First, we will examine whether selected members of the 20 claudins show different immunohistochemical location among

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different cell types of the GI tract. We will determine in human tissues whether the expression levels and patterns change in the colon and small bowel in response to cancer and inflammation. Differential expression patterns and responses will be considered consistent with a role in providing the junction's variable properties. Second, we will directly test the ability of individual claudins to alter barrier properties such as electrical resistance, solute flux and ion selectivity when expressed in cultured epithelial cells. We will attempt to define the protein sequences involving in creating the barrier's variable properties through site-directed mutageneis of the extracellular sequences. Third, we will define the protein structural basis for the barrier by determining the oligomeric state of claudins solubilized from membranes into non-ionic detergents using biochemical and biophysical methods and chemical cross linking. We will determine whether the basic protein unit of the barrier is homo- or heteromeric and attempt direct structural analysis using cryo-electron microscopy. This will allow us to see how the proteins fold and contact to create a selective barrier. Structural information will be correlated with the physiologic and mutagenesis studies. The physiologic and structural properties of a second Tight Junction transmembrane protein occludin, will be compared with the claudins. Together these studies will provide significant and novel advancements in our understanding of how paracellular transport is regulated and is altered in disease Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: MOLECULAR BASIS OF CHOLESTEROL METABOLISM Principal Investigator & Institution: Goldstein, Joseph L.; Chairman and Professor; Molecular Genetics; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-JUL-1977; Project End 30-JUN-2007 Summary: (provided by applicant): This Program Project Grant began 25 years ago when we defined the LDL receptor pathway for the control of cholesterol metabolism and showed that defects in this pathway produce Familial Hypercholesterolemia and its attendant atherosclerosis. After 25 years, our goals remain the same: to understand the genetic and metabolic defects that produce hypercholesterolemia and accelerated atherosclerosis and to use this knowledge to prevent and treat the disease. During the last grant period ( Years 20-24), we have made considerable progress with the following notable achievements: 1) discovery of the SREBP pathway as the central regulatory mechanism for cholesterol homeostasis; 2) appreciation of the role of the SREBP pathway in overproduction of fatty acids in diabetic states; 3) molecular delineation of the pathways for bile acid biosynthesis, and elucidation of the molecular defects responsible for two forms of neonatal intrahepatic cholestasis in humans; 4) discovery that two members of the LDL receptor gene family are required for the development of normal brain architecture; and 5) elucidation of the role of cholesterol-rich caveolae and other cholesterol-rich structures in concentrating signaling receptors at the cell surface. We now apply for a 5-year renewal of our Program Project Grant (Years 26-30) that will allow us to further study these phenomena through an integrated and multidisciplinary approach. We propose to focus on 25 key molecules involved in three biological processes: 1) cholesterol and fatty acid metabolism (SREBP-1a, SREBP-1c, SREBP-2, SCAP, Site-1 protease, Site-2 protease, LDL receptor, HMG CoA reductase, fatty acid synthase, acetyl CoA synthase, IRS-1, IRS-2); 2) oxysterol and bile acid metabolism (cholesterol 7alpha-hydroxylase, oxysterol 7alpha-hydroxylase-1 and -2, cholesterol 24hydroxylase, cholesterol 25-hydroxylase, sterol 27-hydroxylase); and 3) caveolae membrane system and cell signaling (caveolin-1, LRP, VLDL receptor, ApoER2, Reelin, RAP, HDL receptor). A series of model systems will be used to study the mechanisms

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by which these proteins operate at the molecular level (i.e., the gene, the mRNA, and the protein), at the level of the intact cell, at the level of the whole animal, and at the level of the human patient. In conducting these studies, we will use a wide variety of techniques, including biochemistry, immunology, molecular biology, genetics, cell biology, electron microscopy, transgenic and knockout mice, animal physiology, clinical genetics, and human genomics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: MOLECULAR MECHANISMS OF MALTOSE TRANSPORT Principal Investigator & Institution: Davidson, Amy L.; Assistant Professor; Molecular Virology & Microbiol; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 01-MAY-1993; Project End 30-APR-2007 Summary: (provided by applicant): Binding-protein-dependent transport systems in bacteria are members of the ATP-binding cassette (ABC) superfamily. ABC transporters secrete virulence factors in bacteria and contribute to the drug resistance of several pathogens. Genetic defects in human homologs are responsible for over a dozen serious human diseases including cystic fibrosis, adrenoleukodystrophy and cholestasis. The maltose transport system of E. coli is well characterized and is therefore an ideal model for the study of ABC transporters. A periplasmic MBP directs maltose to a membraneassociated transport complex containing two transrnembrane-spanning proteins, MalF and MalG, and two copies of a peripheral ATP-binding-protein, MaIK. ATP hydrolysis by the multisubunit complex drives maltose transport. The applicant's long-term objective is to understand how the structural and mechanistic features of the maltose transport system result in active transport. As this mechanism is complex, the approach is to stabilize intermediates in the pathway and characterize them using biochemical and biophysical approaches. In this project, the investigators will use site-directed spin labeling and EPR, along with other complementary techniques, to define the movements that occur in moving from one intermediate to the next. The purified preparations will also be used in collaborative efforts to obtain high-resolution structures of the multisubunit complex in different conformational states. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR PHYSIOLOGY OF BILIARY LIPID SECRETION Principal Investigator & Institution: Cohen, David E.; Associate Professor; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2003; Project Start 01-FEB-1996; Project End 31-JUL-2008 Summary: (provided by applicant): Bile is the principal pathway for cholesterol elimination from the body, and high density lipoproteins (HDL) in plasma are the principal source of biliary cholesterol. However, hepatocellular mechanisms for uptake, transport and biliary secretion of HDL-derived cholesterol remain poorly understood. Scavenger receptor class B type I (SR-BI) is highly expressed in liver and promotes uptake of HDL lipids. Caveolae are cholesterol- and sphingolipid-rich membrane microdomains, which participate in cellular cholesterol transport. Both caveolin-1, the structural protein of caveolae, and SR-BI are expressed on the sinusoidal and canalicular domains of hepatocyte plasma membranes. Specific Aims 1 and 2 of this proposal will test the hypothesis that caveolae constitute a vesicular pathway that is responsible for sinusoidal HDL uptake and delivery to the canalicular membrane. Using mice with targeted disruption of genes encoding caveolin-1 and SR-BI, Specific Aim 1 will explore contributions of caveolin-1 and SR-BI to hepatic lipoprotein clearance and biliary lipid

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secretion. Primary cultures of hepatocytes from genetically engineered mice will be used to dissect contributions of caveolin-1 and SR-BI to binding and uptake of HDL. Specific Aim 2 will examine a role for caveolae in trafficking of HDL through the hepatocyte. Real time confocal fluorescence microscopy of HUH-7 hepatoma cells, which have been transfected with a green fluorescent protein-caveolin-1 fusion protein, will be employed to characterize uptake of luorescence-labeled HDL, processing within the endosomal compartment and trafficking to the canalicular membrane. An in vitro vesicle motility assay will be used to explore a role for microtubules in transport and sorting of vesicles containing HDL, SR-BI and caveolin-1. Hepatocellular secretion of phosphatidylcholines into blood and bile is critical for HDL metabolism and bile formation, respectively. Phosphatidylcholine transfer protein (PC-TP) is a cytosolic lipid transfer protein of unknown function that is highly expressed in liver. Specific Aim 3 will utilize PC-TP knockout mice to test the hypothesis that PCTP provides a nonvesicular pathway for phosphatidylcholine transport to the plasma membrane for incorporation into biliary vesicles and HDL particles. PC-TP knockout mice will be used to explore a role for this protein in biliary elimination of plasma cholesterol. These studies should elucidate the mechanisms of biliary lipid secretion at a fundamental cellular level and potentially lead to early interventions in cholestasis and cholelithiasis, as well as new strategies for management of hypercholesterolemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: MOLECULAR REGULATION OF HEPATIC TRANSPORTERS Principal Investigator & Institution: Karpen, Saul J.; Associate Professor; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 31-AUG-2004 Summary: Our understanding of the molecular determinants of bile formation and cholestasis has been greatly enhanced over the past few years as direct consequence of the cloning of hepatobiliary transporter genes. Recent findings indicate that reductions in the expression of transporter genes can lead to cholestasis, and that the underlying mechanisms involve specific down-regulation of transcription. The overall objectives of this proposal are to define the humoral mediators and molecular pathways that transcriptionally regulate hepatobiliary transporter genes. Initial studies will concentrate on expanding our ongoing work on the regulation of one of the best characterized hepatobiliary transporter genes, the basolateral Na+-dependent bile acid co-transporter, ntcp, in order to provide a focused framework to explore the regulation of other critical genes involved in bile formation. Aim 1. Determine the cellular and molecular contributions leading to endotoxin-induced down-regulation of the ntcp gene. Aim 2. Determine the molecular signaling pathways and nuclear transactivators that regulate the ntcp gene promoter. Aim 3. Determine if bile acids themselves regulate the ntcp gene promoter. Aim 4. Investigate common regulatory pathways of hepatobiliary transporter genes. The limited availability of effective agents to treat cholestatic diseases detailed explorations into avenues of research that could impact upon the design and use of novel therapeutics. Long-range goals include the potential translation of these studies into the development of transcriptionally active compounds (e.g., bile acids or nuclear hormone receptor ligands) adapted towards ameliorating the pathogenesis of cholestasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR REGULATION OF ILEAL/RENAL BILE ACID TRANSPORT Principal Investigator & Institution: Shneider, Benjamin L.; Associate Professor of Pediatrics; Pediatrics; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2003; Project Start 30-SEP-1997; Project End 31-MAR-2007 Summary: (provided by applicant): The apical sodium-dependent bile acid transporter (ASBT) is the major carrier protein involved in intestinal reclamation of bile salts. Complete genetic disruption of its activity leads to pathologic bile acid induced diarrhea in humans, while partial inhibition can be used to treat hypercholesterolemia and cholestasis. ASBT is expressed on the apical surface of ileal enterocytes, renal tubules, and cholangiocytes. In the rat ileum, ASBT undergoes a biphasic pattern of developmental expression. Bile acid responsiveness of ASBT is species specific. ASBT is down regulated in the ileitis and up regulated by corticosteroids. Adaptation by ASBT after intestinal resection is dependent upon the length of residual ileum. These changes in ASBT expression are controlled at the level of transcription and mRNA stability. The rat, mouse, and human ASBT promoters have been cloned in my laboratory. HNF1alpha, AP-1 and LRH-1 are critical elements in the transcriptional regulation of ASBT. This proposal will define the molecular mechanisms involved in the regulation of the ASBT gene. Transcriptional regulation will be studied with chimeric luciferase promoter reporter constructs, DNA:protein gel shift analysis, and transgenic mice. Molecular mechanisms of transcriptional modulation of ASBT gene expression will be analyzed in normal physiology and pathologic states (altered bile acid homeostasis, ileal inflammation and intestinal resection). The role of mRNA stability will be assessed by identification of mRNA destabilizing elements in the ASBT transcript and by characterization of RNA:protein interactions. Cell-free systems and/or transgenic animals will be utilized to assess the role of these elements in developmental-stage and organ specific expression. The results of these studies will be highly significant in light of the crucial role that ASBT plays in human health and disease. The ASBT gene also represents a valuable model of important and poorly defined biological processes in the intestine, such as transcriptional regulation of ontogeny and tissue specificity and the role of mRNA stability in intestinal gene regulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MRP4 IN DRUG SENSITIVITY AND PHYSIOLOGY Principal Investigator & Institution: Schuetz, John D.; Associate Member; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2004; Project Start 01-APR-2000; Project End 31-MAR-2008 Summary: (provided by applicant): ABC transporters are increasingly recognized as genes that play important roles in normal biology and in the therapeutic response to medications. Among the many mammalian ABC transporters that have been identified in the human genome, the functions of some have been deduced because "accidents of nature" produced mutations that render loss of function. However, for many ABC transporters the biological substrate is unknown and no adventitious accident of nature has been identified. One successful approach to identifying function is to develop drug resistant cell lines with resistance due to drug efflux and then identify an ABC transporter that dominantly imparts this resistance by drug efflux. This was the case for the ABC transporter Mrp4 that was an orphan ABC transporter until our studies first determined that it was unique in its ability to transport nucleotide analogs used in HIV

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therapy. During the last funding period of this application we used cell line model systems to expand Mrp4's biological substrates (e.g., cAMP and conjugated steroids) and the drugs (mercaptopurine nucleotides) it confers resistance. We also discovered that Mrp4 was expressed in the liver and it's expression dramatically increased as an adaptive response to the accumulation of cholestatic bile acids. Our current research will focus on understanding the function of Mrp4 in vivo. I have developed an Mrp4 nullizygous mouse with T cells that have impaired cAMP efflux. In contrast, T cells from Mrp4 +/+ mice readily efflux cAMP. Moreover, these Mrp4 -/- T cells have a defect in proliferation. The relationship between Mrp4 regulation by the second messenger cAMP and the relation with proliferation will be further explored in Aim 1 of the current application. Because our results show that Mrp4 has a role in the transport of cholestatic conjugated bile salts and is upregulated under cholestatic conditions, I will determine if Mrp4 absence renders the liver more susceptible to cholestatic injury. I will also use the Mrp4 -/- animals to identify mechanisms (Aim II) in the liver that compensate under cholestasis, but are independent of Mrp4. I will also determine if nuclear receptors (e.g., the pregnane X receptor, PXR) contribute to Mrp4 upregulation in Aim II by using nuclear receptor knockout models. Finally, to more fully elucidate the signaling processes and cross talk among these Mrp4 activation pathways we will develop an Mrp4-GFP knock-in mouse model in Aim III. Cumulatively, these studies will increase our knowledge of this increasingly important ABC transporter and provide insight into how Mrp4 plays a role in hematopoietic cells and the liver Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: MULTIPLE MECHANISMS OF HEPATOPROTECTIVE MRP3 INDUCTION Principal Investigator & Institution: Cherrington, Nathan J.; Pharmacology and Toxicology; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2003; Project Start 18-SEP-2003; Project End 30-JUN-2006 Summary: The goal of this project is to determine the mechanism(s) by which Mrp3 is transcriptionally activated in a hepatoprotective response. Mrp3, which is localized to the sinusoidal membrane of hepatocytes, exports a wide range of I organic anions from the liver, into the blood. Thus, the role of hepatic Mrp3 is to decrease the concentration of potentially toxic molecules in the liver. Mrp3 expression is normally low in liver but is significantly increased after exposure to certain inducers and also during cholestasis, further demonstrating the importance of Mrp3-mediated export as a means of hepatoprotection. Cholestatic liver injury results in a substantial clinical burden leading to an estimated 100,000 deaths per year often listed as multiple organ dysfunction. The current clinical management of chotestasis includes phenobarbital, which decreases hepatotoxicity as a side effect of cholestasis. I have previously demonstrated that treatment with multiple reducers of CYP2B 1/2, (transcriptionally activated by CAR) such as phenobarbital, as well as inducers of NADP(H):quinone oxidoreductase (activated through Nrf2) are also capable of inducing Mrp3, showing coordinate regulation of both the Phase I drug-metabolizing genes and Phase III xenobiotic transporters. It has also been demonstrated that cholestasis results in increased Mrp3 but decreased CYP2B 1/2 levels suggesting distinct mechanisms involved in the regulation of Mrp3. Additionally, other outcomes of cholestasis include an increase in oxidative stress, hyperbilirubinemia, inflammation and cytokine releasc, all of which, individually, effect the regulation of xenobiotic transporters or Phase I drug metabolizing genes in a manner consistent with the effects of cholestasis. Therefore, the following aims have been designed to test the hypothesis that Mrp3 is differentially

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regulated during periods of both chemical insult and cholestatic stress: 1) Determine the role of the Constitutive Androstane Receptor in transcriptional activation by microsomal enzyme inducers that activate Mrp3 expression. 2) Determine whether the induction of Mrp3 during cholestasis is mediated by either prooxidant or antioxidant activation of Nrf2.3) Determine whether cytokine release, signaling, and NF-kB activation are responsible for the differential regulation of Mrp3 during cholestasis. 4) Define the Mrp3 promoter elements that are responsible for the transcriptional activation during both chemical insult and cholestatic stress. Understanding the mechanisms that control Mrp3-mediated excretion of organic anions can potentially serve the scientific community in our objective to create safe and biologically active drugs that alleviate specific transport deficiencies or up-regulate the excretion of chemicals in patients or exposed individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: NOVEL DRUG TARGET FOR METABOLISM

BILE AND

CHOLESTEROL

Principal Investigator & Institution: Thacher, Scott M.; Orphagen Pharmaceuticals 5310 Eastgate Mall San Diego, Ca 921212804 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-MAY-2004 Summary: (provided by applicant): Regulation of bile acid metabolism is a therapeutic target for treatment of hypercholesterolemia as well as for cholestasis, the pathological buildup of bile in liver. Therapeutic options for direct modulation of hepatic bile formation and transport are limited. Orphagen proposes to develop and commercialize lead molecules that regulate gene transcription by the orphan nuclear receptor LRH-1 (liver receptor homolog-1). LRH-1 appears to stimulate reverse cholesterol transport, bile formation, and bile transport. The effort to identify the first pharmacologically active compounds to LRH-1 is part of a larger program to create drugs to structurallyrelated orphan nuclear receptors that regulate mammalian steroid and cholesterol metabolism. In Phase I, an indirect binding assay for compound screening at LRH-1 will be implemented based on findings from Drs. Holly Ingraham and Kip Guy at U. C. San Francisco. LRH-1 will be screened against a focused small molecule compound library developed at Orphagen. Cell-based reporter gene assays will be implemented in parallel to accelerate identification and confirmation of small molecules that regulate gene transcription by LRH-1. Drug candidates suitable for animal studies of hypercholesterolemia and cholestasis will be synthesized and tested in Phase II and a strategic partner recruited for further development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: NTPDASE2 EXPRESSION AND FUNCTION IN THE LIVER Principal Investigator & Institution: Dranoff, Jonathan A.; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-JUN-2006 Summary: (provided by applicant): The goal of this proposed research is to define the expression and function of the ecto-nucleotidase NTPDase2 in the liver. This project will extend the findings of the intial K08 application into a novel area for the PI, which should ultimately lead to an ongoing stream of research in this area. The aims of the initial K08 application were to define the P2Y receptor subtypes expressed in bile duct epithelia (BDE), to define the polarized expression of these receptors in BDE, and to determine whether these receptors link to bile ductular secretion. As hypothesized, BDE

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were found to express multiple P2Y subtypes, to express these subtypes at both basolateral and apical plasma membrane domains, and to link to bile ductular secretion. However, an unexpected finding was the selective inactivation of basolateral P2Y receptors by nucleotide hydrolysis. To investigate this finding further, the expression of ecto-nucleotidases known as nucleoside triphosphate diphosphohydrolases (NTPDases) in the liver was investigated. The ectonucleotidase NTPDase2 was found to be expressed in portal fibroblasts (PF) surrounding intrahepatic bile ducts, which provides a likely explanation for the selective hydrolysis of nucleotides at the basolateral aspect of BDE. New data suggest that NTPDase2 functions to regulate the proliferation of BDE through inhibition of basolateral bile ductular P2Y receptors. We now propose to investigate the physiologic function of NTPDase2 in the liver through the three following Specific Aims: (1) Determine whether PF suppress the proliferation of bile duct epithelia (2) Determine whether blockade of NTPDase2 expression in PF via NTPDase2 siRNA restores proliferation of bile duct epithelia (3) Determine whether blockade of NTPDase2 expression in PF via common bile duct ligation restores proliferation of bile duct epithelia The experiments proposed in these specific aims will provide the basis of several new lines of liver disease research and should provide novel therapeutic targets for treatment of cholestatic and fibrotic liver disease Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

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 2002; 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

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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 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 x

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 2002; 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: PI KINASES, CANALICULAR TRANSPORTERS AND CHOLESTASIS Principal Investigator & Institution: Arias, Irwin M.; Professor and Chairman; Physiology; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 31-AUG-2004 Summary: Mechanisms responsible for intracellular cholestasis and regulation of intracellular trafficking of the ATP-dependent canalicular transporters spgp (taurocholate), mrp2 (nonbile acid organic anions), mdr1 (organic cations), mdr3 (phosphatidylcholine translocase) and newly described mrp3 (glycocholate) are poorly understood. An intact microtubular network and vesicular trafficking originating in the trans-Golgi network and concluding in the bile canalicular membrane are required. Both are associated with PI 3-kinase activity and are blocked by Wortmannin and LY294002, which are PI 3-kinase inhibitors. Activation of PI 3- kinase in intact cells accelerates bile acid secretion. We propose that PI 3-kinase lipid products are essential for vesicular trafficking of the ATP-dependent canalicular transporters as well as for their activity in the canalicular membrane. We also postulate that generation of these phospholipids is defective in certain forms of cholestasis. Using biochemical, molecular and confocal fluorescence microscopic techniques and novel reagents and experimental models, including genetically engineered p85-/- PI 3- kinase mice, the specific trafficking of canalicular transporters and the role of PI 3-kinase and its lipid producers in bile secretion will be determined. These studies should elucidate intracellular mechanisms of cholestasis. Furthermore, activation of specific PI 3-kinase functions may selectively enhance canalicular transport and have therapeutic potential in cholestasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PILOT STUDY--LIVER DISEASE IN CF MODEL Principal Investigator & Institution: Kent, Geraldine; Hospital for Sick Chldrn (Toronto) 555 University Ave Toronto, On Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: Chronic liver disease is a documented clinical problem in about 10% of CF patients and is the second leading cause of death. Since there is not predictable correlation between the CF gene defect and the presence or absence of liver disease, other genetic factors are clearly modifying the disease pathogenesis in this organ. In our laboratories we have bred a knockout mouse, BcCftr/m1UNC/m1UNC, with develops liver disease starting in infancy. These animals represent the first reported knockout mouse with a liver lesion. No liver lesions were observed in two other lines of mice bearing the identical gene knockout room. Interestingly the BcCftr/m1UNC/m1UNC animals had no lung phenotype but appeared to share the same severe gastrointestinal problems experienced by these other two strains. Wild type littermates of all three lines were predictably free of liver disease. This mouse presents with a unique opportunity to study, not only the genetic modifiers affecting expression of the phenotype but enables to examine some of the biochemical pathways which be involved in the pathogenesis of the disease. Preliminary examination of the phenotype of this animal has identified a catalase deficiency in the livers of these animals and this was associated to a total absence of peroxisomes. The catalase deficiency will be used as a marker enzyme for the location of the modifier gene by cross breeding strains (Rozmahel portion of the pilot). Although not identical to the focal cholestasis lesions of human CF liver disease, the appearance of lesions are limited with no CFTR and represent a pathological consequence of its deficiency. We will attempt to identify some of these defective pathways in this pilot study.

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

Project Title: POSITIONAL CLONING AND CHARACTERISTICS OF FAT-FREE GENE Principal Investigator & Institution: Ho, Shiu-Ying; Microbiology and Immunology; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-JUN-2005 Summary: (provided by applicant): Lipids play essential roles in all living cells, not only as key components of membranes and as a source of energy, but also as important mediators of cellular signaling. At the organismal level, individual differences in lipid metabolism can impact a variety of human diseases. In our laboratory, ethylnitrosurea (ENU) mutagenized zebrafish are screened in vivo for abnormality in lipid processing using the fluorescent reporters. One of the lethal recessive mutant, fat-free, was identified at the beginning of the large-scale screen. Biochemical analysis using fluorescent lipids analogues indicate that fat-free mutation may attenuate biliary synthesis or secretion. Although three genes (FIC1, BSEP, and MDR3) responsible for infants and children with progressive familial intrahepatic cholestasis (PFIC) are identified, it remains unknown if there are undiscovered genes that are involved in bile synthesis and/or regulation may lead to PFIC. Fat-free locus is not relevant to FIC1, BSEP or MDR3 because all three genes are mapped to different linkage groups using zebrafish radiation hybrid panel. Therefore, fat-free mutant provides an ideal potential model to discover a gene that may contribute to PFIC. The specific aims of this proposal are positionatly clone and characterization of the fat-free gene. The PCR-based analysis methods have enabled me to locate a region that is 0.06 cM (1 out of 1700 meioses) from the fat-free locus. The final stage of mapping is relied on BAC walking, SNP detection, and shotgun sequencing. To characterize fat-free gene, morpholino knock-down, genomic DNA rescue, whole mount in situ hybridization, and microarray analysis are included. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RECOMBINANT ABNORMALITIES

AAV

FOR

CORRECTION

OF

GENETIC

Principal Investigator & Institution: Flotte, Terence R.; Professor; Pediatrics; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2002; Project Start 25-SEP-2000; Project End 31-JUL-2005 Summary: The liver plays a pivotal role in numerous biochemical processes, including intermediary metabolism, synthesis and secretion of serum proteins, energy metabolism, and detoxification of drugs and other xenobiotics. Hepatocytes are, therefore, an important target for gene therapy, and important target for gene therapy in many genetic diseases that disrupt these processes. In the current application, our group is seeking to optimize the conditions for gene transfer into hepatocytes using recombinant adeno-associated virus (rAAV) vectors, which possess the inherent advantages of long-term stability, safety, and low immunogenicity. rAAV-mediated gene transfer is very efficient in myofibers and some other cell types, but previous reports have indicated that long-term rAAV transduction of the liver may be limited to maximum of approximately 5% of hepatocytes using current methods. This may not be sufficient for many genetic/metabolic disorders. The primary goal of the current application is to identify and circumvent the rate-limiting steps in rAAV-mediated

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transduction of hepatocytes and thereby increase the efficiency of rAAV-mediated transduction of hepatocytes to a point where it is sufficient for widespread clinical use. The optimization of hepatocyte gene transfer will be accomplished in the context of three gene therapy projects, each of which typifies a defect in one of the major hepatic functions: Project 1: gene therapy for phenylketonuria (a disorder of amino acid metabolism), Project 2: gene therapy for alpha 1-anti-trypsin deficiency (a defect in hepatic synthesis and secretion), and Project 3: gene therapy for glycogen storage (that affect a key process in energy metabolism, the release of free glucose from glycogen). In addition, a pilot study will investigate the feasibility of gene therapy in the murine mdr2 knock-out mouse (a model defect in bile salt secretion analogous to progressive familial Intrahepatic cholestasis), in a paradigm whereby corrected cells could selectively repopulate the liver due to their survival advantage. In order to fully develop rAAV transduction of the liver, it may be necessary to enhance delivery to the hepatocyte, increase attachment to the cell membrane, improve internalization, nuclear entry and uncoating, maximize the transcriptional activity of vector genomes, and optimize conditions for therapeutic protein secretion. Since these disorders may ultimately require therapy in the newborn period or during child-bearing years, biological safety issues related to long-term genetic stability and biodistribution of rAAV genomes will also be addressed. These studies will be supported by the UF Vector Core Facility, for the production of high-titer, highly purified rAAV stocks, and the UF Immunology/Pathology Core. It is anticipated that by the end of this grant period, these basic improvements in rAAV-mediated delivery of genes to the liver will have improved the changes for successful gene therapy in one or more of these disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: REGULATION OF CHOLANGIOCYTES BY INSP3 RECEPTOR ISOFORMS Principal Investigator & Institution: Ehrlich, Barbara E.; Professor; Pharmacology; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Bile secretion is one of the principal functions of the liver. In order to maintain bile flow, not only must hepatocytes secrete bile, but this must then be modified and conditioned further by bile duct epithelial cells, or cholangiocytes. Abnormal cholangiocytes function results in cholestasis, which is a cardinal manifestation of liver disease. Cholestatic liver diseases are responsible for 20% of liver transplants in the US, and are the most common cause of liver disease among pediatric transplant patients. In addition, abnormal cholangiocyte function is responsible for the hepatic manifestations of cystic fibrosis, one of the most common inherited diseases. Bile secretion in cholangiocytes is regulated in part by cytosolic Ca2+. In general, cells are regulated both by the pattern of Ca2+ signals over time and by the regions of the cells in which Ca2+ signals occur. However, little is known about temporal or spatial aspects of Ca2+ signaling in cholangiocytes, and nothing is known about how these Ca2+ signals are regulated. Inositol 1,4,5-trisphosphate receptors (InsP3R) mediate Ca2+ signaling in epithelia, and cholangiocytes express all three isoforms of this receptor. The hypothesis of this proposal is that Ca2+ signals in the cholangiocyte are regulated by the subcellular distribution of the InsP3R isoforms. This hypothesis will be investigated through the following specific aims: The function and regulation of the InsP3Rs will be compared at the single channel level. The contribution that each of the receptors plays to Ca2+ signaling in cholangiocytes will be examined in

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a bile duct cell line modified to express either one or a combination of these receptors. These findings will be related to the organization of Ca2+ signals and secretory function in native cholangiocytes, as determined in isolated microperfused bile duct segments. This work should not only identify the molecular mechanisms responsible for Ca2+ signaling in cholangiocytes, but serve as a model for how the molecular organization of signaling pathways is responsible for regulation of ductular secretion. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: ROLE OF CD40-CD40 LIGAND IN PRIMARY BILIARY CIRRHOSIS Principal Investigator & Institution: Mayo, Marlyn J.; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 15-MAY-2000; Project End 31-MAR-2003 Summary: (adapted from the application) Primary biliary cirrhosis is a chronic autoimmune liver disease characterized by inflammatory destruction of small and medium sized intrahepatic bile ducts, leading to cholestasis, then fibrosis, cirrhosis, and its complications. Although the etiology is unknown, T cells that surround the bile ductules are the likely mediators of bile duct destruction. Other cell types within the portal infiltrate, including macrophages and B cells, probably contribute to this autoimmune process. However, the manner in which these cells communicate and collaborate to cause bile duct lesions is not understood. The hypothesis of this proposed project is that T cells orchestrate the immune attack on cholangiocytes via signaling to other cells in the liver through CD40 ligand. Specifically, expression of CD40 ligand by activated T cells in the liver stimulates B cells to increase production of immunoglobulins; activates macrophages to produce IL-12, which leads to a shift of T helper cells to the Th1 phenotype and subsequent IL-2 and IFN-gamma production; and induces cholangiocytes to undergo apoptosis at an increased rate. This hypothesis will be tested by a correlative analysis of the level of expression of CD40 ligand in the liver of PBC patients with the potential consequences of CD40-CD40 ligand interaction; such as upregulation of immunoglobulin and cytokine production, and apoptosis of cholangiocytes. Expression of CD40 and CD40 ligand will be localized in the liver with immunohistochernistry. These patient-oriented studies will be supplemented by in vitro experiments designed to study CD40-ligand induced apoptosis in cholangiocytes. These studies will provide insight into the role of T cells in the pathogenesis of PBC and provide information useful in developing new treatment modalities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SECRETORY LINEAGES DURING INTESTINAL ADAPTATION Principal Investigator & Institution: Helmrath, Michael A.; Molecular and Cellular Biology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-JUN-2009 Summary: (provided by applicant): As a pediatric surgeon, I have an intense interest in the management of intestinal failure in infants. The most common etiology of "shortgut" in infants is from necrotizing enterocolitis, but may also arise from volvulus, atresias, gastroschesis, and Hirschsprung's disease. Following massive intestinal loss, the remaining intestine attempts to adapt by enhancing proliferation of intestinal stem cells and their progeny resulting in marked increases in the remaining mucosal surface area aiding absorption and digestion. Failure of this process to adequately compensate require many children to depend on parenteral nutrition (TPN) to sustain adequate nutrition subjecting them to the many inherent risks of TPN, including cholestasis and

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liver failure. Developing new therapies to augment the adaptive response will require an understanding of the mechanisms that stimulate intestinal stem cells and their progeny following massive intestinal loss. My ongoing studies in the laboratory of Susan Henning Ph.D. are evaluating the role of secretory lineages during intestinal adapation, and have demonstrated an early increased production of intestinal secretory lineages occurs following resection. I hypothesize that the early increased production of intestinal secretory lineages following massive intestinal loss is essential to amplify the early signals initiating intestinal adaptation. This grant proposes the use of a specific progenitor assay somatic mutation (SPASM) sytem to identify dynamic changes within intestinal progenitor compartments that occur following a 50% intestinal resection in mice. The early role of secretory lineages initiating intestinal adaptation will further be evaluated by performing similar intestinal resections on mice harboring a mosiac inactivation of all secretory lineages in the terminal ileum and on normal mice following administration of growth factors that previously have been shown to stimulate only secretory or columnar lineages. The development of flow cytometry techniques to separate and quantitate epithelial lineages will provide an efficient tool to further assess the molecular mechanisms initiating the early adaptive response. The excellent environment provided by Dr. Henning's laboratory and the support of this application will provide a solid foundation for the development of an independent translational reseach career exploring the mechanisms of intestinal adaptation and treatment of intestinal failure in children. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: SIGNALING MOLECULES IN BILE DUCT DEVELOPMENT Principal Investigator & Institution: Loomes, Kathleen M.; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2002; Project Start 15-AUG-2000; Project End 30-JUN-2005 Summary: Disorders of bile duct development constitute a major cause of morbidity and mortality in the pediatric population, yet little is understood regarding the genetic signaling and molecular control of bile duct formation during development. The gene Jagged1, encoding a ligand in the Notch intercellular signaling pathway, has recently been found to be involved in this process. Jagged1 is expressed in the ductal plate, or primitive bile duct cells, during development as studied by in situ hybridization and immunohistochemistry with antibodies to proteins found specifically in the ductal plate. In addition, patients with a mutation or deletion of one copy of Jagged1 have Alagille syndrome, a disorder characterized by cholestasis and paucity of the intrapepatic bile ducts, along with abnormalities of other organ systems. Based on these data, we hypothesize that jagged1 and the Notch pathway have an integral role in signaling during bile duct development and we propose to use a dual approach to define further their functions in this complex process. The first specific aim of the proposal is to use the approach of conditional gene targeting to create a liver-specific disruption of Jagged1 in a mouse model. In this way, it will be possible to examine the effect of loss of Jagged1 during liver and bile duct development without disturbing its activity in any other organ systems. We hyposthesize that the liver-specific jagged1 knockout mouse will demonstrate a severe abnormality of liver and bile duct development. Specific aim two entails an in depth study of the knockout mouse phenotype, including detailed histologic studies and analysis of ductal plate development through the use of immunohistochemical stains. The third aim of the proposal involves the use of a unique bipotential mouse hepatoblast cell line to study signaling in the Nothch pathway during liver and bile duct differentiation. A detailed analysis of Notch gene expression in this

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cell line provide the basis for transfection experiments that will perturb the signaling pathway. This proposal provides an opportunity to define the role of crucial signaling molecules in bile duct development. The combined approach of a conditional knockout animal model in parallel with a cell culture system will not only elucidate the function of the Notch pathway in liver and bile duct development, but will also identify candidate genes for other bile duct disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen x

Project Title: STRUCTURE AND FUNCTION OF MEMBRANE TRANSPORT PROTEINS Principal Investigator & Institution: Levy, Daniel S.; Biochem and Molecular Biology; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 01-AUG-1979; Project End 31-DEC-2003 Summary: Bile acids play a critical role in numerous biological processes such as a) digestion, b) formation of bile, which functions as an excretory vehicle for cholesterol and metabolites of drugs and carcinogens, c) the regulation of cholesterol metabolism and d) the modulation of hepatocyte signaling pathways. Defects in the transport of these molecules leads to cholestasis, resulting in numerous pathological conditions such as liver injury and failure. Previous studies have demonstrated that microsomal epoxide hydrolase (mEH), which plays a central role in carcinogen metabolism, is also one of the membrane carrier proteins capable of mediating sodium- dependent transport of bile acids across the hepatocyte blood sinusoidal plasma membrane. This protein exists in two distinct topological orientations in the endoplasmic reticulum, one of which is targeted to the plasma membrane. Recent studies have identified several patients with extremely elevated serum bile acid levels (hypercholanemic) that appear to have a greatly reduced capacity to transport bile acids. One of these subjects has been shown to also express greatly reduced levels of mEH and mEH mRNA and the absence of exon 1 in the mEH gene (EPHX1). The long term goals of these studies are to 1) characterize the structure, function and mechanism of action of mEH as a bile acid transporter, and 2) characterize alterations in mEH expression or structure leading to defects in transport. The specific aims of this proposal are to characterize a) the membrane architecture of mEH, b) the effects of expression levels, mediated by development, pregnancy and drugs, on the targeting and functional expression of mEH at the plasma membrane and c) mutations in the mEH gene (EPHX1) in subjects with hypercholanemia to establish the molecular basis for the observed transport defects. Membrane architecture and functional expression of mEH on the hepatocyte cell surface will be investigated using antibody and biotinylation reagents, confocal fluorescence microscopy, glycosylation site insertion technology, co- immunoprecipitation, proteolysis protection analysis, membrane protein crosslinking procedures, and cell cytometry, in conjunction with transport assays. The effect of mutations derived from the sequencing of EPHX1 from hypercholanemic patients will be studied in regard to their effect on promoter activity, or synthesis of mEH with altered transport and/or targeting characteristics. These studies should substantially increase out knowledge of this important transport system which plays a critical role in numerous physiological processes and in the etiology of several major diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE GENETIC BASIS OF CHOLESTASIS Principal Investigator & Institution: Bull, Laura N.; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747

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Timing: Fiscal Year 2002; Project Start 01-FEB-1996; Project End 31-AUG-2004 Summary: This is a revised application to renewal a grant focused on understanding the genetic basis of cholestasis, i.e. impairment in bile formation and/or bile flow. The current award was used to isolate a gene which, when mutated is responsible for two forms of inherited cholestasis, benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis, type 1 (PFIC1). The main goal of the renewal will be to characterize the function of this gene (termed FIC1) by a variety of in vitro and in vivo experiments. A first step will be to identify specific FIC1 mutations responsible for disease in a series of BRIC and PFIC1 patients for whom DNA samples have been collected but in whom mutations have not yet been identified; this mutation analysis will show whether particular FIC1 genotypes are correlated with specific clinical features of BRIC and PFIC1. Screening for FIC1 mutations will also be undertaken in patients with apparently sporadic forms of cholestasis. Mice will be generated in whom the murine ortholog of FIC1 (Fic1) has been disrupted. These mice will be used for anatomic, physiologic, and pharmacological studies aimed at understanding the normal function of FIC1 and as a model for studying cholestasis. These studies will complement efforts by collaborators who will use other approaches to identify the function of FIC1. It was shown recently that mutations in genes other than FIC1 cause forms of cholestasis that are distinct cl8inically, histopathologically, and biochemically from BRIC and PFIC1. Characterizing the function of these genes in conjunction with that of FIC1 will illuminate the molecular basis of normal bile formation and bile flow. 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 “cholestasis” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for cholestasis in the PubMed Central database: x

Effect of Maternal Intrahepatic Cholestasis on Fetal Steroid Metabolism. by Laatikainen TJ, Peltonen JI, Nylander PL.; 1974 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=302667

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Extrahepatic obstructive cholestasis reverses the bile salt secretory polarity of rat hepatocytes. by Fricker G, Landmann L, Meier PJ.; 1989 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=329731

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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Prolonged cholestasis associated with irbesartan. by Hariraj R, Stoner E, Jader S, Preston DM.; 2000 Sep 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27470

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Protoporphyrin-induced Cholestasis in the Isolated In Situ Perfused Rat Liver. by Avner DL, Lee RG, Berenson MM.; 1981 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=370579

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Release of Ca2+ from the endoplasmic reticulum is not the mechanism for bile acidinduced cholestasis and hepatotoxicity in the intact rat liver. by Farrell GC, Duddy SK, Kass GE, Llopis J, Gahm A, Orrenius S.; 1990 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296560

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The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II. by Wang L, Soroka CJ, Boyer JL.; 2002 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151156

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

A case of severe benign intrahepatic cholestasis treated with liver transplantation. Author(s): Mezey E, Burns C, Burdick JF, Braine HG. Source: The American Journal of Gastroenterology. 2002 February; 97(2): 475-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11866291

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

6

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

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A novel inborn error of metabolism detected by elevated methionine and/or galactose in newborn screening: neonatal intrahepatic cholestasis caused by citrin deficiency. Author(s): Ohura T, Kobayashi K, Abukawa D, Tazawa Y, Aikawa J, Sakamoto O, Saheki T, Iinuma K. Source: European Journal of Pediatrics. 2003 May; 162(5): 317-22. Epub 2003 February 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12692712

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A primer on the pathology of cholestasis. Author(s): Mills AS. Source: Indian J Gastroenterol. 2001 March; 20 Suppl 1: C82-4. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11293187

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A randomised controlled trial of ursodeoxycholic acid and S-adenosyl-l-methionine in the treatment of gestational cholestasis. Author(s): Roncaglia N, Locatelli A, Arreghini A, Assi F, Cameroni I, Pezzullo JC, Ghidini A. Source: Bjog : an International Journal of Obstetrics and Gynaecology. 2004 January; 111(1): 17-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14687046

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A second heterozygous MDR3 nonsense mutation associated with intrahepatic cholestasis of pregnancy. Author(s): Gendrot C, Bacq Y, Brechot MC, Lansac J, Andres C. Source: Journal of Medical Genetics. 2003 March; 40(3): E32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12624161

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ABCB4 gene sequence variation in women with intrahepatic cholestasis of pregnancy. Author(s): Mullenbach R, Linton KJ, Wiltshire S, Weerasekera N, Chambers J, Elias E, Higgins CF, Johnston DG, McCarthy MI, Williamson C. Source: Journal of Medical Genetics. 2003 May; 40(5): E70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12746424

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ABCB6 (MTABC3) excluded as the causative gene for the growth retardation syndrome with aminoaciduria, cholestasis, iron overload, and lactacidosis. Author(s): Visapaa I, Fellman V, Lanyi L, Peltonen L. Source: American Journal of Medical Genetics. 2002 May 1; 109(3): 202-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11977179

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Abnormal hepatic expression of fibrillin-1 in children with cholestasis. Author(s): Lamireau T, Dubuisson L, Lepreux S, Bioulac-Sage P, Fabre M, Rosenbaum J, Desmouliere A. Source: The American Journal of Surgical Pathology. 2002 May; 26(5): 637-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11979094

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Abnormal hepatic sinusoidal bile acid transport: new insights into the pathogenesis of cholestasis? Author(s): Trauner M, Fickert P, Zollner G. Source: Gastroenterology. 2001 January; 120(1): 321-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11246511

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Abnormal lipoproteins in the ANIT-treated rat: a transient and reversible animal model of intrahepatic cholestasis. Author(s): Chisholm JW, Dolphin PJ. Source: Journal of Lipid Research. 1996 May; 37(5): 1086-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8725160

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Acute cholestasis by fluoxetine. Author(s): Cosme A, Barrio J, Lobo C, Gil I, Castiella A, Arenas JI. Source: The American Journal of Gastroenterology. 1996 November; 91(11): 2449-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8931446

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Acute pancreatitis, hepatic cholestasis, and erythema nodosum induced by carbimazole treatment for Graves' disease. Author(s): Marazuela M, Sanchez de Paco G, Jimenez I, Carraro R, Fernandez-Herrera J, Pajares JM, Gomez-Pan A. Source: Endocrine Journal. 2002 June; 49(3): 315-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12201214

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Antenatal diagnosis of hereditary fetal growth retardation with aminoaciduria, cholestasis, iron overload, and lactic acidosis in the newborn infant. Author(s): Fellman V, Visapaa I, Vujic M, Wennerholm UB, Peltonen L. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2002 May; 81(5): 398-402. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12027811

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Antidepressant induced cholestasis: hepatocellular redistribution of multidrug resistant protein (MRP2). Author(s): Milkiewicz P, Chilton AP, Hubscher SG, Elias E. Source: Gut. 2003 February; 52(2): 300-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12524417

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Antidepressant-associated fatal intrahepatic cholestasis. Author(s): Dollow S. Source: Lancet. 1996 May 4; 347(9010): 1268-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8622488

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Arthrogryposis, renal dysfunction and cholestasis syndrome. Author(s): Abdullah MA, Al-Hasnan Z, Okamoto E, Abomelha AM. Source: Saudi Med J. 2000 March; 21(3): 297-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11533803

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Arthrogryposis, renal tubular dysfunction, cholestasis, ichthyosis syndrome (ARCI) Author(s): Franceschini P, Barberis L. Source: European Journal of Pediatrics. 1997 January; 156(1): 78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9007499

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Association of single nucleotide polymorphisms of the bile salt export pump gene with intrahepatic cholestasis of pregnancy. Author(s): Eloranta ML, Hakli T, Hiltunen M, Helisalmi S, Punnonen K, Heinonen S. Source: Scandinavian Journal of Gastroenterology. 2003 June; 38(6): 648-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12825874

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Azithromycin-induced intrahepatic cholestasis. Author(s): Chandrupatla S, Demetris AJ, Rabinovitz M. Source: Digestive Diseases and Sciences. 2002 October; 47(10): 2186-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12395890

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Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta. Author(s): Serrano MA, Brites D, Larena MG, Monte MJ, Bravo MP, Oliveira N, Marin JJ. Source: Journal of Hepatology. 1998 May; 28(5): 829-39. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9625319

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Benign recurrent intrahepatic cholestasis and Byler's disease: one gene, two diseases? Author(s): Van Berge Henegouwen GP. Source: Journal of Hepatology. 1996 September; 25(3): 395-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8895021

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Benign recurrent intrahepatic cholestasis in a Saudi child. Author(s): al Drees K, al Zaben A, al Amir A, Abdulla A. Source: Annals of Tropical Paediatrics. 1999 June; 19(2): 215-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10690264

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Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum. Author(s): van Ooteghem NA, Klomp LW, van Berge-Henegouwen GP, Houwen RH. Source: Journal of Hepatology. 2002 March; 36(3): 439-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11867191

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Benign recurrent intrahepatic cholestasis. Author(s): Luketic VA, Shiffman ML. Source: Clinics in Liver Disease. 1999 August; 3(3): 509-28, Viii. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11291237

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Benzylpenicillin-induced prolonged cholestasis. Author(s): Andrade RJ, Guilarte J, Salmeron FJ, Lucena MI, Bellot V. Source: The Annals of Pharmacotherapy. 2001 June; 35(6): 783-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11409000

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Bile acid patterns in meconium are influenced by cholestasis of pregnancy and not altered by ursodeoxycholic acid treatment. Author(s): Rodrigues CM, Marin JJ, Brites D. Source: Gut. 1999 September; 45(3): 446-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10446117

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Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy. Author(s): Reyes H, Sjovall J. Source: Annals of Medicine. 2000 March; 32(2): 94-106. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10766400

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Bile duct apoptosis and cholestasis resembling acute graft-versus-host disease after autologous hematopoietic cell transplantation. Author(s): Saunders MD, Shulman HM, Murakami CS, Chauncey TR, Bensinger WI, McDonald GB. Source: The American Journal of Surgical Pathology. 2000 July; 24(7): 1004-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10895823

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Bile duct bacterial isolates in primary sclerosing cholangitis and certain other forms of cholestasis--a study of bile cultures from ERCP. Author(s): Bjornsson ES, Kilander AF, Olsson RG. Source: Hepatogastroenterology. 2000 November-December; 47(36): 1504-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11148988

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Bile duct paucity - making a case for liver biopsy in the investigation of neonatal cholestasis. Author(s): Sibal A, Mishra U. Source: Indian Pediatrics. 2001 December; 38(12): 1430-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11752749

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Bile salt export pump gene mutations in two Japanese patients with progressive familial intrahepatic cholestasis. Author(s): Goto K, Sugiyama K, Sugiura T, Ando T, Mizutani F, Terabe K, Ban K, Togari H. Source: Journal of Pediatric Gastroenterology and Nutrition. 2003 May; 36(5): 647-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12717091

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Bile secretion--models, mechanisms, and malfunctions. A perspective on the development of modern cellular and molecular concepts of bile secretion and cholestasis. Author(s): Boyer JL. Source: Journal of Gastroenterology. 1996 June; 31(3): 475-81. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8726846

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Biliary diversion by use of the appendix (cholecystoappendicostomy) in progressive familial intrahepatic cholestasis. Author(s): Rebhandl W, Felberbauer FX, Turnbull J, Paya K, Barcik U, Huber WD, Whitington PF, Horcher E. Source: Journal of Pediatric Gastroenterology and Nutrition. 1999 February; 28(2): 217-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9932861

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Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile. Author(s): Kurbegov AC, Setchell KD, Haas JE, Mierau GW, Narkewicz M, Bancroft JD, Karrer F, Sokol RJ. Source: Gastroenterology. 2003 October; 125(4): 1227-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14517804

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Bone involvement in patients with chronic cholestasis. Author(s): Le Gars L. Source: Joint, Bone, Spine : Revue Du Rhumatisme. 2002 June; 69(4): 373-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12184433

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Bone mass and body composition in children with chronic cholestasis before and after liver transplantation. Author(s): Ulivieri FM, Lisciandrano D, Gridelli B, Lucianetti A, Roggero P, Nebbia G, Cataliotti E, Prato P, di Mauro P, Campanini F, Vezzoli M. Source: Transplantation Proceedings. 1999 August; 31(5): 2131-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10455991

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BSEP: function and role in progressive familial intrahepatic cholestasis. Author(s): Thompson R, Strautnieks S. Source: Seminars in Liver Disease. 2001 November; 21(4): 545-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11745042

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Byler-like familial cholestasis in an extended kindred. Author(s): Bourke B, Goggin N, Walsh D, Kennedy S, Setchell KD, Drumm B. Source: Archives of Disease in Childhood. 1996 September; 75(3): 223-7. Erratum In: Arch Dis Child 1996 December; 75(6): 548. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8976662

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Ca2+-dependent protein kinase C isoforms induce cholestasis in rat liver. Author(s): Kubitz R, Saha N, Kuhlkamp T, Dutta S, vom Dahl S, Wettstein M, Haussinger D. Source: The Journal of Biological Chemistry. 2004 March 12; 279(11): 10323-30. Epub 2003 December 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14679204

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Case of multiple myeloma mimicking an infectious disease with fever, intrahepatic cholestasis, renal failure, and pulmonary insufficiency. Author(s): Vella FS, Simone B, Giannelli G, Pesolo M, Ingravallo G, Gentile A, Antonaci S. Source: American Journal of Hematology. 2003 January; 72(1): 38-42. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12508267

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Cellular regulation of hepatic bile acid transport in health and cholestasis. Author(s): Anwer MS. Source: Hepatology (Baltimore, Md.). 2004 March; 39(3): 581-90. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14999673

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Cholestasis and hypoalbuminemia as predictors of outcome after liver transplantation. Author(s): Mor E, Brown M, Michowiz R, Bar-Nathan N, Shaharabani E, Yussim A, Shapira Z, Tur-Kaspa R, Ben-Ari Z. Source: Transplantation Proceedings. 2003 March; 35(2): 617-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12644069

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Cholestasis and hypoglycemia: manifestations of congenital anterior hypopituitarism. Author(s): Choo-Kang LR, Sun CC, Counts DR. Source: The Journal of Clinical Endocrinology and Metabolism. 1996 August; 81(8): 2786-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8768830

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Cholestasis and kidney dysfunction in liver transplant patients reduces cyclosporine metabolite excretion. Author(s): Totterman A, Lalla M, Salmela K, Hockerstedt K. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 1992; 5 Suppl 1: S190-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14621772

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Cholestasis and renal failure in a patient with secondary amyloidosis. Author(s): Unsal C, Paydas S, Gonlusen G. Source: Renal Failure. 2002 November; 24(6): 863-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12472208

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Cholestasis as a presenting feature of acute Epstein-Barr virus infection. Author(s): Massei F, Palla G, Ughi C, Macchia P, Maggiore G. Source: The Pediatric Infectious Disease Journal. 2001 July; 20(7): 721-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11465852

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Cholestasis associated with the use of pravastatin sodium. Author(s): Batey RG, Harvey M. Source: The Medical Journal of Australia. 2002 June 3; 176(11): 561. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12064992

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Cholestasis in Crohn's disease: a diagnostic challenge. Author(s): Hilzenrat N, Lamoureux E, Sherker A, Cohen A. Source: Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. 1997 January-February; 11(1): 35-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9113796

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Cholestasis in juvenile dermatomyositis: report of three cases. Author(s): Russo RA, Katsicas MM, Davila M, Ciocca M, Zelazko M. Source: Arthritis and Rheumatism. 2001 May; 44(5): 1139-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11352246

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Cholestasis with hepatic fibrosis secondary to sarcoidosis--a case report. Author(s): Khan IA, Irfan SM. Source: J Pak Med Assoc. 2001 February; 51(2): 89-92. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11321881

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Cholestasis, sclerosing cholangitis, and liver transplantation in Langerhans cell Histiocytosis. Author(s): Braier J, Ciocca M, Latella A, de Davila MG, Drajer M, Imventarza O. Source: Medical and Pediatric Oncology. 2002 March; 38(3): 178-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11836717

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Cholestasis. Author(s): Elferink RO. Source: Gut. 2003 May; 52 Suppl 2: Ii42-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12651881

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Cholestasis: the ABCs of cellular mechanisms for impaired bile secretion-transporters and genes. Author(s): Shaffer EA. Source: Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. 2002 June; 16(6): 380-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12096302

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Cholesteryl ester transfer activity in liver disease and cholestasis, and its relation with fatty acid composition of lipoprotein lipids. Author(s): Iglesias A, Arranz M, Alvarez JJ, Perales J, Villar J, Herrera E, Lasuncion MA. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 1996 April 30; 248(2): 157-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8740580

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Chronic cholestasis associated with Turner's syndrome: 12 years of clinical and histopathological follow-up. Author(s): Wardi J, Knobel B, Shahmurov M, Melamud E, Avni Y, Shirin H. Source: Digestion. 2003; 67(1-2): 96-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12743447

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Congenital intrathoracic herniation of the right liver--late presentation as anicteric cholestasis. Author(s): Tueche SG, Hardwigsen J, Castellani P, Le Treut YP. Source: Hepatogastroenterology. 2003 May-June; 50(51): 837-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12828098

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Correlation between cholestasis and infection. Author(s): Tanasescu C. Source: Rom J Gastroenterol. 2004 March; 13(1): 23-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15054522

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Cytokines and neuroendocrine dysregulation in obstructive cholestasis: pathophysiological implications. Author(s): Swain MG. Source: Journal of Hepatology. 2001 September; 35(3): 416-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11592605

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Danazol induced cholestasis: pathogenetic hypothesis. Author(s): Malaguarnera M, Santangelo N, Motta M, Pistone G. Source: Panminerva Medica. 1997 September; 39(3): 244-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9360432

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Decrease of cholestasis under "continuous extracorporeal stool transport (CEST)" in prematures and neonates with stomas. Author(s): Schafer K, Schledt A, Linderkamp O, Gfrorer S, Roth H. Source: European Journal of Pediatric Surgery : Official Journal of Austrian Association of Pediatric Surgery. [et Al] = Zeitschrift Fur Kinderchirurgie. 2000 August; 10(4): 224-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11034510

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Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis. Author(s): Deleuze JF, Jacquemin E, Dubuisson C, Cresteil D, Dumont M, Erlinger S, Bernard O, Hadchouel M. Source: Hepatology (Baltimore, Md.). 1996 April; 23(4): 904-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8666348

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Deficiency of the expression of CD45RA isoform of CD45 common leukocyte antigen in CD4+ T lymphocytes in children with infantile cholestasis. Author(s): Socha P, Michalkiewicz J, Stachowski J, Pawlowska J, Jankowska I, Barth C, Socha J, Madalinski K. Source: Immunology Letters. 2001 January 15; 75(3): 179-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11166373

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Demonstration of McCune-Albright mutations in the liver of children with high gammaGT progressive cholestasis. Author(s): Silva ES, Lumbroso S, Medina M, Gillerot Y, Sultan C, Sokal EM. Source: Journal of Hepatology. 2000 January; 32(1): 154-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10673080

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Depletion of mitochondrial DNA associated with infantile cholestasis and progressive liver fibrosis. Author(s): Ducluzeau PH, Lachaux A, Bouvier R, Streichenberger N, Stepien G, Mousson B. Source: Journal of Hepatology. 1999 January; 30(1): 149-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9927162

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Determination of 3-oxo-delta4- and 3-oxo-delta4,6-bile acids and related compounds in biological fluids of infants with cholestasis by gas chromatography-mass spectrometry. Author(s): Suzuki M, Murai T, Yoshimura T, Kimura A, Kurosawa T, Tohma M. Source: J Chromatogr B Biomed Sci Appl. 1997 May 23; 693(1): 11-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9200514

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Diagnostic approach to cholestasis. Author(s): Reichen J. Source: Journal of Hepatology. 1996; 25 Suppl 1: 41-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8954191

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Diagnostic strategies for evaluation and prognosticating the outcome of jaundice among patients with cholestasis caused by neoplastic diseases of the hepatobiliary system and the pancreas. Author(s): Andonov V, Tcholakova E, Ananoshtev N, Stanchev I, Djurkov V. Source: Folia Med (Plovdiv). 1999; 41(1): 72-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10462927

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Diagnostic strategies for extrahepatic cholestasis of indefinite origin: endoscopic ultrasonography or retrograde cholangiography? Results of a prospective study. Author(s): Burtin P, Palazzo L, Canard JM, Person B, Oberti F, Boyer J. Source: Endoscopy. 1997 June; 29(5): 349-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9270914

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Dihydropyridine calcium channel blockers: a rare and reversible cause of hepatotoxicity with cholestasis in a CAPD patient. Author(s): Basile C, Mascia E. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 1999 November; 14(11): 2776-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10534534

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Dipeptidyl peptidase activity of CD26 in serum and urine as a marker of cholestasis: experimental and clinical evidence. Author(s): Perner F, Gyuris T, Rakoczy G, Sarvary E, Gorog D, Szalay F, Kunos I, Szonyi L, Peterfy M, Takacs L. Source: The Journal of Laboratory and Clinical Medicine. 1999 July; 134(1): 56-67. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10402060

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Direct enzymatic assay of urinary sulfated bile acids to replace serum bilirubin testing for selective screening of neonatal cholestasis. Author(s): Matsui A, Kasano Y, Yamauchi Y, Momoya T, Shimada T, Ishikawa T, Abukawa D, Kimura A, Adachi K, Tazuke Y. Source: The Journal of Pediatrics. 1996 August; 129(2): 306-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8765633

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Does ursodeoxycholic acid have a place in the treatment of amiodarone-induced cholestasis? Author(s): Reshef R, Cohen I, Shiller M, Szvalb S, Loberant N. Source: Journal of Clinical Gastroenterology. 1994 March; 18(2): 177-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7514624

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Drug- and chemical-induced cholestasis. Author(s): Lewis JH, Zimmerman HJ. Source: Clinics in Liver Disease. 1999 August; 3(3): 433-64, Vii. Review. Erratum In: Clin Liver Dis 1999 November; 3(4): 917. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11291233

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Drug points: prolonged cholestasis associated with irbesartan. Author(s): Hariraj R, Stoner E, Jader S, Preston DM. Source: Bmj (Clinical Research Ed.). 2000 September 2; 321(7260): 547. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10968816

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Drug-induced cholestasis. Author(s): Velayudham LS, Farrell GC. Source: Expert Opinion on Drug Safety. 2003 May; 2(3): 287-304. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12904107

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Drug-induced cholestasis. Author(s): Levy C, Lindor KD. Source: Clinics in Liver Disease. 2003 May; 7(2): 311-30. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879986

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Drug-induced cholestasis. Author(s): Erlinger S. Source: Journal of Hepatology. 1997; 26 Suppl 1: 1-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9138122

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Early events in sepsis-associated cholestasis. Author(s): Jansen PL, Muller M. Source: Gastroenterology. 1999 February; 116(2): 486-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9922331

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Early shifts of adrenal steroid synthesis before and after relief of short-term cholestasis. Author(s): Zietz B, Wengler I, Messmann H, Lock G, Scholmerich J, Straub RH. Source: Journal of Hepatology. 2001 September; 35(3): 329-37. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11592593

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Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study. Author(s): Terg R, Coronel E, Sorda J, Munoz AE, Findor J. Source: Journal of Hepatology. 2002 December; 37(6): 717-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12445410

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Efficacy of diagnosis of mechanical cholestasis by magnetic resonance cholangiography. Author(s): Urban M, Holzer B, Sebesta C, Schmid L, Schiessel R, Hruby W, Rosen HR. Source: World Journal of Surgery. 2002 March; 26(3): 353-8. Epub 2002 January 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11865374

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Efficacy of molecular adsorbent recirculating system for the treatment of intractable pruritus in cholestasis. Author(s): Macia M, Aviles J, Navarro J, Morales S, Garcia J. Source: The American Journal of Medicine. 2003 January; 114(1): 62-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12543292

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Epidural hematoma complicating cholestasis of pregnancy. Author(s): Yarnell RW, D'Alton ME. Source: Current Opinion in Obstetrics & Gynecology. 1996 June; 8(3): 239-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8818537

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Estrogens in intrahepatic cholestasis of pregnancy. Author(s): Leslie KK, Reznikov L, Simon FR, Fennessey PV, Reyes H, Ribalta J. Source: Obstetrics and Gynecology. 2000 March; 95(3): 372-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10711547

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Evidence for genetic heterogeneity in lymphedema-cholestasis syndrome. Author(s): Fruhwirth M, Janecke AR, Muller T, Carlton VE, Kronenberg F, Offner F, Knisely AS, Geleff S, Song EJ, Simma B, Konigsrainer A, Margreiter R, van der Hagen CB, Eiklid K, Aagenaes O, Bull L, Ellemunter H. Source: The Journal of Pediatrics. 2003 April; 142(4): 441-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12712065

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Evolving concepts of the pathogenesis and treatment of the pruritus of cholestasis. Author(s): Jones EA, Bergasa NV. Source: Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. 2000 January; 14(1): 33-40. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10655025

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Excess zinc and progressive cholestasis: a new disease? Author(s): Sriramachari S, Tandon BN, Acharya SK. Source: Lancet. 1996 March 30; 347(9005): 845-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8622385

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Excess zinc associated with cholestasis. Author(s): Scheinberg IH, Sternlieb I. Source: Lancet. 1996 May 11; 347(9011): 1331. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8622523

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Excess zinc associated with severe progressive cholestasis in Cree and Ojibwa-Cree children. Author(s): Phillips MJ, Ackerley CA, Superina RA, Roberts EA, Filler RM, Levy GA. Source: Lancet. 1996 March 30; 347(9005): 866-8. Erratum In: Lancet 1996 June 22; 347(9017): 1776. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8622393

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Exchange transfusion for severe intrahepatic cholestasis associated with sickle cell disease? Author(s): Chitturi S, George J, Ranjitkumar S, Kench J, Benson W. Source: Journal of Clinical Gastroenterology. 2002 October; 35(4): 362-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12352306

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Cholestasis

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Expression of prolactin receptors in human liver during cholestasis of different etiology and secondary liver cancer. Author(s): Zenkova TY, Kulikov AV, Bogorad RL, Rozenkrants AA, Platonova LV, Shono NI, Gal'perin EI, Smirnova OV. Source: Bulletin of Experimental Biology and Medicine. 2003 June; 135(6): 566-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12937675

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Extracorporal albumin dialysis (MARS) improves cholestasis and normalizes low apo A-I levels in a patient with benign recurrent intrahepatic cholestasis (BRIC). Author(s): Sturm E, Franssen CF, Gouw A, Staels B, Boverhof R, De Knegt RJ, Stellaard F, Bijleveld CM, Kuipers F. Source: Liver. 2002; 22 Suppl 2: 72-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12220310

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Extrahepatic cholestasis: are there any "leftovers" for surgeons? Author(s): Lampe P. Source: Przegl Lek. 2000; 57 Suppl 5: 27-8. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11202286

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Extrahepatic Hodgkin's disease with intrahepatic cholestasis: report of two cases. Author(s): Yalcin S, Kars A, Sokmensuer C, Atahan L. Source: Oncology. 1999 July; 57(1): 83-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10394130

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Extrahepatic manifestations of cholestasis. Author(s): Glasova H, Beuers U. Source: Journal of Gastroenterology and Hepatology. 2002 September; 17(9): 938-48. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12167113

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Facial features in Alagille syndrome: specific or cholestasis facies? Author(s): Kamath BM, Loomes KM, Oakey RJ, Emerick KE, Conversano T, Spinner NB, Piccoli DA, Krantz ID. Source: American Journal of Medical Genetics. 2002 October 1; 112(2): 163-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12244550

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Failure of ursodeoxycholic acid to prevent a cholestatic episode in a patient with benign recurrent intrahepatic cholestasis: a study of bile acid metabolism. Author(s): Crosignani A, Podda M, Bertolini E, Battezzati PM, Zuin M, Setchell KD. Source: Hepatology (Baltimore, Md.). 1991 June; 13(6): 1076-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2050325

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Familial cholestasis with elevated sweat electrolyte concentrations. Author(s): Lloyd-Still JD. Source: The Journal of Pediatrics. 1981 October; 99(4): 580-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7277100

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Familial cholestasis with gallstone, ataxia and visual disturbance. Author(s): Tazawa Y, Konno T. Source: The Tohoku Journal of Experimental Medicine. 1982 June; 137(2): 137-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7112542

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Familial intrahepatic cholestasis associated with progressive neuromuscular disease and vitamin E deficiency. Author(s): Nakagawa M, Tazawa Y, Kobayashi Y, Yamada M, Suzuki H, Konno T, Tada K. Source: Journal of Pediatric Gastroenterology and Nutrition. 1984 June; 3(3): 385-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6737183

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Familial recurrent intrahepatic cholestasis of pregnancy: a genetic study providing evidence for transmission of a sex-limited, dominant trait. Author(s): Holzbach RT, Sivak DA, Braun WE. Source: Gastroenterology. 1983 July; 85(1): 175-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6852450

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Fatal intrahepatic cholestasis and interstitial lung fibrosis following gold therapy for rheumatoid arthritis. Author(s): Shaban MR, Golding DN, Letcher RG. Source: Journal of the Royal Society of Medicine. 1984 November; 77(11): 960-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6438309

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Fatal intrahepatic cholestasis associated with triazolam. Author(s): Cobden I, Record CO, White RW. Source: Postgraduate Medical Journal. 1981 November; 57(673): 730-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6122205

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Fatal toxic intrahepatic cholestasis secondary to glibenclamide. Author(s): Krivoy N, Zaher A, Yaacov B, Alroy G. Source: Diabetes Care. 1996 April; 19(4): 385-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8729168

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Fatigue in chronic cholestasis. Author(s): Milkiewicz P, Heathcote EJ. Source: Gut. 2004 April; 53(4): 475-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15016736

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Female sex steroids and cholestasis. Author(s): Kreek MJ. Source: Seminars in Liver Disease. 1987 February; 7(1): 8-23. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3296217

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Fetal impact of cholestasis of pregnancy: experience at Tenon Hospital and literature review. Author(s): Gaudet R, Merviel P, Berkane N, Schouppe S, Cocheton JJ, Uzan S. Source: Fetal Diagnosis and Therapy. 2000 July-August; 15(4): 191-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10867478

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Fetal intrahepatic cholestasis secondary to BO hemolytic disease. Author(s): Raju TN, Javed DI. Source: Journal of the National Medical Association. 1981 August; 73(8): 747-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7196459

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Fetal mortality associated with cholestasis of pregnancy and the potential benefit of therapy with ursodeoxycholic acid. Author(s): Davies MH, da Silva RC, Jones SR, Weaver JB, Elias E. Source: Gut. 1995 October; 37(4): 580-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7489950

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Fetal outcome in obstetric cholestasis. Author(s): Fisk NM, Storey GN. Source: British Journal of Obstetrics and Gynaecology. 1988 November; 95(11): 1137-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3207643

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FIC1 and BSEP defects in Taiwanese patients with chronic intrahepatic cholestasis with low gamma-glutamyltranspeptidase levels. Author(s): Chen HL, Chang PS, Hsu HC, Ni YH, Hsu HY, Lee JH, Jeng YM, Shau WY, Chang MH. Source: The Journal of Pediatrics. 2002 January; 140(1): 119-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11815775

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FIC1, the protein affected in two forms of hereditary cholestasis, is localized in the cholangiocyte and the canalicular membrane of the hepatocyte. Author(s): Eppens EF, van Mil SW, de Vree JM, Mok KS, Juijn JA, Oude Elferink RP, Berger R, Houwen RH, Klomp LW. Source: Journal of Hepatology. 2001 October; 35(4): 436-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11682026

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Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis. Author(s): Jones EA, Dekker LR. Source: Gastroenterology. 2000 February; 118(2): 431-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10648471

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Follow-up after partial external biliary diversion in familial cholestasis of infancy. Author(s): Felberbauer FX, Amann G, Rebhandl W, Huber WD. Source: Journal of Pediatric Gastroenterology and Nutrition. 2000 September; 31(3): 322. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10997384

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Frequency and clinical progression of the vitamin E deficiency neurologic disorder in children with prolonged neonatal cholestasis. Author(s): Sokol RJ, Guggenheim MA, Heubi JE, Iannaccone ST, Butler-Simon N, Jackson V, Miller C, Cheney M, Balistreri WF, Silverman A. Source: Am J Dis Child. 1985 December; 139(12): 1211-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4061425

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Gabapentin induced cholestasis. Author(s): Richardson CE, Williams DW, Kingham JG. Source: Bmj (Clinical Research Ed.). 2002 September 21; 325(7365): 635. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12242176

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Ganciclovir treatment in infants with cytomegalovirus infection and cholestasis. Author(s): Fischler B, Casswall TH, Malmborg P, Nemeth A. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002 February; 34(2): 154-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11840032

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Gastric ulcer and cholestasis following injection therapy of bleeding duodenal ulcers. Author(s): Raoul JL, Siproudhis L, Ropert A, Bretagne JF, Gosselin M. Source: Endoscopy. 1991 November; 23(6): 351-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1778146

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Gastrointestinal disorders of the critically ill. Cholestasis of sepsis. Author(s): Gilroy RK, Mailliard ME, Gollan JL. Source: Best Practice & Research. Clinical Gastroenterology. 2003 June; 17(3): 357-67. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12763501

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Genes and cholestasis. Author(s): Jansen PL, Muller M, Sturm E. Source: Hepatology (Baltimore, Md.). 2001 December; 34(6): 1067-74. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11731993

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Genetic basis of progressive familial intrahepatic cholestasis. Author(s): Jacquemin E, Hadchouel M. Source: Journal of Hepatology. 1999 August; 31(2): 377-81. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10453956

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Genetic cholestasis syndromes. Author(s): Shneider BL. Source: Journal of Pediatric Gastroenterology and Nutrition. 1999 February; 28(2): 12431. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9932840

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Genetic cholestasis, causes and consequences for hepatobiliary transport. Author(s): Jansen PL, Sturm E. Source: Liver International : Official Journal of the International Association for the Study of the Liver. 2003 October; 23(5): 315-22. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14708891

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Genetic cholestasis. Author(s): Jansen PL, Sturm E. Source: Deutsche Medizinische Wochenschrift. 2003 June 13; 128 Suppl 2: S107-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12817339

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Genetic cholestasis: lessons from the molecular physiology of bile formation. Author(s): Jansen PL, Muller M. Source: Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. 2000 March; 14(3): 233-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10758420

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Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy. Author(s): Savander M, Ropponen A, Avela K, Weerasekera N, Cormand B, Hirvioja ML, Riikonen S, Ylikorkala O, Lehesjoki AE, Williamson C, Aittomaki K. Source: Gut. 2003 July; 52(7): 1025-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12801961

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Genetic mutations causing hereditary cholestasis. Author(s): Denson LA, Karpen SJ. Source: Journal of Pediatric Gastroenterology and Nutrition. 1999 April; 28(4): 451-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10204515

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Genome screening by searching for shared segments: mapping a gene for benign recurrent intrahepatic cholestasis. Author(s): Houwen RH, Baharloo S, Blankenship K, Raeymaekers P, Juyn J, Sandkuijl LA, Freimer NB. Source: Nature Genetics. 1994 December; 8(4): 380-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7894490

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Glibenclamide induced chronic cholestasis simulating primary biliary cirrhosis: a case report. Author(s): Ramanathan M, Wahinuddin S, Kew ST. Source: Med J Malaysia. 1996 March; 51(1): 140-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10967995

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Glibenclamide-associated reversible cholestasis. Author(s): Carratu R, Parisi P, Frullone S. Source: Eur J Med. 1992 November; 1(7): 441-3. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1341488

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Glibenclamide-induced cholestasis. Author(s): Tholakanahalli VN, Potti A, Heyworth MF. Source: The Western Journal of Medicine. 1998 April; 168(4): 274-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9584675

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Glibenclamide-induced cholestasis. Author(s): Del-Val A, Garrigues V, Ponce J, Benages R. Source: Journal of Hepatology. 1991 November; 13(3): 375. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1808229

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Glucose phosphate isomerase and glutathione reductase in benign and malignant extrahepatic cholestasis. Author(s): Tor J, Pascual C, Segura RM, Vilaseca J, Schwartz S, Guardia J. Source: Clinical Chemistry. 1981 April; 27(4): 634-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7471438

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Graphical analysis of laboratory data in the differential diagnosis of cholestasis: a computer-assisted prospective study. Author(s): Borsch G, Baier J, Glocke M, Nathusius W, Gerhardt W. Source: J Clin Chem Clin Biochem. 1988 August; 26(8): 509-19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3065441

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Green teeth associated with cholestasis caused by sepsis: a case report and review of the literature. Author(s): Guimaraes LP, Silva TA. Source: Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 2003 April; 95(4): 446-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12686928

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Hepatic amyloidosis presenting with severe intrahepatic cholestasis. Author(s): Goenka MK, Bhasin DK, Vasisth RK, Dhawan S. Source: Journal of Clinical Gastroenterology. 1996 September; 23(2): 134-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8877643

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Hepatic necrosis with cholestasis induced by long-term voglibose administration. Author(s): Kawakami S, Arima T, Harada K, Miyazono H, Oketani M, Miyazaki H, Arima T. Source: Intern Med. 2001 June; 40(6): 484-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11446671

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Hepatic osteodystrophy in chronic cholestasis: evidence for a multifactorial etiology. Author(s): Klein GL, Soriano H, Shulman RJ, Levy M, Jones G, Langman CB. Source: Pediatric Transplantation. 2002 April; 6(2): 136-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12000470

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Hepatic oxidative alterations in patients with extra-hepatic cholestasis. Effect of surgical drainage. Author(s): Vendemiale G, Grattagliano I, Lupo L, Memeo V, Altomare E. Source: Journal of Hepatology. 2002 November; 37(5): 601-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12399225

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Hepatitis and cholestasis in a middle-aged woman. Author(s): Perrillo RP, Mason AL, Jacob S, Gerber MA. Source: Hepatology (Baltimore, Md.). 1996 September; 24(3): 730-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8781350

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Hepatitis C virus infection is associated with a higher incidence of cholestasis of pregnancy. Author(s): Locatelli A, Roncaglia N, Arreghini A, Bellini P, Vergani P, Ghidini A. Source: British Journal of Obstetrics and Gynaecology. 1999 May; 106(5): 498-500. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10430202

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Hepatitis G virus infection detected in a woman with intrahepatic cholestasis of pregnancy. Author(s): Morton M, Qiao M, Chang G. Source: The Australian & New Zealand Journal of Obstetrics & Gynaecology. 1998 November; 38(4): 428-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9890225

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Hepatobiliary transport: molecular mechanisms of development and cholestasis. Author(s): Arrese M, Ananthananarayanan M, Suchy FJ. Source: Pediatric Research. 1998 August; 44(2): 141-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9702905

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Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Author(s): Jansen PL, Strautnieks SS, Jacquemin E, Hadchouel M, Sokal EM, Hooiveld GJ, Koning JH, De Jager-Krikken A, Kuipers F, Stellaard F, Bijleveld CM, Gouw A, Van Goor H, Thompson RJ, Muller M. Source: Gastroenterology. 1999 December; 117(6): 1370-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10579978

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Hepatocellular bile salt transport: lessons from cholestasis. Author(s): Trauner M, Fickert P, Stauber RE. Source: Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. 2000 November; 14 Suppl D: 99D-104D. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11110621

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Hepatomegaly and cholestasis as primary clinical manifestations of an AL-kappa amyloidosis. Author(s): Mohr A, Miehlke S, Klauck S, Rocken C, Malfertheiner P. Source: European Journal of Gastroenterology & Hepatology. 1999 August; 11(8): 921-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10514129

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Hereditary cholestasis with lymphoedema (Aagenaes syndrome, cholestasislymphoedema syndrome). New cases and follow-up from infancy to adult age. Author(s): Aagenaes O. Source: Scandinavian Journal of Gastroenterology. 1998 April; 33(4): 335-45. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9605254

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Hereditary forms of intrahepatic cholestasis. Author(s): Bull LN. Source: Current Opinion in Genetics & Development. 2002 June; 12(3): 336-42. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12076678

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Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. Author(s): Dixon PH, Weerasekera N, Linton KJ, Donaldson O, Chambers J, Egginton E, Weaver J, Nelson-Piercy C, de Swiet M, Warnes G, Elias E, Higgins CF, Johnston DG, McCarthy MI, Williamson C. Source: Human Molecular Genetics. 2000 May 1; 9(8): 1209-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10767346

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Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy. Author(s): Jacquemin E, Cresteil D, Manouvrier S, Boute O, Hadchouel M. Source: Lancet. 1999 January 16; 353(9148): 210-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9923886

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Histopathological diagnosis of intra- and extrahepatic neonatal cholestasis. Author(s): Santos JL, Almeida H, Cerski CT, Silveira TR. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. 1998 July; 31(7): 911-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9698754

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HLA-A33/B44/DR6 is highly related to intrahepatic cholestasis induced by tiopronin. Author(s): Kurosaki M, Takagi H, Mori M. Source: Digestive Diseases and Sciences. 2000 June; 45(6): 1103-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10877223

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Hypereosinophilia associated with intrahepatic cholestasis in early infancy. Author(s): Al-Binali AM, Al-Fifi SH, Al-Harthi AA, Al-Barki AA, Annobil SH. Source: Saudi Med J. 2000 December; 21(12): 1182-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11360096

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Hyperthyroidism with severe intrahepatic cholestasis. Author(s): Viallard JF, Tabarin A, Neau D, Longy-Boursier M. Source: Digestive Diseases and Sciences. 1999 October; 44(10): 2001-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10548349

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Ileal absorption of bile acids in patients with chronic cholestasis: SeHCAT test results and effect of ursodeoxycholic acid (UDCA). Author(s): Chazouilleres O, Marteau P, Haniche M, Jian R, Poupon R. Source: Digestive Diseases and Sciences. 1996 December; 41(12): 2417-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9011452

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Impaired mixed lymphocyte reaction in intrahepatic cholestasis of pregnancy. Author(s): Dong M, Xie X, Wang Z, He J, Zhou J, Cheng Q. Source: Gynecologic and Obstetric Investigation. 2002; 54(4): 191-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12592060

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Improvement in cholestasis associated with total parenteral nutrition after treatment with an antibody against tumour necrosis factor alpha. Author(s): Forrest EH, Oien KA, Dickson S, Galloway D, Mills PR. Source: Liver. 2002 August; 22(4): 317-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12296965

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In search of a gene for hereditary cholestasis. Author(s): Sela-Herman S, Bull L, Lomri N, Rahmaoui C, Luther T, Hammerman P, Genant J, Freimer N, Scharschmidt B. Source: Biochemical and Molecular Medicine. 1996 December; 59(2): 98-103. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8986630

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Increased incidence of parenteral nutrition-associated cholestasis with aminosyn PF compared to trophamine. Author(s): Wright K, Ernst KD, Gaylord MS, Dawson JP, Burnette TM. Source: Journal of Perinatology : Official Journal of the California Perinatal Association. 2003 September; 23(6): 444-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13679929

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Increased intercellular adhesion molecule-1 serum concentration in cholestasis. Author(s): Polzien F, Ramadori G. Source: Journal of Hepatology. 1996 December; 25(6): 877-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9007716

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Infant cholestasis in McCune-Albright syndrome. Author(s): El-Rifai N, Lumbroso S, Cartigny M, Weill J, Sultan C, Gottrand F. Source: Acta Paediatrica (Oslo, Norway : 1992). 2004 January; 93(1): 141. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14989456

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Infantile leukemia presenting with cholestasis secondary to massive pancreatic infiltration. Author(s): Rausch DR, Norton KI, Glass RB, Kogan D. Source: Pediatric Radiology. 2002 May; 32(5): 360-1. Epub 2002 March 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11956725

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Infection by cytomegalovirus in patients with neonatal cholestasis. Author(s): Oliveira NL, Kanawaty FR, Costa SC, Hessel G. Source: Arquivos De Gastroenterologia. 2002 April-June; 39(2): 132-6. Epub 2003 February 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12612719

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Intractable cough and abnormal pulmonary function in benign recurrent intrahepatic cholestasis. Author(s): Chatila R, Bergasa NV, Lagarde S, West AB. Source: The American Journal of Gastroenterology. 1996 October; 91(10): 2215-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8855752

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Intrahepatic cholestasis after liver transplantation. Author(s): Yang JM, Zhu B. Source: Hepatobiliary Pancreat Dis Int. 2002 May; 1(2): 176-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14607733

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Intrahepatic cholestasis after liver transplantation. Author(s): Ben-Ari Z, Pappo O, Mor E. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2003 October; 9(10): 1005-18. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14526393

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Intrahepatic cholestasis of pregnancy impairs the activities of human placental xenobiotic and steroid metabolizing enzymes in vitro. Author(s): Pasanen M, Helin-Martikainen HL, Pelkonen O, Kirkinen P. Source: Placenta. 1997 January; 18(1): 37-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9032808

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Intrahepatic cholestasis of pregnancy. Author(s): den Dulk M, Valentijn RM, Welten CA, Beyer GP. Source: The Netherlands Journal of Medicine. 2002 October; 60(9): 366-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12572710

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Intrahepatic cholestasis of pregnancy: changes in maternal-fetal bile acid balance and improvement by ursodeoxycholic acid. Author(s): Brites D. Source: Ann Hepatol. 2002 January-March; 1(1): 20-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15114292

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Intrahepatic cholestasis of pregnancy: perinatal outcome associated with expectant management. Author(s): Alsulyman OM, Ouzounian JG, Ames-Castro M, Goodwin TM. Source: American Journal of Obstetrics and Gynecology. 1996 October; 175(4 Pt 1): 95760. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8885754

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Intrahepatic cholestasis of pregnancy: what's new. Author(s): Kroumpouzos G. Source: Journal of the European Academy of Dermatology and Venereology : Jeadv. 2002 July; 16(4): 316-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12224684

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Intrahepatic cholestasis without hepatitis induced by amoxycillin/clavulanic acid. Author(s): Pedro-Botet J, Supervia A, Barranco C, Sola R, Bruguera M. Source: Journal of Clinical Gastroenterology. 1996 September; 23(2): 137-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8877644

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Intrahepatic cholestasis. Author(s): Balistreri WF. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002; 35 Suppl 1: S17-23. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12151816

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Is intrahepatic cholestasis of pregnancy an MDR3-related disease? Author(s): Arrese M, Accatino L. Source: Gastroenterology. 2003 December; 125(6): 1922-3; Author Reply 1923-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14727640

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Jaundice and cholestasis. Some common and uncommon causes. Author(s): Gordon SC. Source: Postgraduate Medicine. 1991 September 15; 90(4): 65-71. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1891435

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Jaundice and cholestasis: past, present and future ideas. Author(s): Casarin P, Cellini A, Tiribelli C. Source: Ital J Gastroenterol. 1990 August; 22(4): 214-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2131948

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Laparoscopic gastrojejunostomy and endoscopic biliary stent placement for palliation of incurable gastric outlet obstruction with cholestasis. Author(s): Brune IB, Feussner H, Neuhaus H, Classen M, Siewert JR. Source: Surgical Endoscopy. 1997 August; 11(8): 834-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9266646

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Large-cell change of hepatocytes in cirrhosis may represent a reaction to prolonged cholestasis. Author(s): Natarajan S, Theise ND, Thung SN, Antonio L, Paronetto F, Hytiroglou P. Source: The American Journal of Surgical Pathology. 1997 March; 21(3): 312-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9060601

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Lichenification and enlargement of hands and feet: a sign of progressive familial intrahepatic cholestasis with normal gamma-glutamyl-transpeptidase. Author(s): Ooi BC, Phua KB, Lee BL, Tan CE, Ng IS, Quak SH. Source: Journal of Pediatric Gastroenterology and Nutrition. 2001 February; 32(2): 21923. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11321400

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Linkage of Cholestasis Familiaris Groenlandica/Byler-like disease to chromosome 18. Author(s): Eiberg H, Nielsen IM. Source: Int J Circumpolar Health. 2000 January; 59(1): 57-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10850008

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Linkage studies of cholestasis familiaris groenlandica/Byler-like disease with polymorphic protein and blood group markers. Author(s): Eiberg H, Nielsen IM. Source: Human Heredity. 1993 July-August; 43(4): 250-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8344670

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Lipoprotein-X in patients with cirrhosis: its relationship to cholestasis and hypercholesterolemia. Author(s): Soros P, Bottcher J, Maschek H, Selberg O, Muller MJ. Source: Hepatology (Baltimore, Md.). 1998 November; 28(5): 1199-205. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9794902

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Liver biopsy in neonatal cholestasis: a review on statistical grounds. Author(s): Zerbini MC, Gallucci SD, Maezono R, Ueno CM, Porta G, Maksoud JG, Gayotto LC. Source: Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. 1997 August; 10(8): 793-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9267821

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Liver histology in the arthrogryposis multiplex congenita, renal dysfunction, and cholestasis (ARC) syndrome: report of three new cases and review. Author(s): Horslen SP, Quarrell OW, Tanner MS. Source: Journal of Medical Genetics. 1994 January; 31(1): 62-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8151641

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Liver in parenteral nutrition cholestasis. Author(s): Phillips MJ. Source: Gastroenterology. 1982 June; 82(6): 1482-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6802700

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Liver transplant rejection and cholestasis: comparison of technetium 99m-diisopropyl iminodiacetic acid hepatobiliary imaging with liver biopsy. Author(s): Engeler CM, Kuni CC, Nakhleh R, Engeler CE, duCret RP, Boudreau RJ. Source: European Journal of Nuclear Medicine. 1992; 19(10): 865-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1451702

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Liver transplantation for cholestasis associated with cystic fibrosis in the pediatric population. Author(s): Molmenti EP, Squires RH, Nagata D, Roden JS, Molmenti H, Fasola CG, Prestidge C, D'Amico L, Casey D, Sanchez EQ, Goldstein RM, Levy MF, Benser M, McPhail W, Andrews W, Andersen JA, Klintmalm GB. Source: Pediatric Transplantation. 2003 April; 7(2): 93-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12654048

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Liver transplantation in a patient with acute liver failure due to sickle cell intrahepatic cholestasis. Author(s): Emre S, Kitibayashi K, Schwartz ME, Ahn J, Birnbaum A, Thung SN, Miller CM. Source: Transplantation. 2000 February 27; 69(4): 675-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10708131

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Locus heterogeneity in progressive familial intrahepatic cholestasis. Author(s): Strautnieks SS, Kagalwalla AF, Tanner MS, Gardiner RM, Thompson RJ. Source: Journal of Medical Genetics. 1996 October; 33(10): 833-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8933336

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Long-chain 3-hydroxyacylCoA dehydrogenase deficiency: a new case presenting with liver dysfunction, cholestasis and fibrosis. Author(s): Odievre MH, Sevin C, Laurent J, Laboureau JP, Rabier D, Brivet M, Roe C, Wanders RJ, Saudubray JM. Source: Acta Paediatrica (Oslo, Norway : 1992). 2002; 91(6): 719-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12162610

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Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: variable expressivity of maternal illness during pregnancy and unusual presentation with infantile cholestasis and hypocalcaemia. Author(s): Ibdah JA, Dasouki MJ, Strauss AW. Source: Journal of Inherited Metabolic Disease. 1999 October; 22(7): 811-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10518281

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Long-term asymptomatic biochemical cholestasis after fulminant or subfulminant liver failure is associated with extensive postnecrotic collapse with regeneration of the liver. Author(s): Ngassa M, Van Beers BE, Geubel AP. Source: Liver. 2002 February; 22(1): 83-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11906623

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Long-term outcome after partial external biliary diversion for intractable pruritus in patients with intrahepatic cholestasis. Author(s): Ng VL, Ryckman FC, Porta G, Miura IK, de Carvalho E, Servidoni MF, Bezerra JA, Balistreri WF. Source: Journal of Pediatric Gastroenterology and Nutrition. 2000 February; 30(2): 152-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10697133

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Lovastatin and cholestasis. Author(s): Yoshida EM, Levin A. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 1993 February 1; 148(3): 374. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8439902

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Low body mass index and use of corticosteroids, but not cholestasis, are risk factors for osteoporosis in patients with chronic liver disease. Author(s): Ormarsdottir S, Ljunggren O, Mallmin H, Brahm H, Loof L. Source: Journal of Hepatology. 1999 July; 31(1): 84-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10424287

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Male sex predisposes the newborn surgical patient to parenteral nutrition-associated cholestasis and to sepsis. Author(s): Albers MJ, de Gast-Bakker DA, van Dam NA, Madern GC, Tibboel D. Source: Archives of Surgery (Chicago, Ill. : 1960). 2002 July; 137(7): 789-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12093333

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Maternal midtrimester free beta-HCG and AFP serum levels in spontaneous singleton pregnancies complicated by gestational diabetes mellitus, pregnancyinduced hypertension or obstetric cholestasis. Author(s): Raty R, Anttila L, Virtanen A, Koskinen P, Laitinen P, Morsky P, Tiitinen A, Martikainen H, Ekblad U. Source: Prenatal Diagnosis. 2003 December 30; 23(13): 1045-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14691989

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Metastatic malignant melanoma of the papilla of Vater: an unusual case of obstructive cholestasis treated with biliary prostheses. Author(s): Sans M, Llach J, Bordas JM, Andreu V, Campo A, Castells A, Mondelo E, Teres J, Rodes J. Source: Endoscopy. 1996 November; 28(9): 791-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9007447

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Microbiology of bile in patients with cholangitis or cholestasis with and without plastic biliary endoprosthesis. Author(s): Rerknimitr R, Fogel EL, Kalayci C, Esber E, Lehman GA, Sherman S. Source: Gastrointestinal Endoscopy. 2002 December; 56(6): 885-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12447303

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Microsatellite marker association at chromosome region 2p13 in Finnish patients with preeclampsia and obstetric cholestasis suggests a common risk locus. Author(s): Laasanen J, Hiltunen M, Romppanen EL, Punnonen K, Mannermaa A, Heinonen S. Source: European Journal of Human Genetics : Ejhg. 2003 March; 11(3): 232-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12673277

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Molecular basis of neonatal cholestasis. Author(s): Emerick KM, Whitington PF. Source: Pediatric Clinics of North America. 2002 February; 49(1): 221-35. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11826806

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MR cholangiography in the evaluation of neonatal cholestasis: initial results. Author(s): Norton KI, Glass RB, Kogan D, Lee JS, Emre S, Shneider BL. Source: Radiology. 2002 March; 222(3): 687-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11867786

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Much ado about nothing? Diagnosis and management of obstetric cholestasis. Author(s): McDermott E. Source: Pract Midwife. 2001 April; 4(4): 14-7. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12026607

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Mucosal morphologic changes of intestinal transplant recipients with severe cholestasis. Author(s): Sileri P, Jao W, Holaysan J, Morini S, Chejfec G, Rastellini C, Abcarian H, Benedetti E, Cicalese L. Source: Transplantation Proceedings. 2002 May; 34(3): 925. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12034242

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Multidrug resistance 3 gene mutation 1712delT and estrogen receptor alpha gene polymorphisms in Finnish women with obstetric cholestasis. Author(s): Eloranta ML, Heiskanen JT, Hiltunen MJ, Mannermaa AJ, Punnonen KR, Heinonen ST. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2002 November 15; 105(2): 132-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12381474

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Multidrug resistance 3 gene mutation 1712delT and estrogen receptor alpha gene polymorphisms in Finnish women with obstetric cholestasis. Author(s): Eloranta ML, Heiskanen JT, Hiltunen MJ, Mannermaa AJ, Punnonen KR, Heinonen ST. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2002 September 10; 104(2): 109-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12206920

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Necrotizing enterocolitis and total parenteral nutrition-associated cholestasis. Author(s): Moss RL, Das JB, Raffensperger JG. Source: Nutrition (Burbank, Los Angeles County, Calif.). 1996 May; 12(5): 340-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8875518

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Neonatal cholestasis and infantile Gaucher disease: a case report. Author(s): Barbier C, Devisme L, Dobbelaere D, Noizet O, Nelken B, Gottrand F. Source: Acta Paediatrica (Oslo, Norway : 1992). 2002; 91(12): 1399-401. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12578302

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Neonatal cholestasis as the presenting feature in cystic fibrosis. Author(s): Lykavieris P, Bernard O, Hadchouel M. Source: Archives of Disease in Childhood. 1996 July; 75(1): 67-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8813874

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Neonatal cholestasis resulting from vertical transmission of hepatitis A infection. Author(s): Urganci N, Arapoglu M, Akyildiz B, Nuhoglu A. Source: The Pediatric Infectious Disease Journal. 2003 April; 22(4): 381-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12712976

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Neonatal cholestasis syndrome in India--a diagnostic and therapeutic challenge. Author(s): Bhave SA, Bavdekar AR, Pandit AN. Source: Indian Pediatrics. 1996 September; 33(9): 753-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9057403

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Neonatal cholestasis syndrome: an appraisal at a tertiary center. Author(s): Yachha SK, Khanduri A, Kumar M, Sikora SS, Saxena R, Gupta RK, Kishore J. Source: Indian Pediatrics. 1996 September; 33(9): 729-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9057399

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Neonatal cholestasis. Author(s): Arora NK. Source: Trop Gastroenterol. 1996 April-June; 17(2): 61-9. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8783979

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Nodular regenerative hyperplasia of the liver: a rare differential diagnosis of cholestasis with response to ursodeoxycholic acid. Author(s): Faust D, Fellbaum C, Zeuzem S, Dietrich CF. Source: Zeitschrift Fur Gastroenterologie. 2003 March; 41(3): 255-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12664346

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Novel surgical and pharmacological approaches to chronic cholestasis in children: partial external biliary diversion for intractable pruritus and xanthomas in Alagille Syndrome. Author(s): Neimark E, Shneider B. Source: Journal of Pediatric Gastroenterology and Nutrition. 2003 February; 36(2): 296-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12593401

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Nutritional factors contributing to the development of cholestasis during total parenteral nutrition. Author(s): Forchielli ML, Walker WA. Source: Adv Pediatr. 2003; 50: 245-67. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14626490

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Obstetric cholestasis with elevated gamma glutamyl transpeptidase: incidence, presentation and treatment. Author(s): Milkiewicz P, Gallagher R, Chambers J, Eggington E, Weaver J, Elias E. Source: Journal of Gastroenterology and Hepatology. 2003 November; 18(11): 1283-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14535985

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Obstetric cholestasis, outcome with active management: a series of 70 cases. Author(s): Kenyon AP, Piercy CN, Girling J, Williamson C, Tribe RM, Shennan AH. Source: Bjog : an International Journal of Obstetrics and Gynaecology. 2002 March; 109(3): 282-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11950183

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Obstetric cholestasis. Author(s): Milkiewicz P, Elias E, Williamson C, Weaver J. Source: Bmj (Clinical Research Ed.). 2002 January 19; 324(7330): 123-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11799014

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Obstetric cholestasis: current opinions and management. Author(s): Tan LK. Source: Ann Acad Med Singapore. 2003 May; 32(3): 294-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12854371

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Obstetric cholestasis: outcome with active management. Author(s): Roncaglia N, Arreghini A, Locatelli A, Bellini P, Andreotti C, Ghidini A. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2002 January 10; 100(2): 167-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11750958

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Ondansetron for pruritus in child with chronic cholestasis. Author(s): Trioche P, Samuel D, Odievre M, Labrune P. Source: European Journal of Pediatrics. 1996 November; 155(11): 990. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8911904

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Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions. Author(s): Jones EA, Neuberger J, Bergasa NV. Source: Qjm : Monthly Journal of the Association of Physicians. 2002 August; 95(8): 54752. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12145394

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Organic anion transporting polypeptides, cholestasis, and nuclear receptors. Author(s): Kullak-Ublick GA, Jung D, Hagenbuch B, Meier PJ. Source: Hepatology (Baltimore, Md.). 2002 March; 35(3): 732-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11870396

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Paediatric cholestasis: is villin the villain? Author(s): Jansen PL, Sturm E. Source: Lancet. 2003 October 4; 362(9390): 1090-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14550691

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Pain as a complication of use of opiate antagonists for symptom control in cholestasis. Author(s): McRae CA, Prince MI, Hudson M, Day CP, James OF, Jones DE. Source: Gastroenterology. 2003 August; 125(2): 591-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12891561

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Parenteral nutrition-associated cholestasis in neonates: the role of aluminum. Author(s): Arnold CJ, Miller GG, Zello GA. Source: Nutrition Reviews. 2003 September; 61(9): 306-10. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14552065

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Parenteral nutrition-related cholestasis in postsurgical neonates: multivariate analysis of risk factors. Author(s): Beath SV, Davies P, Papadopoulou A, Khan AR, Buick RG, Corkery JJ, Gornall P, Booth IW. Source: Journal of Pediatric Surgery. 1996 April; 31(4): 604-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8801324

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Prochlorperazine-induced cholestasis in a patient with alpha-1 antitrypsin deficiency. Author(s): Mindikoglu AL, Anantharaju A, Hartman GG, Li SD, Villanueva J, Van Thiel DH. Source: Hepatogastroenterology. 2003 September-October; 50(53): 1338-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14571732

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Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation. Author(s): Lykavieris P, van Mil S, Cresteil D, Fabre M, Hadchouel M, Klomp L, Bernard O, Jacquemin E. Source: Journal of Hepatology. 2003 September; 39(3): 447-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12927934

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Progressive familial intrahepatic cholestasis type 3 revealed by oral contraceptive pills. Author(s): Ganne-Carrie N, Baussan C, Grando V, Gaudelus J, Cresteil D, Jacquemin E. Source: Journal of Hepatology. 2003 May; 38(5): 693-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12713886

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Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity. Author(s): Chen F, Ananthanarayanan M, Emre S, Neimark E, Bull LN, Knisely AS, Strautnieks SS, Thompson RJ, Magid MS, Gordon R, Balasubramanian N, Suchy FJ, Shneider BL. Source: Gastroenterology. 2004 March; 126(3): 756-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14988830

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Prolonged cholestasis and ductopenia associated with tenoxicam. Author(s): Trak-Smayra V, Cazals-Hatem D, Asselah T, Duchatelle V, Degott C. Source: Journal of Hepatology. 2003 July; 39(1): 125-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12821054

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Prolonged cholestasis and ductopenia following gold salt therapy. Author(s): Basset C, Vadrot J, Denis J, Poupon J, Zafrani ES. Source: Liver International : Official Journal of the International Association for the Study of the Liver. 2003 April; 23(2): 89-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12654130

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Quantitative changes in liver-cell organelles in cholestasis. Author(s): Grainger JM, Scheuer PJ. Source: The Journal of Pathology. 1972 January; 106(1): Pv. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5035755

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Quantitative determination of the abnormal lipoprotein of cholestasis, LP-X, in liver disease. Author(s): Ritland S. Source: Scandinavian Journal of Gastroenterology. 1975; 10(1): 5-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=164686

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Re: ganciclovir treatment in infants with cytomegalovirus infection and cholestasis. Author(s): Jonas MM. Source: Journal of Pediatric Gastroenterology and Nutrition. 2002 September; 35(3): 399400; Author Reply 400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12352538

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Recurrent cholestasis and hypereosinophilia in a young female. Author(s): Pometta R, Callea F, Mangano M, Zuccoli E, Conte D. Source: Dig Liver Dis. 2000 October; 32(7): 630-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11142565

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Recurrent cholestasis due to ampicillin. Author(s): Koklu S, Yuksel O, Filik L, Uskudar O, Altundag K, Altiparmak E. Source: The Annals of Pharmacotherapy. 2003 March; 37(3): 395-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12639171

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Reduced activity of 11 beta-hydroxysteroid dehydrogenase in patients with cholestasis. Author(s): Quattropani C, Vogt B, Odermatt A, Dick B, Frey BM, Frey FJ. Source: The Journal of Clinical Investigation. 2001 November; 108(9): 1299-305. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11696574

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Relationship between apoptosis, tumour necrosis factor, and cell proliferation in chronic cholestasis. Author(s): Floreani A, Guido M, Bortolami M, Della Zentil G, Venturi C, Pennelli N, Naccarato R. Source: Dig Liver Dis. 2001 October; 33(7): 570-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11816546

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Respective value of alkaline phosphatase, gamma-glutamyl transpeptidase and 5' nucleotidase serum activity in the diagnosis of cholestasis: a prospective study of 80 patients. Author(s): Sapey T, Mendler MH, Guyader D, Morio O, Corbinais S, Deugnier Y, Brissot P. Source: Journal of Clinical Gastroenterology. 2000 April; 30(3): 259-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10777184

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Reversal of severe cholestasis caused by chronic graft-versus-host disease with the MARS liver-support device. Author(s): Sen S, Jalan R, Morris EC, Steiner C, Mackinnon S, Williams R. Source: Transplantation. 2003 May 27; 75(10): 1766-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12777879

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Risk factors of cholestasis in very low-birth-weight infants. Author(s): Wu TJ, Teng RJ, Yau KI. Source: Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1996 July-August; 37(4): 27882. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8854350

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Risk of obstetric cholestasis in sisters of index patients. Author(s): Eloranta ML, Heinonen S, Mononen T, Saarikoski S. Source: Clinical Genetics. 2001 July; 60(1): 42-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11531968

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Role of lipid emulsions in cholestasis associated with long-term parenteral nutrition in children. Author(s): Colomb V, Jobert-Giraud A, Lacaille F, Goulet O, Fournet JC, Ricour C. Source: Jpen. Journal of Parenteral and Enteral Nutrition. 2000 November-December; 24(6): 345-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11071594

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S-adenosylmethionine versus ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy: preliminary results of a controlled trial. Author(s): Floreani A, Paternoster D, Melis A, Grella PV. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. 1996 August; 67(2): 109-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8841797

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Sepsis and cholestasis: basic findings in the sinusoid and bile canaliculus. Author(s): Hirata K, Ikeda S, Honma T, Mitaka T, Furuhata T, Katsuramaki T, Hata F, Mukaiya M. Source: Journal of Hepato-Biliary-Pancreatic Surgery. 2001; 8(1): 20-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11294287

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Sepsis-associated cholestasis. Author(s): Moseley RH. Source: Gastroenterology. 1997 January; 112(1): 302-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8978375

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Serotonin in pregnancies complicated by intrahepatic cholestasis. Author(s): Laskowska K, Laskowska M, Skrzydlo-Radomanska B, Slomka M, Oleszczuk J. Source: Ann Univ Mariae Curie Sklodowska [med]. 2000; 55: 389-94. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11482103

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Serum cholestasis markers as predictors of early outcome after liver transplantation. Author(s): Ben-Ari Z, Weiss-Schmilovitz H, Sulkes J, Brown M, Bar-Nathan N, Shaharabani E, Yussim A, Shapira Z, Tur-Kaspa R, Mor E. Source: Clinical Transplantation. 2004 April; 18(2): 130-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15016125

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Severe cholestasis in a patient with acute hepatitis C treated with interferon alpha-2b. Author(s): Mukherjee S, Gilroy RK, Schafer DF. Source: The American Journal of Gastroenterology. 2002 August; 97(8): 2152-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12190203

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Severe intrahepatic cholestasis in an elderly patient with primary amyloidosis and colon adenocarcinoma. Author(s): Liu CJ, Chien RN, Huang SF, Chiang JM. Source: Chang Gung Med J. 2004 January; 27(1): 74-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15074894

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Sickle cell anemia connected with chronic intrahepatic cholestasis: a case report. Author(s): Altintas E, Tiftik EN, Ucbilek E, Sezgin O. Source: Turk J Gastroenterol. 2003 September; 14(3): 215-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14655071

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Suppression of bile acid synthesis, but not of hepatic cholesterol 7alpha-hydroxylase expression, by obstructive cholestasis in humans. Author(s): Bertolotti M, Carulli L, Concari M, Martella P, Loria P, Tagliafico E, Ferrari S, Del Puppo M, Amati B, De Fabiani E, Crestani M, Amorotti C, Manenti A, Carubbi F, Pinetti A, Carulli N. Source: Hepatology (Baltimore, Md.). 2001 August; 34(2): 234-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11481606

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Surgical treatment of progressive familial intrahepatic cholestasis: comparison of partial external biliary diversion and ileal bypass. Author(s): Kalicinski PJ, Ismail H, Jankowska I, Kaminski A, Pawlowska J, Drewniak T, Markiewicz M, Szymczak M. Source: European Journal of Pediatric Surgery : Official Journal of Austrian Association of Pediatric Surgery. [et Al] = Zeitschrift Fur Kinderchirurgie. 2003 October; 13(5): 30711. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14618520

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The evaluation by magnetic resonance imaging of hepatic periportal fibrosis in infants with neonatal cholestasis: preliminary report. Author(s): Avni FE, Segers V, De Maertelaer V, Cadranel S, Dassonville M, Delaet MH, Nicaise N, Metens T. Source: Journal of Pediatric Surgery. 2002 August; 37(8): 1128-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12149687

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The pruritus of cholestasis is relieved by an opiate antagonist: is this pruritus a centrally mediated phenomenon? Author(s): Heathcote J. Source: Hepatology (Baltimore, Md.). 1996 May; 23(5): 1280-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8621166

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The road to elucidating the mechanism of manganese-bilirubin-induced cholestasis. Author(s): Goering PL. Source: Toxicological Sciences : an Official Journal of the Society of Toxicology. 2003 June; 73(2): 216-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12778929

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The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II. Author(s): Wang L, Soroka CJ, Boyer JL. Source: The Journal of Clinical Investigation. 2002 October; 110(7): 965-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12370274

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Total parenteral nutrition-associated cholestasis: prematurity or amino acids? Author(s): Adamkin DH. Source: Journal of Perinatology : Official Journal of the California Perinatal Association. 2003 September; 23(6): 437-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13679927

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Transient cholestasis in newborn infants with perinatal asphyxia. Author(s): Herzog D, Chessex P, Martin S, Alvarez F. Source: Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. 2003 March; 17(3): 179-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12677267

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Treatment of itching associated with intrahepatic cholestasis of pregnancy. Author(s): Jenkins JK, Boothby LA. Source: The Annals of Pharmacotherapy. 2002 September; 36(9): 1462-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12196068

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Trials of opiate antagonists for the pruritus of cholestasis: primary efficacy endpoints and opioid withdrawal-like reactions. Author(s): Jones EA. Source: Journal of Hepatology. 2002 December; 37(6): 863-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12445430

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Tumor necrosis factor alpha-dependent up-regulation of Lrh-1 and Mrp3(Abcc3) reduces liver injury in obstructive cholestasis. Author(s): Bohan A, Chen WS, Denson LA, Held MA, Boyer JL. Source: The Journal of Biological Chemistry. 2003 September 19; 278(38): 36688-98. Epub 2003 July 01. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12837754

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Two cases of early-onset obstetric cholestasis. Author(s): Muammar B, Bhatti NR. Source: Journal of Obstetrics and Gynaecology : the Journal of the Institute of Obstetrics and Gynaecology. 2003 March; 23(2): 207-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12751522

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Ultrastructural features of danazol-induced cholestasis: a case study. Author(s): Alvaro D, Piat C, Francia C, Franchitto A, Furfaro S, Valente C, Capocaccia L, Gaudio E. Source: Ultrastructural Pathology. 1996 September-October; 20(5): 491-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8883334

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Ultrastructural sinusoidal changes in extrahepatic cholestasis. Light and electron microscopic immunohistochemical localization of collagen type III and type IV. Author(s): Gulubova MV. Source: Acta Histochemica. 1996 July; 98(3): 271-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8863856

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Update on the etiologies and management of neonatal cholestasis. Author(s): Karpen SJ. Source: Clin Perinatol. 2002 March; 29(1): 159-80. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11917736

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Urinary bile acid profile in children with inborn errors of bile acid metabolism and chronic cholestasis; screening technique using electrospray tandem massspectrometry (ES/MS/MS). Author(s): Yousef IM, Perwaiz S, Lamireau T, Tuchweber B. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 March; 9(3): Mt21-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12640349

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Urinary sulfated bile acids: a new simple urine test for cholestasis in infants and children. Author(s): Obatake M, Muraji T, Satoh S, Nishijima E, Tsugawa C. Source: Journal of Pediatric Surgery. 2002 December; 37(12): 1707-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12483636

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Ursodeoxycholic acid for the treatment of intrahepatic cholestasis of pregnancy. Author(s): Laifer SA, Stiller RJ, Siddiqui DS, Dunston-Boone G, Whetham JC. Source: The Journal of Maternal-Fetal Medicine. 2001 April; 10(2): 131-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11392594

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Ursodeoxycholic acid for treatment of cholestasis in children on long-term total parenteral nutrition: a pilot study. Author(s): Spagnuolo MI, Iorio R, Vegnente A, Guarino A. Source: Gastroenterology. 1996 September; 111(3): 716-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8780577

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Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy. A retrospective study of 19 cases. Author(s): Berkane N, Cocheton JJ, Brehier D, Merviel P, Wolf C, Lefevre G, Uzan S. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2000 November; 79(11): 941-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11081677

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Ursodeoxycholic acid in the treatment of cholestasis and hyperbilirubinemia in pediatric intensive care unit patients. Author(s): George R, Stevens A, Berkenbosch JW, Turpin J, Tobias J. Source: Southern Medical Journal. 2002 November; 95(11): 1276-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12539993

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Usual and unusual causes of extrahepatic cholestasis: assessment with magnetic resonance cholangiography and fast MRI. Author(s): Mortele KJ, Wiesner W, Cantisani V, Silverman SG, Ros PR. Source: Abdominal Imaging. 2004 January-February; 29(1): 87-99. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15160760

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Value of serum alkaline phosphatase, aminotransferases, gamma-glutamyl transferase, leucine aminopeptidase, and bilirubin in the distinction between benign and malignant diseases causing jaundice and cholestasis: results from a prospective study. Author(s): Pasanen P, Pikkarainen P, Alhava E, Partanen K, Penttila I. Source: Scandinavian Journal of Clinical and Laboratory Investigation. 1993 February; 53(1): 35-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8095735

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Vanishing bile duct syndrome: a possible mechanism for intrahepatic cholestasis in Hodgkin's lymphoma. Author(s): Hubscher SG, Lumley MA, Elias E. Source: Hepatology (Baltimore, Md.). 1993 January; 17(1): 70-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7678577

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Variceal bleeding is associated with reduced risk of severe cholestasis in primary biliary cirrhosis. Author(s): Thornton JR, Triger DR, Losowsky MS. Source: The Quarterly Journal of Medicine. 1989 May; 71(265): 467-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2602544

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Viral hepatitis complicated by cholestasis and unconjugated hyperbilirubinaemia. Author(s): Kenwright S. Source: Proc R Soc Med. 1972 November; 65(11): 979-80. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4642033

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Visual stool examination--a screening test for infants with prolonged neonatal cholestasis. Author(s): Brown SC, Househam KC. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 1990 April 7; 77(7): 358-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2321106

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Vitamin D and mineral metabolism in intrahepatic cholestasis of pregnancy. Author(s): Kuoppala T, Tuimala R, Parviainen M, Koskinen T. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. 1986 October; 23(1-2): 45-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3781071

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Vitamin E deficiency neuropathy in children with fat malabsorption. Studies in cystic fibrosis and chronic cholestasis. Author(s): Sokol RJ, Butler-Simon N, Heubi JE, Iannaccone ST, McClung HJ, Accurso F, Hammond K, Heyman M, Sinatra F, Riely C, et al. Source: Annals of the New York Academy of Sciences. 1989; 570: 156-69. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2629595

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Vitamin E deficiency with normal serum vitamin E concentrations in children with chronic cholestasis. Author(s): Sokol RJ, Heubi JE, Iannaccone ST, Bove KE, Balistreri WF. Source: The New England Journal of Medicine. 1984 May 10; 310(19): 1209-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6709026

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Vitamin E status in cholestasis. Author(s): Sokol RJ. Source: The Journal of Pediatrics. 1988 February; 112(2): 324-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3339514

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Vitamin E sufficiency in children with cholestasis: a comparison between erythrocyte peroxide hemolysis and serum alpha-tocopherol. Author(s): Clark JH, Nagamori KE, Ellett ML, Fitzgerald JF. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 1985 December 13; 153(2): 117-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4064341

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What is cholestasis in 1985? Author(s): Erlinger S. Source: Journal of Hepatology. 1985; 1(6): 687-93. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3902958

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What is cholestasis? Author(s): Magnenat P. Source: Helv Med Acta. 1973 September; 37(2): 175-81. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4748927

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What is rifampicin doing in pruritus of cholestasis? Author(s): Duseja A, Chawla YK. Source: Trop Gastroenterol. 2001 July-September; 22(3): 123-4. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11681101

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What is the role of major histocompatibility complex expression in cholestasis? Author(s): Lindor K. Source: Gastroenterology. 1992 April; 102(4 Pt 1): 1429-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1551554

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What the Amish can tell us about cholestasis. Author(s): Moseley RH. Source: Hepatology (Baltimore, Md.). 1998 September; 28(3): 888-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9731587

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

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

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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 “cholestasis” (or a synonym): x

Captopril-associated cholestasis complicating the management of pancreatic cancer. Author(s): H. Lee Moffitt Cancer Center and Research Institute and the University of South Florida, 12902 Magnolia Drive, Tampa FL 33612-9497, USA. Source: Kocab, M A Coppola, D Hiotis, S Karl, R C Barthel, J S Surg-Endosc. 2000 July; 14(7): 681 0930-2794

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Choleretic effects of curcuminoids on an acute cyclosporin-induced cholestasis in the rat. Author(s): Institute of Experimental and Clinical Pharmacology and Toxicology, Rostock, Germany. Source: Deters, M Siegers, C Muhl, P Hansel, W Planta-Med. 1999 October; 65(7): 610-3 0032-0943

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Hepatotoxicity and cholestasis in rats induced by the sesquiterpene, 9-oxo-10,11dehydroageraphorone, isolated from Eupatorium adenophorum. Author(s): Department of Chemistry and Biochemistry, Himachal Pradesh Krishi Vishvavidyalaya, Palampur 176 062, HP, India. Source: Bhardwaj, R Singh, A Sharma, O P Dawra, R K Kurade, N P Mahato, S B JBiochem-Mol-Toxicol. 2001; 15(5): 279-86 1095-6670

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Interventions for treating cholestasis in pregnancy (Cochrane Review). Author(s): Department of Obstetrics and Gynaecology, Monash University, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, AUSTRALIA, 3168. [email protected] Source: Burrows, R F Clavisi, O Burrows, E Cochrane-Database-Syst-Revolume 2001; 4: CD000493 1469-493X

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Intractable diarrhea in infancy--whether infection, zinc deficiency, cholestasis and hemorrhage are causes or results? Author(s): Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. Source: Yamagishi, M Hamamoto, F Shirakawa, Y Kawada, Y Kajiwara, Y Komatsu, K JUOEH. 1987 September 1; 9(3): 329-39 0387-821X

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Intravenous amino acids, cholestasis and kwashiorkor. Author(s): Division of Gastroenterology and Nutrition, Schneider Children's Medical Center of Israel, Sackler School of Medicine, Tel-Aviv University, Israel. [email protected] Source: Shamir, R Tershakovec, A M Barsky, D L J-Med. 1998; 29(1-2): 37-44 0025-7850

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Mechanism for the prevention of cholestasis involving cytochrome P4503A overexpression. Author(s): Department of Pharmacology, University of Bologna, Italy. Source: Paolini, M Pozzetti, L Piazza, F Guerra, M C Speroni, E Cantelli Forti, G Roda, A J-Investig-Med. 2000 January; 48(1): 49-59 1081-5589

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Relation between liver necrosis and intrahepatic cholestasis in rats poisoned with CCl4. Source: Carini, R Chiarpotto, E Biasi, F Leonarduzzi, G Comoglio, A Carpi, C Poli, G Boll-Soc-Ital-Biol-Sper. 1987 March 31; 63(3): 273-80 0037-8771

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S-adenosylmethionine for the treatment of intrahepatic cholestasis of pregnancy. Results of a controlled clinical trial. Author(s): Department of Medical Pathology, University of Trieste, Italy.

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Source: Frezza, M Centini, G Cammareri, G Le Grazie, C Di Padova, C Hepatogastroenterology. 1990 December; 37 Suppl 2122-5 0172-6390 x

The effect of total parenteral nutrition-induced cholestasis on theophylline clearance in neonates. Author(s): Moses H. Cone Memorial Hospital, Greensboro, North Carolina. Source: Kandrotas, R J Gal, P Hansen, C J Ransom, J L Weaver, R L Ther-Drug-Monit. 1988; 10(4): 390-4 0163-4356

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The optimum pH of serum alkaline phosphatase after induced cholestasis in the male rat, mouse and rabbit. Author(s): Department of Experimental Pathology, Nippon Boehringer Ingelheim Co., Ltd., Hyogo, Japan. Source: Yabe, T Kast, A J-Toxicol-Sci. 1988 November; 13(4): 179-91 0388-1350

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TPN cholestasis in premature infants: the role of parenteral nutrition solutions. Source: Sheard, N F Kleinman, R E Pediatr-Ann. 1987 March; 16(3): 243, 246, 248 passim 0090-4481

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Ultrastructural abnormalities in the skeletal muscle of children with chronic cholestasis and a long-term vitamin E replacement. Author(s): Department of Pediatrics, Akita University School of Medicine, Japan. Source: Kobayashi, Y Tazawa, Y Nakagawa, M Higashi, O Yamamoto, T Y Tohoku-JExp-Med. 1988 March; 154(3): 285-96 0040-8727

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: x

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

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

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

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

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

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

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

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

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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: x

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

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

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

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

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

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

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WebMDHealth: http://my.webmd.com/nutrition

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

The following is a specific Web list relating to cholestasis; 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: x

Minerals Manganese Source: Healthnotes, Inc.; www.healthnotes.com

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CHAPTER 3. ALTERNATIVE MEDICINE AND CHOLESTASIS Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to cholestasis. 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 “cholestasis” (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: x

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. x

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 cholestasis 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 “cholestasis” (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 cholestasis: x

17 beta-estradiol glucuronide: an inducer of cholestasis and a physiological substrate for the multidrug resistance transporter. Author(s): Gosland M, Tsuboi C, Hoffman T, Goodin S, Vore M. Source: Cancer Research. 1993 November 15; 53(22): 5382-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8106146

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Absorption of water-miscible forms of vitamin E in a patient with cholestasis and in thoracic duct-cannulated rats. Author(s): Traber MG, Kayden HJ, Green JB, Green MH.

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Source: The American Journal of Clinical Nutrition. 1986 December; 44(6): 914-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3788838 x

Anti-cholestatic activity of HD-03, a herbal formulation in thioacetamide (TAA)induced experimental cholestasis. Author(s): Mitra SK, Venkataranganna MV, Gopumadhavan S, Sundaram R. Source: Indian J Exp Biol. 1999 April; 37(4): 409-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10641180

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Anticholestatic effect of picroliv, active hepatoprotective principle of Picrorhiza kurrooa, against carbon tetrachloride induced cholestasis. Author(s): Saraswat B, Visen PK, Patnaik GK, Dhawan BN. Source: Indian J Exp Biol. 1993 April; 31(4): 316-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8359830

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BAPS prize lecture: New insight into mechanisms of parenteral nutrition-associated cholestasis: role of plant sterols. British Association of Paediatric Surgeons. Author(s): Iyer KR, Spitz L, Clayton P. Source: Journal of Pediatric Surgery. 1998 January; 33(1): 1-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9473088

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BCNU-induced quantitative and qualitative changes in hepatic cytochrome P-450 can be correlated with cholestasis. Author(s): Stolzenbach JC, Larson RE. Source: Cancer Chemotherapy and Pharmacology. 1990; 25(4): 227-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2295110

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Beneficial effects of silymarin on estrogen-induced cholestasis in the rat: a study in vivo and in isolated hepatocyte couplets. Author(s): Crocenzi FA, Sanchez Pozzi EJ, Pellegrino JM, Favre CO, Rodriguez Garay EA, Mottino AD, Coleman R, Roma MG. Source: Hepatology (Baltimore, Md.). 2001 August; 34(2): 329-39. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11481618

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Cascara sagrada-induced intrahepatic cholestasis causing portal hypertension: case report and review of herbal hepatotoxicity. Author(s): Nadir A, Reddy D, Van Thiel DH. Source: The American Journal of Gastroenterology. 2000 December; 95(12): 3634-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11151906

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Choleretic effects of alpha-iridodiol on experimentally induced intrahepatic cholestasis. Author(s): Mizoguchi Y, Sakagami C, Ichikawa Y, Kobayashi K.

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Source: Planta Medica. 1992 October; 58(5): 394-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1470661 x

Choleretic effects of curcuminoids on an acute cyclosporin-induced cholestasis in the rat. Author(s): Deters M, Siegers C, Muhl P, Hansel W. Source: Planta Medica. 1999 October; 65(7): 610-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10575375

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Cholestasis associated with parenteral alimentation. Author(s): Widder D. Source: The Journal of Pediatrics. 1980 September; 97(3): 505-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6774075

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Cholestasis-induced fibrosis is reduced by interferon alpha-2a and is associated with elevated liver metalloprotease activity. Author(s): Bueno MR, Daneri A, Armendariz-Borunda J. Source: Journal of Hepatology. 2000 December; 33(6): 915-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11131453

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Colchicine inhibits lithocholate-3-O-glucuronide-induced cholestasis in rats. Author(s): Takikawa H, Sano N, Yamazaki R, Yamanaka M. Source: Journal of Hepatology. 1995 January; 22(1): 88-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7751593

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Copper chelation therapy in intrahepatic cholestasis of childhood. Author(s): Evans J, Zerpa H, Nuttall L, Boss M, Sherlock S. Source: Gut. 1983 January; 24(1): 42-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6848432

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Drug-induced cholestasis. Author(s): Chitturi S, Farrell GC. Source: Semin Gastrointest Dis. 2001 April; 12(2): 113-24. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11352118

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Effect of oral vitamin E supplementation in children with cholestasis. Author(s): Roongpraiwan R, Suthutvoravut U, Feungpean B, Phuapradit P. Source: J Med Assoc Thai. 2002 November; 85 Suppl 4: S1199-205. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12549795

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Effects of curcumin on cyclosporine-induced cholestasis and hypercholesterolemia and on cyclosporine metabolism in the rat. Author(s): Deters M, Klabunde T, Meyer H, Resch K, Kaever V. Source: Planta Medica. 2003 April; 69(4): 337-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12709901

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Erythrocyte membrane lipid peroxidation before and after vitamin E supplementation in children with cholestasis. Author(s): Lubrano R, Frediani T, Citti G, Cardi E, Mannarino O, Elli M, Cozzi F, Giardini O. Source: The Journal of Pediatrics. 1989 September; 115(3): 380-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2769496

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Essential fatty acid metabolism in infants with cholestasis. Author(s): Socha P, Koletzko B, Swiatkowska E, Pawlowska J, Stolarczyk A, Socha J. Source: Acta Paediatrica (Oslo, Norway : 1992). 1998 March; 87(3): 278-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9560034

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Hodgkin's disease associated cholestasis in a man with thymoma. Author(s): Opeskin K, Burke M, McCaffrey G, Nandurkar H. Source: Pathology. 2003 August; 35(4): 349-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12959773

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Immunogenicity of rat hepatocytes in vivo: effect of cholestasis-induced changes in major histocompatibility complex expression. Author(s): Arvieux C, Calmus Y, Gane P, Legendre C, Mariani P, Delelo R, Poupon R, Nordlinger B. Source: Journal of Hepatology. 1993 July; 18(3): 335-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8228127

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Induction of multidrug resistance gene expression during cholestasis in rats and nonhuman primates. Author(s): Schrenk D, Gant TW, Preisegger KH, Silverman JA, Marino PA, Thorgeirsson SS. Source: Hepatology (Baltimore, Md.). 1993 May; 17(5): 854-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8098315

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Intrahepatic cholestasis associated with an enlarged gall-bladder. Author(s): Lok AS, Lai CL, Wong KL, Lam WK. Source: The Medical Journal of Australia. 1986 July 7; 145(1): 36-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3523178

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Intrahepatic cholestasis of pregnancy: an estrogen-related disease. Author(s): Reyes H, Simon FR. Source: Seminars in Liver Disease. 1993 August; 13(3): 289-301. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8235718

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Intravenous fish oil emulsion attenuates total parenteral nutrition-induced cholestasis in newborn piglets. Author(s): Van Aerde JE, Duerksen DR, Gramlich L, Meddings JB, Chan G, Thomson AB, Clandinin MT. Source: Pediatric Research. 1999 February; 45(2): 202-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10022591

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Jaundice and intrahepatic cholestasis following high-dose megestrol acetate for breast cancer. Author(s): Foitl DR, Hyman G, Lefkowitch JH. Source: Cancer. 1989 February 1; 63(3): 438-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2912522

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Liver copper levels in intrahepatic cholestasis of childhood. Author(s): Evans J, Newman S, Sherlock S. Source: Gastroenterology. 1978 November; 75(5): 875-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=700330

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Long-chain PUFA supplementation improves PUFA profile in infants with cholestasis. Author(s): Socha P, Koletzko B, Jankowska I, Pawlowska J, Demmelmair H, Stolarczyk A, Swiatkowska E, Socha J. Source: Lipids. 2002 October; 37(10): 953-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12530554

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MDR1 substrates/modulators protect against beta-estradiol-17beta-D-glucuronide cholestasis in rat liver. Author(s): Liu Y, Huang L, Hoffman T, Gosland M, Vore M. Source: Cancer Research. 1996 November 1; 56(21): 4992-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8895755

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Mechanism for the prevention of cholestasis involving cytochrome P4503A overexpression. Author(s): Paolini M, Pozzetti L, Piazza F, Guerra MC, Speroni E, Cantelli-Forti G, Roda A.

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Source: Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research. 2000 January; 48(1): 49-59. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10695269 x

Modification of lectin binding in rat gut mucosa during experimental cholestasis. Author(s): Vaccaro R, Casu C, Renda T. Source: Journal of Anatomy. 1992 October; 181 ( Pt 2): 239-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1295862

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New approaches to understanding the etiology and treatment of total parenteral nutrition-associated cholestasis. Author(s): Moss RL, Amii LA. Source: Semin Pediatr Surg. 1999 August; 8(3): 140-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10461327

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Obstetric cholestasis. Author(s): Axten S. Source: Mod Midwife. 1996 April; 6(4): 32-3. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8788907

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Obstetric cholestasis. A mother's experience. Author(s): Chambers J. Source: Pract Midwife. 2001 April; 4(4): 18. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12026608

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Oral guar gum treatment of intrahepatic cholestasis and pruritus in pregnant women: effects on serum cholestanol and other non-cholesterol sterols. Author(s): Gylling H, Riikonen S, Nikkila K, Savonius H, Miettinen TA. Source: European Journal of Clinical Investigation. 1998 May; 28(5): 359-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9650008

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Polyphenols from Camellia sinenesis attenuate experimental cholestasis-induced liver fibrosis in rats. Author(s): Zhong Z, Froh M, Lehnert M, Schoonhoven R, Yang L, Lind H, Lemasters JJ, Thurman RG. Source: American Journal of Physiology. Gastrointestinal and Liver Physiology. 2003 November; 285(5): G1004-13. Epub 2003 June 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791596

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Preventive effect of silymarin against taurolithocholate-induced cholestasis in the rat. Author(s): Crocenzi FA, Sanchez Pozzi EJ, Pellegrino JM, Rodriguez Garay EA, Mottino AD, Roma MG.

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Source: Biochemical Pharmacology. 2003 July 15; 66(2): 355-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12826278 x

Primary cultures of rat hepatocytes as a model system of canalicular development, biliary secretion, and intrahepatic cholestasis. IV. Disintegration of bile canaliculi and disturbance of tight junction formation caused by vinblastine. Author(s): Robenek H, Gebhardt R. Source: European Journal of Cell Biology. 1983 September; 31(2): 283-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6641739

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Prolonged postpartum course of intrahepatic cholestasis of pregnancy. Author(s): Olsson R, Tysk C, Aldenborg F, Holm B. Source: Gastroenterology. 1993 July; 105(1): 267-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8514043

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Protective effects of various Chinese traditional medicines against experimental cholestasis. Author(s): Sasaki T, Ohta S, Kamogawa A, Shinoda M. Source: Chemical & Pharmaceutical Bulletin. 1990 February; 38(2): 513-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2337968

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Regulation of synthesis and trafficking of canalicular transporters and its alteration in acquired hepatocellular cholestasis. Experimental therapeutic strategies for its prevention. Author(s): Crocenzi FA, Mottino AD, Roma MG. Source: Current Medicinal Chemistry. 2004 February; 11(4): 501-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14965230

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Removal of cellular debris formed in the Disse space in patients with cholestasis. Author(s): Dubuisson L, Bioulac-Sage P, Boussarie L, Quinton A, Saric J, de Mascarel A, Balabaud C. Source: Virchows Arch a Pathol Anat Histopathol. 1987; 410(6): 501-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3105169

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Taurine supplementation induces multidrug resistance protein 2 and bile salt export pump expression in rats and prevents endotoxin-induced cholestasis. Author(s): Muhlfeld A, Kubitz R, Dransfeld O, Haussinger D, Wettstein M. Source: Archives of Biochemistry and Biophysics. 2003 May 1; 413(1): 32-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12706339

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The spectrum of liver and gastrointestinal disease seen in cholestasis of pregnancy. Author(s): Reyes H.

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Source: Gastroenterology Clinics of North America. 1992 December; 21(4): 905-21. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1478743 x

Transient cholestasis during treatment with ajmaline, and chronic xanthomatous cholestasis after administration of ajmaline, methyltestosterone and ethinylestradiol. Two case reports. Author(s): Beermann B, Ericsson JL, Hellstrom K, Wengle B, Werner B. Source: Acta Med Scand. 1971 October; 190(4): 241-50. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5124256

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Treatment of EFA deficiency with dietary triglycerides or phospholipids in a murine model of extrahepatic cholestasis. Author(s): Werner A, Havinga R, Kuipers F, Verkade HJ. Source: American Journal of Physiology. Gastrointestinal and Liver Physiology. 2004 May; 286(5): G822-32. Epub 2003 December 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14670824

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Treatment of progressive familial intrahepatic cholestasis: liver transplantation or partial external biliary diversion. Author(s): Ismail H, Kalicinski P, Markiewicz M, Jankowska I, Pawlowska J, Kluge P, Eliadou E, Kaminski A, Szymczak M, Drewniak T, Revillon Y. Source: Pediatric Transplantation. 1999 August; 3(3): 219-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10487283

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

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

x

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

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

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

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

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

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

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

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

x

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

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WebMDHealth: 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 cholestasis; 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: x

General Overview Hepatitis Source: Healthnotes, Inc.; www.healthnotes.com Liver Cirrhosis Source: Healthnotes, Inc.; www.healthnotes.com Pregnancy and Postpartum Support Source: Healthnotes, Inc.; www.healthnotes.com

x

Herbs and Supplements Milk Thistle Alternative names: Silybum marianum, Carduus marianus Source: Healthnotes, Inc.; www.healthnotes.com 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 SAMe (S-Adenosylmethionine) Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,818,00.html

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

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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. PATENTS ON CHOLESTASIS 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.8 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 “cholestasis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cholestasis, we have not necessarily excluded nonmedical patents in this bibliography.

Patents on Cholestasis By performing a patent search focusing on cholestasis, 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 8Adapted

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 cholestasis: x

Cholestasis ameliorant Inventor(s): Koiso; Kumiko (Tokyo, JP), Maeda; Minoru (Tokyo, JP), Sekido; Shozaburo (Tokyo, JP) Assignee(s): Tokyo Tanabe Company Limited (Tokyo, JP) Patent Number: 5,863,550 Date filed: December 1, 1995 Abstract: Disclosed is a cholestasis ameliorant containing tauroursodeoxycholic acid, which is more excellent in solubility than ursodeoxycholic acid, as the active ingredient. The ameliorant is useful for the treatment of intrahepatic cholestasis due to druginduced hepatopathy, viral hepatitis or the like and the treatment of cholestasis occurring after surgical operation for the treatment of obstructive jaundice. Excerpt(s): This application claims benefit of international application PCT JP94/00282, filed Feb. 23, 1994. Cholestasis is a pathological condition where the choleresis, which is one of the important functions of the liver, is suppressed and the bile flow from the liver through the bile duct to the duodenum is reduced, resulting in congestion of biliary components, and it is categorized into extrahepatic obstructive jaundice, which is caused by an apparent mechanical obstruction such as tumor or gallstones, and intrahepatic cholestasis, which occurs with no macroscopically noticeable site of obstruction. Intrahepatic cholestasis is further classified into acute type due to druginduced hepatitis or viral hepatitis, chronic type represented by primary biliary cirrhosis (PBC), recurrent type occurring familially or during pregnancy and the like and the main clinical symptoms common to all types of intrahepatic cholestasis are severe jaundice and persistent itching. Steroid and phenobarbital preparations are currently used for the treatment of intrahepatic cholestasis, showing a certain level of, but often insufficient, efficacy. Web site: http://www.delphion.com/details?pn=US05863550__

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Compositions of gastric acid-resistant microspheres containing buffered bile acids Inventor(s): Sipos; Tibor (Lebanon, NJ) Assignee(s): Digestive Care Inc. (Lebanon, NJ) Patent Number: 5,405,621 Date filed: November 10, 1993 Abstract: Disclosed are gastric acid-resistant polymer-coated buffered-bile acid compositions, process for their preparations and methods of treating digestive disorders, impaired liver function, autoimmune diseases of the liver and biliary tract, preventing colon cancer, cholestasis associated with cystic fibrosis, dissolving gallstones and regulating dietary cholesterol absorption by administering said compositions to a mammal in need of such treatment. Excerpt(s): This invention relates to buffer-stabilized bile acid compositions for ingestion by a mammal, a process for preparing said compositions, and a method for treating digestive disorders, impaired liver function, autoimmune diseases of the liver and

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biliary tract, preventing colon cancer, cholestasis associated with cystic fibrosis, dissolving gallstones and regulating dietary cholesterol absorption by administering said compositions to a mammal in need of such treatment. It is known in the prior art that ursodeoxycholic acid (hereinafter sometimes referred to as UDCA) administered to mammals can remedy UDCA deficiency caused by various diseased conditions of the liver, such as gallstones, liver toxicity due to toxic metabolites, alcohol induced hangover, drug related toxicity, colon cancer following gallbladder surgery, and deficiency associated with poor digestion of fats and lipids in the intestine. UDCA requires the presence of certain conditions in order for it to be safe and effective as will be described hereunder. Once the exogenously introduced buffer-stabilized UDCA reaches the duodenum, another requirement must be satisfied: the buffer-stabilized UDCA must be released from its protective environment and intimately mixed with the food transferred from the stomach to effect digestion. Web site: http://www.delphion.com/details?pn=US05405621__ x

Compositions of gastric acid-resistant microspheres containing salts of bile acids Inventor(s): Sipos; Tibor (Lebanon, NJ) Assignee(s): Digestive Care Inc. (Lebanon, NJ) Patent Number: 5,415,872 Date filed: October 20, 1993 Abstract: Disclosed are buffer-stabilized gastric acid resistant polymer-coated bile salt compositions, process for their preparations and methods of treating digestive disorders, impaired liver function, autoimmune diseases of the liver and biliary tract, preventing colon cancer, cholestasis associated with cystic fibrosis, dissolving gallstones and regulating dietary cholesterol absorption by administering said compositions to a mammal in need of such treatment. Excerpt(s): This invention relates to buffer-stabilized salts of bile acid compositions for ingestion by a mammal, a process for preparing said compositions, and a method for treating digestive disorders, impaired liver function, autoimmune diseases of the liver and biliary tract, preventing colon cancer, cholestasis associated with cystic fibrosis, dissolving gallstones, and regulating dietary cholesterol absorption by administering said compositions to a mammal in need of such treatment. It is known in the prior art that ursodeoxycholic acid (hereinafter sometimes referred to as UDCA) administered to mammals can remedy various diseased conditions of the liver, gallstones, liver toxicity due to toxic metabolites, alcohol induced hang-over, drug related toxicity, colon cancer following gallbladder surgery, and deficiency associated with poor digestion of fats and lipids in the intestine. UDCA requires the presence of certain conditions in order for it to be safe and effective as will be described hereunder. Once the exogenously introduced UDCA reaches the duodenum, another requirement must be satisfied: the UDCA must be released from its protective environment and intimately mixed with the food transferred from the stomach to effect digestion. Web site: http://www.delphion.com/details?pn=US05415872__

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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 Cholestasis As of December 2000, U.S. patent applications are open to public viewing.9 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 cholestasis: x

Bile secretagogues Inventor(s): Kawamura, Ikuo; (Osaka, JP), Manda, Toshitaka; (Osaka, JP), Ota, Mariko; (Hyogo, JP) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20030220269 Date filed: May 27, 2003 Abstract: The invention provides a choleretic composition, a bile acid secretionpromoting composition and a therapeutic composition for cholestasis each comprising insulin-like growth factor I or an analog thereof as well as a method of promoting secretion of bile which comprises administering insulin-like growth factor I or an analog thereof, a method of promoting secretion of bile acids, and a method for therapy of cholestasis in mammals.

9

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

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Excerpt(s): This invention relates to a choleretic composition, a bile acid secretionpromoting composition and a therapeutic composition for cholestasis. More particularly, the invention relates to a choleretic composition, a bile acid secretionpromoting composition and a therapeutic composition for cholestasis each comprising insulin-like growth factor (I) or an analog thereof and to a method of promoting secretion of bile, a method of promoting secretion of bile acids, and a method for therapy of cholestasis, each comprising administering insulin-like growth factor I or an analog thereof to mammals. Cholestasis is a symptom of various diseases of the liver. Its etiology, roughly classified, may be iatrogenic (drug-related), viral or congenital. As therapeutic drugs for cholestasis, adrenocortical hormones and ursodeoxycholic acid have heretofore been chiefly used, but adrenocortical hormones have the disadvantage of side effects, while the effect of ursodeoxycholic acid is not fully satisfactory. The inventors of this invention made intensive investigations and found that insulin-like growth factor I (IGF-I) has a potent choleretic action and have developed this instant invention. To be an additional surprise, whereas adrenocortical hormones, such as prednisolone, and ursodeoxycholic acid, all in routine use, exert choleretic actions, IGF-I has both choleretic and bile acid secretion-promoting actions and is expected to provide a new selective therapeutic modality. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html x

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,

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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 x

Prevention or treatment of abnormal lipoprotein, atherosclerosis and cholestasis Inventor(s): Braun-Egles, Anne; (Strasbourg, FR), Krieger, Monty; (Needham, MA), Miettinen, Helena E.; (Helsinki, FI) Correspondence: Patrea L. Pabst; Holland & Knight Llp; Suite 2000, One Atlantic Center; 1201 West Peachtree Street, N.E.; Atlanta; GA; 30309-3400; US Patent Application Number: 20040006129 Date filed: May 5, 2003 Abstract: Using an animal model, transgenic animals that do not express functional SRBI and apoE which develop severe atherosclerosis, by age four weeks in transgenic mice, a class of drugs, PROBUCOL (4,4'-(isopropylidenedithio) bis(2,6-di-tert-butylphenol)) and monoesters of PROBUCOL, and BO 653, 2,3-Dihydro-5-hydroxy-2,2-dipentyl-4,6-ditert-butyl-benzofuran, has been discovered which is useful in normalizing abnormal lipoprotein levels and/or characteristics, such as those found in lipoprotein X-associated disease. These animals are good models for screening of drugs useful in the treatment and/or prevention of cardiac fibrosis, myocardial infarction, defects in electrical conductance, atherosclerosis, unstable plaque, and stroke, as well as for lipoprotein disorders such as cholestasis and lipoprotein X associated disorders. Studies demonstrate normalization of lipoprotein levels and structure, as well as significant decreases in atherosclerosis and prevention of heart attack, even when administered after disease onset. Excerpt(s): This application claims priority to U.S. Ser. No. 10/147,651 filed May 16, 2002, entitled "Screening of Compounds for Treatment of Atherosclerosis and Heart Attack" by Monty Krieger, Anne Braun-Egles and Helena Miettinen. The present invention is generally in the area of methods of prevention or treatment of abnormal lipoprotein disorders, atherosclerosis, and heart attack. Atherosclerosis is the leading cause of death in western industrialized countries. Atherosclerosis is the process in which deposits of fatty substances, cholesterol, cellular waste products, calcium and other substances build up in the inner lining of an artery. This buildup is called plaque. It usually affects large and medium-sized arteries. Some hardening of arteries often occurs when people grow older. Plaques can grow large enough to significantly reduce the blood's flow through an artery, and it is thought that much damage occurs when they become fragile and rupture. Plaques that rupture cause blood clots to form that can block blood flow or break off and travel to another part of the body. If either happens (occlusive plaques with or without occlusive blood clots) and blocks a blood vessel that feeds the heart, it causes a heart attack. If it blocks a blood vessel that feeds the brain, it causes a stroke. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Screening of a novel hepatic syndrome and its uses Inventor(s): Hermelin, Brigitte; (Versailles, FR), Poupon, Raoul; (Paris, FR), Rosmorduc, Olivier; (Paris, FR) Correspondence: Morgan Lewis & Bockius Llp; 1111 Pennsylvania Avenue NW; Washington; DC; 20004; US Patent Application Number: 20030215843 Date filed: February 10, 2003 Abstract: The invention concerns methods of screening for a hepatic syndrome occurring in the young adult and associating cholesterol biliary microlithiasis, intrahepatic cholestasis and several mutations of the MDR3 gene. The invention is also directed to methods for the treatment of said syndrome. The hepatic syndrome screening methods comprise detecting, from a nucleic acid sample extracted from peripheral blood mononucleate cells, heterozygous mutations of the MDR3 gene and/or homozygous mutations of the MDR3 gene that do not eliminate the expression of the protein expressed by the MDR3 gene, which has phosphatidylcholine carrier activity, in adult subjects associating cholesterol biliary microlithiasis and intrahepatic cholestasis. Excerpt(s): This application is a continuation-in-part of co-pending international application PCT/FR01/02553, filed Aug. 6, 2001 which claims priority to French application 00/10428, filed Aug. 8, 2000. The disclosures of these two prior applications are hereby expressly incorporated by reference in their entireties into the present application. The present invention relates to the screening of a hepatic syndrome occurring in young adults and associating (i) intrahepatic hyperechoic foci with or without intrahepatic sludge or microlithiasis and further on a cholesterol microcholelithiasis, intrahepatic cholestasis and (ii) one or more mutations of the MDR3 gene (point mutations and/or SNPs). The present invention also relates to the treatment of said syndrome. 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 cholestasis, 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 “cholestasis” (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 cholestasis. You can also use this procedure to view pending patent applications concerning cholestasis. 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 5. BOOKS ON CHOLESTASIS Overview This chapter provides bibliographic book references relating to cholestasis. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on cholestasis 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 “cholestasis” (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 cholestasis: x

Diseases of the Liver and Biliary System, Eleventh Edition Source: Malden, MA: Blackwell Science, Inc. 2002. 706 p. 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: Designed to serve practicing physicians, surgeons and pathologists, as well as clinical students, this textbook presents a comprehensive and up-to-date account of diseases of the liver and biliary system. The text offers 38 chapters: anatomy and function; the assessment of liver function; biopsy of the liver; the hematology of liver disease; ultrasound, computed tomography (CT scan) and magnetic resonance imaging (MRI); hepatocellular failure; hepatic encephalopathy; acute liver failure; ascites (fluid accumulation); the portal venous system and portal hypertension; the hepatic artery and

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hepatic vein, and the liver in circulatory failure; jaundice; cholestasis; primary biliary cirrhosis (PBC); sclerosing cholangitis; viral hepatitis, including general features, hepatitis A, hepatitis E, and other viruses; hepatitis B virus and hepatitis Delta virus; hepatitis C virus; chronic hepatitis, its general features and autoimmune chronic disease; drugs and the liver; hepatic cirrhosis (scarring); alcohol and the liver; iron overload states; Wilson's disease; nutritional and metabolic liver diseases; the liver in infancy and childhood; the liver in pregnancy; the liver is systemic disease, granulomas, and hepatic trauma; the liver in infections; nodules and benign liver lesions; malignant liver tumors; the role of interventional radiology and endoscopy in imaging of the biliary tract; cysts and congenital biliary abnormalities; gallstones and inflammatory gallbladder diseases; benign stricture of the bile ducts; diseases of the ampulla of Vater and the pancreas; tumors of the gallbladder and bile ducts; and hepatic transplantation. The text includes full-color and black-and-white illustrations and photographs. A detailed subject index concludes the volume. x

Gastrointestinal and Hepatobiliary Pathophysiology Source: Madison, CT: Fence Creek Publishing. 1998. 475 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: $27.95 plus shipping and handling. ISBN: 1889325015. Summary: This book on gastrointestinal and hepatobiliary pathophysiology is one from a series designed to meet the second and third year medical students' needs for a concise but comprehensive resource that focuses on organ system pathophysiology. The test covers the pathogenesis, diagnosis, treatment, and management of common diseases, using a format that includes one or more clinical cases integrated throughout the chapters to foster direct application of clinical problem solving skills; extensive use of margin notes that concisely highlight important concepts, define key terms, and pinpoint clinical correlations; questions at the end of each chapter, using the NBME format, that offer a means for accurate self assessment; and wide margins to accommodate note taking by students as they study. Thirty chapters cover an overview of gastrointestinal and hepatobiliary function; regulation of the digestive system; the anatomy, histology, and embryology of the gastrointestinal tract; an overview of gastrointestinal motility; gastrointestinal electrolyte and fluid secretion; digestion and absorption; management of water and electrolytes; liver anatomy and physiology; liver metabolism, physiology of bile formation, and gallstones; normal and disordered swallowing; peptic ulcer disease; small bowel disorders; acute and chronic pancreatitis; functional bowel disorders; the mucosal immune system; inflammatory bowel disease; infectious disorders of the gastrointestinal tract; viral hepatitis; hereditary liver disease; autoimmune liver disease; pathogenesis and consequences of portal hypertension; disorders of cholestasis, bilirubin metabolism, and jaundice; orthotopic liver transplantation; alcohol and the gastrointestinal tract; the pathophysiology of abdominal pain and pain syndromes; gastrointestinal disorders in pregnancy; the molecular biology of gastrointestinal malignancies and overview of neoplasms of the gastrointestinal tract; pharmacology; principles of nutritional support in the gastrointestinal patient; and gastrointestinal bleeding. A subject index concludes the textbook.

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Diseases of the Liver and Biliary Tract: Standardization of Nomenclature, Diagnostic Criteria and Prognosis Source: New York, NY: Raven Press. 1994. 205 p. Contact: Available from Raven Press. 1185 Avenue of the Americas, New York, NY 10036. (212) 930-9500. Fax (212) 869-3495. PRICE: $40 (as of 1995). ISBN: 0781702119. Order Code 2775. Summary: This book presents nomenclature for diseases of the liver and biliary tract and represents an expansion and modification of previously adopted international terminology, with ICD rubric to facilitate standardization of data coding, collection, storage and retrieval. The book includes six chapters that address the standardization of nomenclature, diagnostic criteria, and prognosis for these diseases. Additional chapters present diagnostic criteria for hepatitis, cirrhosis, cholestasis and biliary tract disorders, congenital/perinatal/metabolic disorders, fatty liver, nonviral infections and systemic diseases of the liver, vascular disorders, tumors of the liver and intrahepatic bile ducts, and diseases of the gallbladder. Diagnostic criteria presented consists of a definition followed by clinical, laboratory, radiologic, morphologic, and etiologic criteria. Prognosis is also provided for common disorders where such information is widely accepted and used. A subject index concludes the volume. (AA-M).

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Diseases of the Liver and Biliary System. 10th ed Source: Oxford, England: Blackwell Science. 1997. 714 p. 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]. PRICE: $150.00. ISBN: 0865429065. Summary: This medical textbook presents a comprehensive account of diseases of the liver and biliary system, designed to be of use to physicians, surgeons and pathologists, and also as a reference text for the clinical student. Chapters cover anatomy and function; assessment of liver function; needle biopsy of the liver; the hematology of liver disease; ultrasound, computed tomography, and magnetic resonance imaging; hepatocellular failure; hepatic encephalopathy; fulminant hepatic failure; ascites; the portal venous system and portal hypertension; the hepatic artery and hepatic veins, i.e., the liver in circulatory failure; jaundice; cholestasis; primary biliary cirrhosis; sclerosing cholangitis; virus hepatitis; chronic hepatitis; drugs and the liver; hepatic cirrhosis; alcohol and the liver; iron overload states; Wilson's disease; nutritional and metabolic liver disease; the liver in infancy and childhood; the liver in pregnancy; the liver in systemic disease and hepatic trauma; the liver in infections; hepatic tumors, including hepato-cellular carcinoma; imaging of the biliary tract, including interventional radiology and endoscopy; cysts and congenital biliary abnormalities; gallstones and inflammatory gallbladder diseases; benign stricture of the bile ducts; diseases of the ampulla of Vater and pancreas; tumors of the gallbladder and bile ducts; and hepatic transplantation. The volume includes full color photographs, extensive reference lists with each chapter, and a detailed subject index.

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Primary Biliary Cirrhosis: From Pathogenesis to Clinical Treatment Source: Boston, MA: Kluwer Academic Publishers. 1998. 176 p. Contact: Available from Kluwer Academic Publishers. Customer Service Deparment, P.O. Box 358, Accord Station, Hingham, MA 02018-0358. (781) 871-6600. Fax (781) 6819045. E-mail: [email protected]. Website: www.wkap.nl.

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Summary: This monograph reprints papers from a conference held in November 1997 in Chicago, Illinois, on the clinical features (symptoms), pathogenesis, and treatment of primary biliary cirrhosis (PBC). PBC is generally considered to be an autoimmune disease and one that occurs in patients who are genetically predisposed to the disease. The part played by mitochondrial antibodies (AMA) in pathogenesis of PBC remains controversial. Alternatively, the disease may have an infectious etiology (cause). Therapy can be directed against any of these injurious processes. Drug therapy, notably combinations of drugs, can be used. Fibrosis (scarring) of the bile ducts occurs in PBC and is responsible for the end picture of cirrhosis (liver scarring). Complications such as ascites (fluid accumulation) and portal hypertension (high blood pressure) need to be treated; other complications can include bone thinning and pruritus (itching). Liver (hepatic) transplantation performed before the terminal stages of PBC offers a five year survival exceeding 85 percent. There is evidence of recurrence in the graft. The monograph includes 20 chapters covering the natural history and demography of PBC, the immune basis for PBC, isolation and cloning of antimitochondrial antibodies, determining pathogenesis, molecular considerations of PBC, animal models of PBC, fibrogenesis in PBC, natural history models, portal hypertension in patients with PBC, osteoporosis, managing fatigue in the patients with PBC, pruritus associated with cholestasis (suppression of the flow of bile), immunosuppressant agents, methotrexate and colchicine in the treatment of PBC, corticosteroids in PBC, ursodeoxycholic acid treatment of PBC, ursodiol and combination therapy, transplantation, and new clinical trials in PBC. Each chapter concludes with references and a subject index concludes the monograph. x

Endoscopic Retrograde Cholangiopancreatography: Technique, Diagnosis, and Therapy Source: New York, NY: Raven Press, Ltd. 1992. 426 p. Contact: Available from Raven Press. 1185 Avenue of the Americas, Dept. 5B, New York, NY 10036. (800) 777-2836 or (212) 930-9500. Fax (212) 869-3495. PRICE: $167 plus shipping (as of 1995). Summary: This volume is an up-to-date review of the procedure of endoscopic retrograde cholangiopancreatography (ERCP). The author brings together the disciplines of radiology and endoscopy by presenting endoscopic techniques and findings along with a compendium of radiographs that contain the key elements of interpretation. Three sections (technique, diagnosis, and therapeutic endoscopy) present 14 chapters covering an introduction and history of ECRP; indications, contraindications, and preparation; endoscopic technique; radiologic interpretation of the normal biliary system and variations and the normal pancreatic duct and variations; intrahepatic cholestasis; extrahepatic cholestasis (obstructive jaundice); periampullary findings; advantages and limitations of endoscopic manometry of the Sphincter of Oddi; inflammatory, congenital, and malignant pancreatic disorders; techniques for biliary and pancreatic endoscopic sphincterotomy; stone extraction, lithotripsy, stents and stones; decompression techniques of nasobiliary catheters and endoprostheses; cholangiopancreatoplasty; and the newer techniques of intraluminal radiation, bipolar sphincterotomy, and cholangioscopy. A detailed subject index is included.

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

Bile Acids and Cholestasis - XV International Bile Acid Meeting by Germany) Bile Acid Meeting 1998 Titisee, et al; ISBN: 079238752X; http://www.amazon.com/exec/obidos/ASIN/079238752X/icongroupinterna

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Cholestasis in infancy: Its pathogenesis, diagnosis and treatment : proceedings of the International Symposium on Cholestasis in Infancy held June 7-9. lication / Japan Medical Research Foundation); ISBN: 0839141025; http://www.amazon.com/exec/obidos/ASIN/0839141025/icongroupinterna

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Cholestasis: Proceedings of the International Meeting on Cholestasis and Related Disorders, Florence, Italy, 23-26 March 1994 (International Congres) by P. Gentilini, et al; ISBN: 0444816380; http://www.amazon.com/exec/obidos/ASIN/0444816380/icongroupinterna

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Hepatobiliary Diseases: Cholestasis and Gallstone (Falk Symposium, Vol 17A) by M. Acalovschi, G. Paumgartner; ISBN: 0792387708; http://www.amazon.com/exec/obidos/ASIN/0792387708/icongroupinterna

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Molecular Pathogenesis of Cholestasis (Medical Intelligence Unit) by Michael Trauner, Peter L. M. Jansen; ISBN: 0306482401; http://www.amazon.com/exec/obidos/ASIN/0306482401/icongroupinterna

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

Cholestasis Source: in Sherlock, S.; Dooley, J. Diseases of the Liver and Biliary System. Malden, MA: Blackwell Science, Inc. 2002. p.219-240. 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.

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Summary: Cholestasis is defined as the failure of normal bile to reach the duodenum. Prolonged cholestasis produces biliary cirrhosis (scarring); the time taken for its development varies from months to year. This chapter on cholestasis is from a textbook that presents a comprehensive and up-to-date account of diseases of the liver and biliary system. The chapter covers the anatomy of the biliary system; secretion of bile, particularly the cellular mechanisms; and the syndrome of cholestasis, including definition, classification, pathogenesis, pathology, clinical features, diagnostic approach, and diagnostic possibilities. 20 figures. 5 tables. 92 references. x

Bile Secretion and Cholestasis Source: in Textbook of Gastroenterology. 4th ed. [2-volume set]. Hagerstown, MD: Lippincott Williams and Wilkins. 2003. p. 366-388. 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: The formation and secretion of bile are among the most central and earliest recognized functions of the liver. In addition to its digestive function as the source of intraintestinal bile acids, bile formation is necessary for numerous other functions of the liver. These include the obvious functions, such as elimination of toxins, heavy metals, and xenobiotics, and the less obvious, such as regulation of whole-body lipid homeostasis. Cholestasis is an abnormality of the composition and rate of bile formation. This chapter describes the cellular and molecular processes responsible for bile formation and the mechanisms that result in cholestasis. 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 include general aspects of bile formation, hepatic transport mechanisms, mechanisms of regulation of bile formation, and mechanisms of cholestasis. Specific cholestatic states are discussed as examples of the mechanisms involved, but the focus of this chapter is on cellular processes, and the reader is referred to other chapters for specific discussions of diagnosis and management of cholestatic liver diseases. 5 figures. 3 tables. 360 references.

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Disorders of Cholestasis, Bilirubin Metabolism, and Jaundice Source: in Rose, S. Gastrointestinal and Hepatobiliary Pathophysiology. Malden, MA: Blackwell Science, Inc. 1998. p. 327-334. 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. PRICE: $26.00 plus shipping and handling. Summary: This chapter on disorders of cholestasis, bilirubin metabolism, and jaundice is from a textbook that focuses on the pathophysiologic basis of gastrointestinal and hepatobiliary (liver and biliary tract) diseases while encouraging an integrative, problem-solving approach. The chapter begins with a list of learning objectives and an illustrative case study, then covers definitions of each of the three disorders; bile synthesis and secretion; the consequences of alterations in bile secretion; extrahepatic (outside the liver) and intrahepatic (inside the liver) cholestasis and their causes; and disorders of bilirubin metabolism and excretion. The chapter concludes with a follow up to the case study, a list of review questions, and the answers to the review questions, with brief explanations. 3 tables. 2 references.

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CHAPTER 6. MULTIMEDIA ON CHOLESTASIS Overview In this chapter, we show you how to keep current on multimedia sources of information on cholestasis. 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 cholestasis is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “cholestasis” 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 “cholestasis” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on cholestasis: x

Diagnosing Alpha 1 Antitrypsin Deficiency Source: Minneapolis, MN: Alpha 1 Association. 199x. (videocassette). Contact: Available from Alpha 1 Association. 8120 Penn Avenue, South, Suite 549, Minneapolis, MN 55431-1326. (800) 521-3025 or (612) 703-9979. Fax (612) 703-9977. Email: [email protected]. Website: www.alpha1.org. PRICE: $3.00 plus shipping and handling. Summary: This videotape program, narrated by Sandra Brandley, the Executive Director of the Alpha 1 National Association, reminds physicians of the symptoms and differential diagnosis of alpha 1 antitrypsin deficiency (A1AD or Alpha 1). The program features Dr. James Stoller, who describes the typical underdiagnosis of A1AD which is typical: the mean time until diagnosis is 7 years (from onset of symptoms) and the mean number of doctors consulted before diagnosis is 3.5. Alpha 1 is a relatively common genetic disorder that affects infants, children, and adults. It is the most common metabolic disorder that causes liver disease in infants and children; the disorder also

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causes cirrhosis and cancer of the liver in adults. Symptoms of A1AD deficiency in children include prolonged obstructive jaundice, low birth weight, mildly elevated liver enzymes, cholestasis, enlarged liver, abnormal bleeding, feeding difficulties, poor growth (or failure to thrive), and ascites (abnormal accumulation of fluids). In adults, the spectrum of liver disease associated with A1AD deficiency varies from mild to severe. Symptoms include chronic active hepatitis, cryptogenic cirrhosis (liver scarring of unknown cause), portal hypertension (high blood pressure in the portal vein of the liver), and hepatocellular carcinoma (liver cancer). A rare but telling symptom is panniculitis, a chronic inflammation of subcutaneous fat featuring ulcerated skin lesions on the torso. Dr. Stoller reminds viewers of the indications for A1AD screening: premature onset of moderate to severe chronic obstructive pulmonary disease (COPD) before age 50; predominant basilar emphysema; chronic bronchitis with airflow obstruction in a nonsmoker; bronchiectasis (irreversible dilation and destruction of the bronchial walls) without clear risk factors; development of unremitting asthma; family history of A1AD; cirrhosis without apparent risk factors; and family history of panniculitis. The program includes a chart of laboratory values and the risk of development of A1AD, and a series of interviews with patients about the interplay of early diagnosis and good quality of life. The program concludes with the contact information for the Alpha 1 National Association (800-521-3025).

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CHAPTER 7. PERIODICALS AND NEWS ON CHOLESTASIS Overview In this chapter, we suggest a number of news sources and present various periodicals that cover cholestasis.

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

Ursodeoxycholic Acid Reverses Cholestasis In Children On Total Parenteral Nutrition Source: Reuters Medical News Date: September 18, 1996

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Excess Zinc Linked To Severe Cholestasis In Six Canadian Children Source: Reuters Medical News Date: April 04, 1996

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 “cholestasis” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests.

Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “cholestasis” (or synonyms). If you know the name of a company that is relevant to cholestasis, 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 “cholestasis” (or synonyms).

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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 “cholestasis” (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 cholestasis: x

Focus On: Renal Disease in Alagille Syndrome Source: LiverLink. 7(4): 1, 3-8. October-December 2000. Contact: Available from Alagille Syndrome Alliance. 10630 S.W. Garden Park Place, Tigard, OR 97223. (503) 639-6217. E-mail: [email protected]. Website: www.alagille.org. Summary: Kidney (renal) disease is now recognized as a common feature of Alagille syndrome (AGS) and may be present in up to 40 percent of AGS patients. A variety of renal abnormalities that have a very wide spectrum of clinical significance (symptoms and complications) and severity have been described in AGS. This newsletter article reviews renal disease associated with AGS. AGS renal disease is a mixture of defects in the formation of the kidney, problems from lipid (fat) deposition in the kidney secondary to cholestasis (retention of bile contents in the blood stream), and vascular abnormalities. Each of these problems can lead to alteration in the normal filtration of the kidney. The article reviews the normal function of the kidney, which is to produce urine and keep the body's composition of electrolytes (sodium, potassium, bicarbonate) stable, and to filter proteins and waste products. The author describes defects in the formation of the kidney in AGS, including renal agenesis (absent kidney), duplications of the urinary tract, renal dysplasia (malformation), renal hypoplasia (small kidney with decreased ability to filter), and medullary cystic disease. Renal artery stenosis is a narrowing of the artery supplying the kidney that compromises the blood flow to the kidney. As a result of this stenosis, the kidney eventually shrinks and may lose some function. Many of these conditions lead to a functional renal condition called renal tubular acidosis (RTA); the author reviews this problem and stresses the importance of regular screening for and diagnosis of kidney problems in patients with AGS. 1 table.

Academic Periodicals covering Cholestasis Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to cholestasis. In addition to these sources, you can search for articles covering cholestasis 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.

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At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

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CHAPTER 8. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for cholestasis. 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 cholestasis. 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 cholestasis: Cholestyramine x

Oral - U.S. Brands: Questran; Questran Light http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202137.html

Colestipol x

Oral - U.S. Brands: Colestid http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202161.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.

Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to cholestasis by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/. Scroll down the page, and on the left toolbar, click on “Orphan Drug Designation Database.”

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On this page (http://www.rarediseases.org/search/noddsearch.html), type “cholestasis” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for cholestasis: x

Choline chloride (trade name: Intrachol) http://www.rarediseases.org/nord/search/nodd_full?code=636

If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

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APPENDICES

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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute10: x

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

x

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

x

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

x

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

x

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

x

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

x

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

x

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

10

These publications are typically written by one or more of the various NIH Institutes.

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x

National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm

x

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

x

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

x

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

x

National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

x

National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/

x

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

x

National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

x

National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

x

National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm

x

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

x

National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

x

National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

x

Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

x

National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

x

National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

x

Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

x

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.11 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:12 x

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

x

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

x

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

x

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/

x

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

x

Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

x

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/

x

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

x

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

x

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

x

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

11

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). 12 See http://www.nlm.nih.gov/databases/databases.html.

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x

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

x

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html

The NLM Gateway13 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.14 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “cholestasis” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 25244 149 25 26 178 25622

HSTAT15 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.16 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.17 Simply search by “cholestasis” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

13

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

14

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). 15 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 16 17

The HSTAT URL is http://hstat.nlm.nih.gov/.

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.

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Coffee Break: Tutorials for Biologists18 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.19 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.20 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: x

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

x

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

18 Adapted 19

from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 20 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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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 cholestasis 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 cholestasis. 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 cholestasis. 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 “cholestasis”:

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Digestive Diseases http://www.nlm.nih.gov/medlineplus/digestivediseases.html Liver Diseases http://www.nlm.nih.gov/medlineplus/liverdiseases.html Liver Transplantation http://www.nlm.nih.gov/medlineplus/livertransplantation.html Nutritional Support http://www.nlm.nih.gov/medlineplus/nutritionalsupport.html Porphyria http://www.nlm.nih.gov/medlineplus/porphyria.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search.

The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on cholestasis. 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: x

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 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

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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. x

Diet and Your Liver Source: Cedar Grove, NJ: American Liver Foundation. 1997. 5 p. Contact: Available from American Liver Foundation. 75 Maiden Lane, Suite 603, New York, NY 10038-4810. (800) 465-4837. Fax (212) 483-8179. E-mail: [email protected]. Website: www.liverfoundation.org. PRICE: Full-text available online at no charge; $.75 for single copy; discounts available for bulk orders. Summary: This brochure discusses the role of the liver in processing nutrients and other foreign substances and the importance of good nutrition in patients recovering from liver disease. Nutritional changes required by cirrhosis, cholestasis, Wilson's disease, hemochromatosis and other liver disorders are addressed separately. Background information on the four primary functions of the liver and role of the liver in processing carbohydrate, fat and protein is presented. Patients are strongly advised not to use vitamin therapy or nutritional products sold in special stores or catalogs without consulting a doctor.

x

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.

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 cholestasis. 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

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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.

NORD (The National Organization of Rare Disorders, Inc.) NORD provides an invaluable service to the public by publishing short yet comprehensive guidelines on over 1,000 diseases. NORD primarily focuses on rare diseases that might not be covered by the previously listed sources. NORD’s Web address is http://www.rarediseases.org/. A complete guide on cholestasis can be purchased from NORD for a nominal fee.

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: x

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

x

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

x

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

x

Med Help International: http://www.medhelp.org/HealthTopics/A.html

x

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

x

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

x

WebMDHealth: http://my.webmd.com/health_topics

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to cholestasis. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with cholestasis.

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 cholestasis. 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.

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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 “cholestasis” (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 “cholestasis”. 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 “cholestasis” (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 “cholestasis” (or a synonym) into the search box, and click “Submit Query.”

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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.21

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

21

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)22: x

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

x

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

x

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

x

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

x

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

x

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

x

California: Gateway Health Library (Sutter Gould Medical Foundation)

x

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

x

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

x

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

x

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

x

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

x

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

x

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

x

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

x

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

x

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

x

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

22

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

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x

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

x

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

x

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

x

Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

x

Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

x

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

x

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

x

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

x

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

x

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

x

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

x

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

x

Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

x

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

x

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

x

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

x

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

x

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

x

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

x

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

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x

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

x

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

x

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

x

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

x

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

x

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

x

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

x

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

x

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

x

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

x

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

x

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

x

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

x

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

x

Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

x

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

x

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

x

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/

x

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

Finding Medical Libraries

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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

x

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

x

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

x

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

x

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

x

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

x

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

x

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

x

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

x

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

x

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

x

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

x

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

x

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

x

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

x

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

x

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

x

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

x

Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

x

Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

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x

South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

x

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

x

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

x

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: x

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

x

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

x

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

x

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

x

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

x

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

x

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 cholestasis: x

Basic Guidelines for Cholestasis Cholestasis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000215.htm

x

Signs & Symptoms for Cholestasis Itching Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003217.htm

x

Diagnostics and Tests for Cholestasis Alkaline phosphatase Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003470.htm Bilirubin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003479.htm

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Background Topics for Cholestasis Bile Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002237.htm

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: x

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

x

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

x

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

x

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

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CHOLESTASIS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Ablation: The removal of an organ by surgery. [NIH] 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] 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] 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] Action Potentials: The electric response of a nerve or muscle to its stimulation. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] 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]

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Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] 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] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Agenesis: Lack of complete or normal development; congenital absence of an organ or part. [NIH]

Agonists: Drugs that trigger an action from a cell or another drug. [NIH] Ajmaline: An alkaloid found in the root of Rauwolfia serpentina, among other plant sources. It is a class Ia antiarrhythmic agent that apparently acts by changing the shape and threshold of cardiac action potentials. [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] 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]

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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] 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] 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] Aluminum: A metallic element that has the atomic number 13, atomic symbol Al, and atomic weight 26.98. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amino Acid Motifs: Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a conserved sequence which can be represented by a consensus sequence. [NIH]

Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amiodarone: An antianginal and antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting Na,K-activated myocardial adenosine triphosphatase. There is a resulting decrease in heart rate and in vascular resistance. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Ampicillin: Semi-synthetic derivative of penicillin that functions as an orally active broadspectrum antibiotic. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [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]

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Anabolic: Relating to, characterized by, or promoting anabolism. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] 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] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgenic: Producing masculine characteristics. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [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] Anode: Electrode held at a positive potential with respect to a cathode. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antianginal: Counteracting angina or anginal conditions. [EU] Antiarrhythmic: An agent that prevents or alleviates cardiac arrhythmia. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this

Dictionary 149

binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antidepressant: A drug used to treat depression. [NIH] 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] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Anti-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] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Anus: The opening of the rectum to the outside of the body. [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] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Aqueous: Having to do with water. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU]

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Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Articular: Of or pertaining to a joint. [EU] Ascites: Accumulation or retention of free fluid within the peritoneal cavity. [NIH] Asphyxia: A pathological condition caused by lack of oxygen, manifested in impending or actual cessation of life. [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] Atresia: Lack of a normal opening from the esophagus, intestines, or anus. [NIH] Atrial: Pertaining to an atrium. [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] 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] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autopsy: Postmortem examination of the body. [NIH] Autosuggestion: Suggestion coming from the subject himself. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bacterial toxin: A toxic substance, made by bacteria, that can be modified to kill specific tumor cells without harming normal cells. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH]

Dictionary 151

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] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Beta-Galactosidase: A group of enzymes that catalyzes the hydrolysis of terminal, nonreducing beta-D-galactose residues in beta-galactosides. Deficiency of beta-Galactosidase A1 may cause gangliodisosis GM1. EC 3.2.1.23. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile Canaliculi: Minute intercellular channels that occur between liver cells and carry bile towards interlobar bile ducts. Also called bile capillaries. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [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] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some

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cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotinylation: Incorporation of biotinyl groups into molecules. [NIH] Biphasic: Having two phases; having both a sporophytic and a gametophytic phase in the life cycle. [EU] 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] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Body Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [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 Resorption: Bone loss due to osteoclastic activity. [NIH] Boron: A trace element with the atomic symbol B, atomic number 5, and atomic weight 10.81. Boron-10, an isotope of boron, is used as a neutron absorber in boron neutron capture therapy. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH]

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Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Bradycardia: Excessive slowness in the action of the heart, usually with a heart rate below 60 beats per minute. [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] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchiectasis: Persistent abnormal dilatation of the bronchi. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [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 Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cell membranes or on the release and binding of calcium in intracellular pools. Since they are inducers of vascular and other smooth muscle relaxation, they are used in the drug therapy of hypertension and cerebrovascular spasms, as myocardial protective agents, and in the relaxation of uterine spasms. [NIH] Calcium Signaling: Signal transduction mechanisms whereby calcium mobilization (from outside the cell or from intracellular storage pools) to the cytoplasm is triggered by external stimuli. Calcium signals are often seen to propagate as waves, oscillations, spikes or puffs. The calcium acts as an intracellular messenger by activating calcium-responsive proteins. [NIH]

Canaliculus: A membranous duct for tear drainage, leading from a lacrimal punctum at the eyelid margin and ending at the sinus of Maier. [NIH] Carbimazole: An imidazole antithyroid agent. Carbimazole is metabolized to methimazole, which is responsible for the antithyroid activity. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogen: Any substance that causes cancer. [NIH]

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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] 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] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] 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] Catalogs: Ordered compilations of item descriptions and sufficient information to afford access to them. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [NIH] Cathode: An electrode, usually an incandescent filament of tungsten, which emits electrons in an X-ray tube. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Caveolae: Endocytic/exocytic cell membrane structures rich in glycosphingolipids, cholesterol, and lipid-anchored membrane proteins that function in endocytosis (potocytosis), transcytosis, and signal transduction. Caveolae assume various shapes from open pits to closed vesicles. Caveolar coats are composed of caveolins. [NIH] Caveolins: The main structural proteins of caveolae. Several distinct genes for caveolins have been identified. [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] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Membrane Structures: Structures which are part of the cell membrane or have cell membrane as a major part of their structure. [NIH] 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

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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] 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] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] 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] Chelation: Combination with a metal in complexes in which the metal is part of a ring. [EU] Chemoembolization: A procedure in which the blood supply to the tumor is blocked surgically or mechanically, and anticancer drugs are administered directly into the tumor. This permits a higher concentration of drug to be in contact with the tumor for a longer period of time. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] 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] Cholangiography: Radiographic examination of the bile ducts. [NIH] Cholangitis: Inflammation of a bile duct. [NIH] Cholecystectomy: Surgical removal of the gallbladder. [NIH] Cholelithiasis: Presence or formation of gallstones. [NIH] Choleretic: A choleretic agent. [EU]

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Cholestanol: A cholesterol derivative found in human feces, gallstones, eggs, and other biological matter. [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] 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, and in lipid metabolism. [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] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clavulanic Acid: Clavulanic acid (C8H9O5N) and its salts and esters. The acid is a suicide inhibitor of bacterial beta-lactamase enzymes from Streptomyces clavuligerus. Administered alone, it has only weak antibacterial activity against most organisms, but given in combination with beta-lactam antibiotics prevents antibiotic inactivation by microbial lactamase. [NIH] Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in

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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] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] 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] 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] Computational Biology: A field of biology concerned with the development of techniques

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for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Congenita: Displacement, subluxation, or malposition of the crystalline lens. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Conjugated: Acting or operating as if joined; simultaneous. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a consensus sequence. Amino acid motifs are often composed of conserved sequences. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [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]

Contraceptive: An agent that diminishes the likelihood of or prevents conception. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral

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discharge (e.g., in response to hypotension). [NIH] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [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] Cryoelectron Microscopy: Electron microscopy involving rapid freezing of the samples. The imaging of frozen-hydrated molecules and organelles permits the best possible resolution closest to the living state, free of chemical fixatives or stains. [NIH] Curative: Tending to overcome disease and promote recovery. [EU]

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Curcumin: A dye obtained from tumeric, the powdered root of Curcuma longa Linn. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes. [NIH] 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] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cystic Duct: The tube that carries bile from the gallbladder into the common bile duct and the small intestine. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Cytomegalovirus Infections: Infection with Cytomegalovirus, characterized by enlarged cells bearing intranuclear inclusions. Infection may be in almost any organ, but the salivary glands are the most common site in children, as are the lungs in adults. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytostatic: An agent that suppresses cell growth and multiplication. [EU] Cytotoxic: Cell-killing. [NIH] Danazol: A synthetic steroid with antigonadotropic and anti-estrogenic activities that acts as an anterior pituitary suppressant by inhibiting the pituitary output of gonadotropins. It possesses some androgenic properties. Danazol has been used in the treatment of endometriosis and some benign breast disorders. [NIH] 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] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized,

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the decidua is shed during menstruation. [NIH] Decompression: Decompression external to the body, most often the slow lessening of external pressure on the whole body (especially in caisson workers, deep sea divers, and persons who ascend to great heights) to prevent decompression sickness. It includes also sudden accidental decompression, but not surgical (local) decompression or decompression applied through body openings. [NIH] Decompression Sickness: A condition occurring as a result of exposure to a rapid fall in ambient pressure. Gases, nitrogen in particular, come out of solution and form bubbles in body fluid and blood. These gas bubbles accumulate in joint spaces and the peripheral circulation impairing tissue oxygenation causing disorientation, severe pain, and potentially death. [NIH] 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] Delivery of Health Care: The concept concerned with all aspects of providing and distributing health services to a patient population. [NIH] Demography: Statistical interpretation and description of a population with reference to distribution, composition, or structure. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]

Detergents: Purifying or cleansing agents, usually salts of long-chain aliphatic bases or acids, that exert cleansing (oil-dissolving) and antimicrobial effects through a surface action that depends on possessing both hydrophilic and hydrophobic properties. [NIH] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diathesis: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the person more than usually susceptible to certain diseases. [EU] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH]

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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] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [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] 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] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Design: The molecular designing of drugs for specific purposes (such as DNAbinding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenal Ulcer: An ulcer in the lining of the first part of the small intestine (duodenum). [NIH]

Duodenum: The first part of the small intestine. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Eclampsia: Onset of convulsions or coma in a previously diagnosed pre-eclamptic patient. [NIH]

Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH]

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Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] 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] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryology: The study of the development of an organism during the embryonic and fetal stages of life. [NIH] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] 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] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endometriosis: A condition in which tissue more or less perfectly resembling the uterine mucous membrane (the endometrium) and containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity. [NIH] Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endoscopic retrograde cholangiopancreatography: ERCP. A procedure to x-ray the pancreatic duct, hepatic duct, common bile duct, duodenal papilla, and gallbladder. In this procedure, a thin, lighted tube (endoscope) is passed through the mouth and down into the

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first part of the small intestine (duodenum). A smaller tube (catheter) is then inserted through the endoscope into the bile and pancreatic ducts. A dye is injected through the catheter into the ducts, and an x-ray is taken. [NIH] Endoscopy: Endoscopic examination, therapy or surgery performed on interior parts of the body. [NIH] 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] 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] Enhancer: Transcriptional element in the virus genome. [NIH] Enterocolitis: Inflammation of the intestinal mucosa of the small and large bowel. [NIH] Enterocytes: Terminally differentiated cells comprising the majority of the external surface of the intestinal epithelium (see intestinal mucosa). Unlike goblet cells, they do not produce or secrete mucins, nor do they secrete cryptdins as do the paneth cells. [NIH] Enterohepatic: Of or involving the intestine and liver. [EU] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [NIH]

Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] 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] Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythema Nodosum: An erythematous eruption commonly associated with drug reactions

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or infection and characterized by inflammatory nodules that are usually tender, multiple, and bilateral. These nodules are located predominantly on the shins with less common occurrence on the thighs and forearms. They undergo characteristic color changes ending in temporary bruise-like areas. This condition usually subsides in 3-6 weeks without scarring or atrophy. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] 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]

Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [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] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [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] Excrete: To get rid of waste from the body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] 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] Extracorporeal: Situated or occurring outside the body. [EU] Extraction: The process or act of pulling or drawing out. [EU]

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Extravasation: A discharge or escape, as of blood, from a vessel into the tissues. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Failure to Thrive: A condition in which an infant or child's weight gain and growth are far below usual levels for age. [NIH] 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] 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] Fetal Distress: Adverse or threatening condition of the fetus identified by fetal bradycardia or tachycardia and passage of meconium in vertex presentation. [NIH] Fetal Growth Retardation: The failure of a fetus to attain its expected growth potential at any gestational stage. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [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] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibronectin: An adhesive glycoprotein. One form circulates in plasma, acting as an opsonin; another is a cell-surface protein which mediates cellular adhesive interactions. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Fine-needle aspiration: The removal of tissue or fluid with a needle for examination under a microscope. Also called needle biopsy. [NIH] Fixatives: Agents employed in the preparation of histologic or pathologic specimens for the purpose of maintaining the existing form and structure of all of the constituent elements. Great numbers of different agents are used; some are also decalcifying and hardening agents. They must quickly kill and coagulate living tissue. [NIH] Flatus: Gas passed through the rectum. [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.

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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, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fluid Therapy: Therapy whose basic objective is to restore the volume and composition of the body fluids to normal with respect to water-electrolyte balance. Fluids may be administered intravenously, orally, by intermittent gavage, or by hypodermoclysis. [NIH] 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] Fluoxetine: The first highly specific serotonin uptake inhibitor. It is used as an antidepressant and often has a more acceptable side-effects profile than traditional antidepressants. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Fulminant Hepatic Failure: Liver failure that occurs suddenly in a previously healthy person. The most common causes of FHF are acute hepatitis, acetaminophen overdose, and liver damage from prescription drugs. [NIH] Galactosides: Glycosides formed by the reaction of the hydroxyl group on the anomeric carbon atom of galactose with an alcohol to form an acetal. They include both alpha- and beta-galactosides. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gamma-interferon: Interferon produced by T-lymphocytes in response to various mitogens and antigens. Gamma interferon appears to have potent antineoplastic, immunoregulatory and antiviral activity. [NIH] Ganciclovir: Acyclovir analog that is a potent inhibitor of the Herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from AIDS-associated cytomegalovirus infections. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Acid: Hydrochloric acid present in gastric juice. [NIH]

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Gastric Juices: Liquids produced in the stomach to help break down food and kill bacteria. [NIH]

Gastric Outlet Obstruction: The hindering of output from the stomach to the small intestine. The source varies: peptic ulcer, foreign bodies, aging, neoplasms, etc. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastroesophageal Reflux: Reflux of gastric juice and/or duodenal contents (bile acids, pancreatic juice) into the distal esophagus, commonly due to incompetence of the lower esophageal sphincter. Gastric regurgitation is an extension of this process with entry of fluid into the pharynx or mouth. [NIH] 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] 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] Gene Targeting: The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] 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] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU]

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Gestational: Psychosis attributable to or occurring during pregnancy. [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]

Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

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] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Goblet Cells: Cells of the epithelial lining that produce and secrete mucins. [NIH] Gonadal: Pertaining to a gonad. [EU]

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Gout: Hereditary metabolic disorder characterized by recurrent acute arthritis, hyperuricemia and deposition of sodium urate in and around the joints, sometimes with formation of uric acid calculi. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] 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-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [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] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Health Care Costs: The actual costs of providing services related to the delivery of health care, including the costs of procedures, therapies, and medications. It is differentiated from health expenditures, which refers to the amount of money paid for the services, and from fees, which refers to the amount charged, regardless of cost. [NIH] Health Expenditures: The amounts spent by individuals, groups, nations, or private or public organizations for total health care and/or its various components. These amounts may or may not be equivalent to the actual costs (health care costs) and may or may not be shared among the patient, insurers, and/or employers. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hematoma: An extravasation of blood localized in an organ, space, or tissue. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH]

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Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [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 Duct, Common: Predominantly extrahepatic bile duct which is formed by the junction of the right and left hepatic ducts, which are predominantly intrahepatic, and, in turn, joins the cystic duct to form the common bile duct. [NIH] Hepatic Encephalopathy: A condition that may cause loss of consciousness and coma. It is usually the result of advanced liver disease. Also called hepatic coma. [NIH] 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 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] Hepatobiliary: Pertaining to the liver and the bile or the biliary ducts. [EU] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] Hepatocyte: A liver cell. [NIH] Hepatocyte Growth Factor: Multifunctional growth factor which regulates both cell growth and cell motility. It exerts a strong mitogenic effect on hepatocytes and primary epithelial cells. Its receptor is proto-oncogene protein C-met. [NIH] Hepatoma: A liver tumor. [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]

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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]

Histology: The study of tissues and cells under a microscope. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] 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] Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [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] 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 collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor

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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] 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] Hypoglycemia: Abnormally low blood sugar [NIH] Hypopituitarism: Diminution or cessation of secretion of one or more hormones from the anterior pituitary gland (including LH; FSH; somatotropin; and corticotropin). This may result from surgical or radiation ablation, non-secretory pituitary neoplasms, metastatic tumors, infarction, pituitary apoplexy, infiltrative or granulomatous processes, and other conditions. [NIH] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Iatrogenic: Resulting from the activity of physicians. Originally applied to disorders induced in the patient by autosuggestion based on the physician's examination, manner, or discussion, the term is now applied to any adverse condition in a patient occurring as the result of treatment by a physician or surgeon, especially to infections acquired by the patient during the course of treatment. [EU] Ichthyosis: Any of several generalized skin disorders characterized by dryness, roughness, and scaliness, due to hypertrophy of the stratum corneum epidermis. Most are genetic, but some are acquired, developing in association with other systemic disease or genetic syndrome. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Ileal: Related to the ileum, the lowest end of the small intestine. [NIH] Ileitis: Inflammation of the ileum. [EU] Ileostomy: Surgical creation of an external opening into the ileum for fecal diversion or drainage. Loop or tube procedures are most often employed. [NIH] Ileum: The lower end of the small intestine. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] 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] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulins: Glycoproteins present in the blood (antibodies) and in other tissue. They are classified by structure and activity into five classes (IgA, IgD, IgE, IgG, IgM). [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH]

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Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incompetence: Physical or mental inadequacy or insufficiency. [EU] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infantile: Pertaining to an infant or to infancy. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

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]

Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH]

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Ingestion: Taking into the body by mouth [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insomnia: Difficulty in going to sleep or getting enough sleep. [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 monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]

Intercellular Adhesion Molecule-1: A cell-surface ligand with a role in leukocyte adhesion and inflammation. Its production is induced by gamma-interferon and it is required for neutrophil migration into inflamed tissue. [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] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestinal Mucosa: The surface lining of the intestines where the cells absorb nutrients. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intrahepatic: Within the liver. [NIH] Intrahepatic bile ducts: The bile ducts that pass through and drain bile from the liver. [NIH] Intramuscular: IM. Within or into muscle. [NIH]

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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]

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] 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] 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]

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] Kinetics: The study of rate dynamics in chemical or physical systems. [NIH] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lacrimal: Pertaining to the tears. [EU] Lactation: The period of the secretion of milk. [EU] Laparoscopy: Examination, therapy or surgery of the abdomen's interior by means of a laparoscope. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]

Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] 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] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes.

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[NIH]

Leukemia: Cancer of blood-forming tissue. [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] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligase: An enzyme that repairs single stranded discontinuities in double-stranded DNA molecules in the cell. Purified DNA ligase is used in gene cloning to join DNA molecules together. [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] Lipopolysaccharides: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Lithotripsy: The destruction of a calculus of the kidney, ureter, bladder, or gallbladder by physical forces, including crushing with a lithotriptor through a catheter. Focused percutaneous ultrasound and focused hydraulic shock waves may be used without surgery. Lithotripsy does not include the dissolving of stones by acids or litholysis. Lithotripsy by laser is laser lithotripsy. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver cancer: A disease in which malignant (cancer) cells are found in the tissues of the liver. [NIH]

Liver Regeneration: Repair or renewal of hepatic tissue. [NIH] Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [NIH] 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] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lower Esophageal Sphincter: The muscle between the esophagus and stomach. When a person swallows, this muscle relaxes to let food pass from the esophagus to the stomach. It stays closed at other times to keep stomach contents from flowing back into the esophagus.

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[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] 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]

Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malformation: A morphologic developmental process. [EU]

defect

resulting

from

an

intrinsically

abnormal

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

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spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Manometry: Tests that measure muscle pressure and movements in the GI tract. [NIH] Meconium: The thick green-to-black mucilaginous material found in the intestines of a fullterm fetus. It consists of secretions of the intestinal glands, bile pigments, fatty acids, amniotic fluid, and intrauterine debris. It constitutes the first stools passed by a newborn. [NIH]

Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Megestrol: 17-Hydroxy-6-methylpregna-3,6-diene-3,20-dione. A progestational hormone used most commonly as the acetate ester. As the acetate, it is more potent than progesterone both as a progestagen and as an ovulation inhibitor. It has also been used in the palliative treatment of breast cancer. [NIH] Megestrol Acetate: A drug that belongs to the group of hormones called progestins, used as hormone therapy to block estrogen and to suppress the effects of estrogen and androgens. [NIH]

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] Membrane Lipids: Lipids, predominantly phospholipids, cholesterol and small amounts of glycolipids found in membranes including cellular and intracellular membranes. These lipids may be arranged in bilayers in the membranes with integral proteins between the layers and peripheral proteins attached to the outside. Membrane lipids are required for active transport, several enzymatic activities and membrane formation. [NIH] Membrane Microdomains: Detergent-insoluble cell membrane components. They are enriched in sphingolipids and cholesterol and clustered with glycosyl-phosphatidylinositol (GPI)-anchored proteins. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and

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drug, hormone, and lectin receptors. [NIH] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mercaptopurine: An anticancer drug that belongs to the family of drugs called antimetabolites. [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] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in 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 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] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] Methyltestosterone: A synthetic hormone used for androgen replacement therapy and as an hormonal antineoplastic agent. [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] 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]

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Microspheres: Small uniformly-sized spherical particles frequently radioisotopes or various reagents acting as tags or markers. [NIH]

labeled

with

Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [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] Miscible: Susceptible of being mixed. [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] Mitotic: Cell resulting from mitosis. [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] Mode of Transmission: Hepatitis A [NIH] 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] 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] 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] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the

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drugs less effective. [NIH] Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [NIH] Multivariate Analysis: A set of techniques used when variation in several variables has to be studied simultaneously. In statistics, multivariate analysis is interpreted as any analytic method that allows simultaneous study of two or more dependent variables. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] 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] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Naloxone: A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors. [NIH] Naltrexone: Derivative of noroxymorphone that is the N-cyclopropylmethyl congener of naloxone. It is a narcotic antagonist that is effective orally, longer lasting and more potent than naloxone, and has been proposed for the treatment of heroin addiction. The FDA has approved naltrexone for the treatment of alcohol dependence. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] 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] Necrotizing Enterocolitis: A condition in which part of the tissue in the intestines is destroyed. Occurs mainly in under-weight newborn babies. A temporary ileostomy may be necessary. [NIH] Needle biopsy: The removal of tissue or fluid with a needle for examination under a microscope. Also called fine-needle aspiration. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neonatal Hepatitis: Irritation of the liver with no known cause. Occurs in newborn babies. Symptoms include jaundice and liver cell changes. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH]

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Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] 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] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [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] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] 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] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with nucleoproteins which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleoproteins: Proteins conjugated with nucleic acids. [NIH]

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Nucleotidases: A class of enzymes that catalyze the conversion of a nucleotide and water to a nucleoside and orthophosphate. EC 3.1.3.-. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nutritional Support: The administration of nutrients for assimilation and utilization by a patient by means other than normal eating. It does not include fluid therapy which normalizes body fluids to restore water-electrolyte balance. [NIH] Omentum: A fold of the peritoneum (the thin tissue that lines the abdomen) that surrounds the stomach and other organs in the abdomen. [NIH] Omeprazole: A highly effective inhibitor of gastric acid secretion used in the therapy of gastric ulcers and Zollinger-Ellison syndrome. The drug inhibits the H(+)-K(+)-ATPase (H(+)-K(+)-exchanging ATPase) in a pH-dependent manner. This ATPase is considered the proton pump in the secretory membrane of the parietal cell. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oogenesis: The formation, development, and maturation of the female germ cell. [NIH] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] 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] 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] Osmolarity: The concentration of osmotically active particles expressed in terms of osmoles of solute per litre of solution. [EU] Osmoles: The standard unit of osmotic pressure. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Osteodystrophy: Defective bone formation. [EU] 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] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH]

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Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidative 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] 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 Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease; less commonly it may be associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] Paneth Cells: Epithelial cells found in the basal part of the intestinal glands (crypts of Lieberkuhn). Paneth cells synthesize and secrete lysozyme and cryptdins. [NIH] Panniculitis: General term for inflammation of adipose tissue, usually of the skin, characterized by reddened subcutaneous nodules. [NIH] Papilla: A small nipple-shaped elevation. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parenteral Nutrition: The administering of nutrients for assimilation and utilization by a patient who cannot maintain adequate nutrition by enteral feeding alone. Nutrients are administered by a route other than the alimentary canal (e.g., intravenously, subcutaneously). [NIH] Parotid: The space that contains the parotid gland, the facial nerve, the external carotid artery, and the retromandibular vein. [NIH] Particle: A tiny mass of material. [EU] Parturition: The act or process of given birth to a child. [EU] Pathogen: Any disease-producing microorganism. [EU] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU]

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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]

Penicillin: An antibiotic drug used to treat infection. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU] Peptic Ulcer: An ulceration of the mucous membrane of the esophagus, stomach or duodenum, caused by the action of the acid gastric juice. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [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] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perforation: 1. The act of boring or piercing through a part. 2. A hole made through a part or substance. [EU] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] 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] 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] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Petrolatum: A colloidal system of semisolid hydrocarbons obtained from petroleum. It is used as an ointment base, topical protectant, and lubricant. [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] Pharmacokinetics: Dynamic and kinetic mechanisms of exogenous chemical and drug absorption, biotransformation, distribution, release, transport, uptake, and elimination as a function of dosage, and extent and rate of metabolic processes. It includes toxicokinetics, the pharmacokinetic mechanism of the toxic effects of a substance. [NIH]

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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] Phenobarbital: A barbituric acid derivative that acts as a nonselective central nervous system depressant. It promotes binding to inhibitory GABA subtype receptors, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations. [NIH] Phenolphthalein: An acid-base indicator which is colorless in acid solution, but turns pink to red as the solution becomes alkaline. It is used medicinally as a cathartic. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phorbol Esters: Tumor-promoting compounds obtained from croton oil (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C. [NIH] Phosphatidic Acids: Fatty acid derivatives of glycerophosphates. They are composed of glycerol bound in ester linkage with 1 mole of phosphoric acid at the terminal 3-hydroxyl group and with 2 moles of fatty acids at the other two hydroxyl groups. [NIH] Phosphatidylcholines: Derivatives of phosphatidic acids in which the phosphoric acid is bound in ester linkage to a choline moiety. Complete hydrolysis yields 1 mole of glycerol, phosphoric acid and choline and 2 moles of fatty acids. [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] Phosphorylates: 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] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Apoplexy: Sudden hemorrhage or ischemic necrosis involving the pituitary gland which may be associated with acute visual loss, severe headache, meningeal signs, cranial nerve palsies, panhypopituitarism, and rarely coma. The most common cause is hemorrhage (intracranial hemorrhages) related to a pituitary adenoma. Ischemia, meningitis, intracranial hypertension, and other disorders may be associated with this condition. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected

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to the hypothalamus by a short stalk. [NIH] Pituitary Hormones: Hormones secreted by the anterior and posterior lobes of the pituitary gland and the pars intermedia, an ill-defined region between the two. Their secretion is regulated by the hypothalamus. [NIH] Pituitary Neoplasms: Neoplasms which arise from or metastasize to the pituitary gland. The majority of pituitary neoplasms are adenomas, which are divided into non-secreting and secreting forms. Hormone producing forms are further classified by the type of hormone they secrete. Pituitary adenomas may also be characterized by their staining properties (adenoma, basophil; adenoma, acidophil; and adenoma, chromophobe). Pituitary tumors may compress adjacent structures, including the hypothalamus, several cranial nerves, and the optic chiasm. Chiasmal compression may result in bitemporal hemianopsia. [NIH]

Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plant sterols: Plant-based compounds that can compete with dietary cholesterol to be absorbed by the intestines. This results in lower blood cholesterol levels. They may have some effect in cancer prevention. Also known as phytosterols. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma 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] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [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] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU]

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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] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Porphyria: A group of disorders characterized by the excessive production of porphyrins or their precursors that arises from abnormalities in the regulation of the porphyrin-heme pathway. The porphyrias are usually divided into three broad groups, erythropoietic, hepatic, and erythrohepatic, according to the major sites of abnormal porphyrin synthesis. [NIH]

Portal Hypertension: High blood pressure in the portal vein. This vein carries blood into the liver. Portal hypertension is caused by a blood clot. This is a common complication of cirrhosis. [NIH] Portal Vein: A short thick vein formed by union of the superior mesenteric vein and the splenic vein. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [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] 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] Pravastatin: An antilipemic fungal metabolite isolated from cultures of Nocardia autotrophica. It acts as a competitive inhibitor of HMG CoA reductase (hydroxymethylglutaryl CoA reductases). [NIH] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Preeclampsia: A toxaemia of late pregnancy characterized by hypertension, edema, and proteinuria, when convulsions and coma are associated, it is called eclampsia. [EU] Prevalence: The total number of cases of a given disease in a specified population at a

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designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] 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 Sclerosing Cholangitis: Irritation, scarring, and narrowing of the bile ducts inside and outside the liver. Bile builds up in the liver and may damage its cells. Many people with this condition also have ulcerative colitis. [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] Problem Solving: A learning situation involving more than one alternative from which a selection is made in order to attain a specific goal. [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] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Promotor: In an operon, a nucleotide sequence located at the operator end which contains all the signals for the correct initiation of genetic transcription by the RNA polymerase holoenzyme and determines the maximal rate of RNA synthesis. [NIH] 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] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protective Agents: Synthetic or natural substances which are given to prevent a disease or disorder or are used in the process of treating a disease or injury due to a poisonous agent. [NIH]

Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va

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and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Kinase C: An enzyme that phosphorylates proteins on serine or threonine residues in the presence of physiological concentrations of calcium and membrane phospholipids. The additional presence of diacylglycerols markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by phorbol esters and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters. EC 2.7.1.-. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] 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] Proton Pump: Integral membrane proteins that transport protons across a membrane against a concentration gradient. This transport is driven by hydrolysis of ATP by H(+)transporting ATP synthase. [NIH] Proton Pump Inhibitors: Medicines that stop the stomach's acid pump. Examples are omeprazole (oh-MEH-prah-zol) (Prilosec) and lansoprazole (lan-SOH-prah-zol) (Prevacid). [NIH]

Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Pruritus: An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. [NIH] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] 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] Pulse: The rhythmical expansion and contraction of an artery produced by waves of

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pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Pupil: The aperture in the iris through which light passes. [NIH] 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] 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] Radioactive: Giving off radiation. [NIH] Radiofrequency ablation: The use of electrical current to destroy tissue. [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] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral 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] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU]

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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] 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 agenesis: The absence or severe malformation of one or both kidneys. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renal tubular: A defect in the kidneys that hinders their normal excretion of acids. Failure to excrete acids can lead to weak bones, kidney stones, and poor growth in children. [NIH] Renal tubular acidosis: A rare disorder in which structures in the kidney that filter the blood are impaired, producing using that is more acid than normal. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into 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] Response Elements: Nucleotide sequences, usually upstream, which are recognized by specific regulatory transcription factors, thereby causing gene response to various regulatory agents. These elements may be found in both promotor and enhancer regions. [NIH]

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] Retrospective study: A study that looks backward in time, usually using medical records and interviews with patients who already have or had a disease. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] 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] 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

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or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sarcoidosis: An idiopathic systemic inflammatory granulomatous disorder comprised of epithelioid and multinucleated giant cells with little necrosis. It usually invades the lungs with fibrosis and may also involve lymph nodes, skin, liver, spleen, eyes, phalangeal bones, and parotid glands. [NIH] 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] Screening: Checking for disease when there are no symptoms. [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] Secular trends: A relatively long-term trend in a community or country. [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sepsis: The presence of bacteria in the bloodstream. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [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]

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Shunt: A surgically created diversion of fluid (e.g., blood or cerebrospinal fluid) from one area of the body to another area of the body. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] 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] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sludge: A clump of agglutinated red blood cells. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

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] 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

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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] Somatotropin: A small peptide hormone released by the anterior pituitary under hypothalamic control. Somatotropin, or growth hormone, stimulates mitosis, cell growth, and, for some cell types, differentiation in many tissues of the body. It has profound effects on many aspects of gene expression and metabolism. [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] 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] Steatosis: Fatty degeneration. [EU] Stellate: Star shaped. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stenosis: Narrowing or stricture of a duct or canal. [EU] Stent: A device placed in a body structure (such as a blood vessel or the gastrointestinal tract) to provide support and keep the structure open. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] 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

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the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

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] Supplementation: Adding nutrients to the diet. [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] Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [NIH] Sweat Glands: Sweat-producing structures that are embedded in the dermis. Each gland consists of a single tube, a coiled body, and a superficial duct. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU]

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Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [NIH] Technetium: The first artificially produced element and a radioactive fission product of uranium. The stablest isotope has a mass number 99 and is used diagnostically as a radioactive imaging agent. Technetium has the atomic symbol Tc, atomic number 43, and atomic weight 98.91. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [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] Theophylline: Alkaloid obtained from Thea sinensis (tea) and others. It stimulates the heart and central nervous system, dilates bronchi and blood vessels, and causes diuresis. The drug is used mainly in bronchial asthma and for myocardial stimulation. Among its more prominent cellular effects are inhibition of cyclic nucleotide phosphodiesterases and antagonism of adenosine receptors. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [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] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

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]

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Thymoma: A tumor of the thymus, an organ that is part of the lymphatic system and is located in the chest, behind the breastbone. [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] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonicity: The normal state of muscular tension. [NIH] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Toxaemia: 1. The condition resulting from the spread of bacterial products (toxins) by the bloodstream. 2. A condition resulting from metabolic disturbances, e.g. toxaemia of pregnancy. [EU] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The

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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] Translocating: The attachment of a fragment of one chromosome to a non-homologous chromosome. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Triazolam: A short-acting benzodiazepine used in the treatment of insomnia. Some countries temporarily withdrew triazolam from the market because of concerns about adverse reactions, mostly psychological, associated with higher dose ranges. Its use at lower doses with appropriate care and labeling has been reaffirmed by the FDA and most other countries. [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] 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] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [NIH]

Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [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] Untranslated Regions: The parts of the messenger RNA sequence that do not code for

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product, i.e. the 5' untranslated regions and 3' untranslated regions. [NIH] Uraemia: 1. An excess in the blood of urea, creatinine, and other nitrogenous end products of protein and amino acids metabolism; more correctly referred to as azotemia. 2. In current usage the entire constellation of signs and symptoms of chronic renal failure, including nausea, vomiting anorexia, a metallic taste in the mouth, a uraemic odour of the breath, pruritus, uraemic frost on the skin, neuromuscular disorders, pain and twitching in the muscles, hypertension, edema, mental confusion, and acid-base and electrolyte imbalances. [EU]

Uranium: A radioactive element of the actinide series of metals. It has an atomic symbol U, atomic number 92, and atomic weight 238.03. U-235 is used as the fissionable fuel in nuclear weapons and as fuel in nuclear power reactors. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] 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] Ursodeoxycholic Acid: An epimer of chenodeoxycholic acid. It is a mammalian bile acid found first in the bear and is apparently either a precursor or a product of chenodeoxycholate. Its administration changes the composition of bile and may dissolve gallstones. It is used as a cholagogue and choleretic. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccines: Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa, or rickettsiae), antigenic proteins derived from them, or synthetic constructs, administered for the prevention, amelioration, or treatment of infectious and other diseases. [NIH]

Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] Vasodilators: Any nerve or agent which induces dilatation of the blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH]

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Cholestasis

Venous: Of or pertaining to the veins. [EU] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [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] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Hepatitis: Hepatitis caused by a virus. Five different viruses (A, B, C, D, and E) most commonly cause this form of hepatitis. Other rare viruses may also cause hepatitis. [NIH] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] 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] Volvulus: A twisting of the stomach or large intestine. May be caused by the stomach being in the wrong position, a foreign substance, or abnormal joining of one part of the stomach or intestine to another. Volvulus can lead to blockage, perforation, peritonitis, and poor blood flow. [NIH] War: Hostile conflict between organized groups of people. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Xenobiotics: Chemical substances that are foreign to the biological system. They include naturally occurring compounds, drugs, environmental agents, carcinogens, insecticides, etc.

Dictionary 203

[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] Zebrafish: A species of North American fishes of the family Cyprinidae. They are used in embryological studies and to study the effects of certain chemicals on development. [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]

205

INDEX A Abdominal, 13, 17, 79, 108, 145, 154, 185, 186, 200 Abdominal Pain, 108, 145, 186, 200 Ablation, 145, 173 Acatalasia, 145, 154 Acceptor, 145, 177, 185, 199 Acetaminophen, 18, 145, 167 Acetylcholine, 145, 156, 183 Acidosis, 40, 145 Action Potentials, 145, 146 Acute renal, 145, 171 Adaptability, 145, 154, 155 Adaptation, 6, 26, 35, 145, 181 Adenocarcinoma, 75, 145, 171 Adenosine, 145, 147, 187, 198 Adenovirus, 17, 18, 145 Adipose Tissue, 146, 185 Adjustment, 145, 146 Adrenal Cortex, 146, 159, 165, 190 Adrenal Glands, 146, 147 Adrenoleukodystrophy, 24, 146 Adverse Effect, 4, 87, 146, 195 Aerobic, 146, 181 Affinity, 11, 146, 195 Agar, 146, 188 Agenesis, 146 Agonists, 21, 146 Ajmaline, 95, 146 Albumin, 52, 146, 188 Algorithms, 146, 152 Alimentary, 6, 146, 185 Alkaline, 74, 79, 85, 143, 145, 146, 147, 153, 187 Alkaline Phosphatase, 74, 79, 85, 147 Alkaloid, 146, 147, 156, 198 Alpha Particles, 147, 192 Alpha-1, 72, 147 Alternative medicine, 116, 147 Aluminum, 71, 147 Ameliorating, 21, 25, 147 Amino Acid Motifs, 5, 147 Amino Acid Sequence, 147, 148, 165, 168 Amino Acids, 77, 84, 147, 158, 168, 186, 189, 191, 193, 194, 200, 201 Amiodarone, 49, 147 Ammonia, 147, 197, 201 Amniotic Fluid, 147, 179

Ampicillin, 73, 147 Ampulla, 108, 109, 147, 163 Amyloidosis, 45, 58, 59, 75, 147 Anabolic, 11, 148, 161 Anaesthesia, 148, 174 Anal, 148, 182 Analgesic, 145, 148, 184 Analog, 102, 103, 148, 167 Analogous, 33, 148, 162, 199 Anaphylatoxins, 148, 157 Anaplasia, 148 Anatomical, 148, 174 Androgenic, 148, 160 Androgens, 146, 148, 159, 179 Anemia, 76, 148, 182 Animal model, 36, 40, 104, 110, 148 Anions, 27, 29, 31, 146, 148, 176 Anode, 148 Antagonism, 148, 198 Antianginal, 147, 148 Antiarrhythmic, 146, 147, 148 Antibacterial, 148, 156, 196 Antibiotic, 147, 148, 153, 156, 186, 196 Antibodies, 35, 110, 148, 149, 170, 171, 173, 188 Antibody, 36, 61, 146, 148, 149, 157, 170, 172, 173, 174, 179, 196 Anticoagulant, 149, 190, 191 Antidepressant, 40, 41, 149, 167 Antigen, 18, 47, 146, 148, 149, 157, 161, 172, 173, 174, 179 Antigen-Antibody Complex, 149, 157 Antigen-presenting cell, 149, 161 Anti-inflammatory, 145, 149, 159, 169 Antimetabolite, 149, 180 Antimicrobial, 149, 161 Antineoplastic, 149, 159, 167, 180, 202 Antioxidant, 28, 102, 149, 185, 195 Antipyretic, 145, 149 Anus, 148, 149, 150, 153, 157 Apolipoproteins, 149, 177 Apoptosis, 6, 16, 18, 22, 30, 34, 42, 74, 149, 154 Applicability, 16, 149 Aqueous, 149, 151, 160, 163, 172, 176 Arginine, 148, 149, 183, 200 Arterial, 14, 149, 154, 156, 159, 173, 191, 197

206

Cholestasis

Arteries, 104, 149, 150, 152, 154, 159, 177, 182 Arterioles, 150, 152, 201 Artery, 104, 117, 149, 150, 159, 185, 191 Articular, 150, 184 Ascites, 107, 109, 110, 114, 132, 150 Asphyxia, 77, 150 Assay, 25, 28, 35, 49, 150 Asymptomatic, 66, 145, 150, 171, 185 Ataxia, 53, 150, 198 Atresia, 7, 8, 9, 150, 151, 159 Atrial, 147, 150, 159 Atrophy, 150, 165 Attenuated, 10, 150, 201 Attenuation, 10, 150 Atypical, 22, 150 Autodigestion, 150, 185 Autoimmune disease, 100, 101, 110, 150 Autologous, 42, 150 Autopsy, 16, 150 Autosuggestion, 150, 173 B Bacteria, 24, 148, 149, 150, 151, 164, 165, 166, 168, 171, 178, 180, 192, 194, 196, 199, 201 Bacterial Physiology, 145, 150 Bacterial toxin, 22, 150 Bactericidal, 150, 165 Bacterium, 150, 171 Basal Ganglia, 150, 151 Basal Ganglia Diseases, 150, 151 Base, 151, 168, 176, 186, 187, 188, 198, 201 Basement Membrane, 151, 165 Benign, 37, 38, 41, 42, 52, 57, 58, 62, 79, 108, 109, 151, 160, 182 Beta-Galactosidase, 15, 151 Bilateral, 151, 165 Bile Acids and Salts, 151 Bile Canaliculi, 94, 151 Bile Pigments, 151, 176, 179 Biliary, 6, 7, 8, 9, 11, 14, 15, 17, 24, 32, 34, 38, 43, 55, 64, 66, 67, 70, 75, 76, 94, 95, 100, 101, 105, 107, 109, 110, 111, 112, 151, 157, 171, 185 Biliary Atresia, 7, 8, 9, 11, 151 Biliary Tract, 100, 101, 108, 109, 112, 151, 185 Bilirubin, 6, 49, 76, 79, 108, 112, 143, 146, 151, 172 Binding Sites, 15, 151 Biochemical, 4, 22, 23, 24, 31, 32, 61, 66, 94, 133, 149, 151, 167, 169, 176, 184, 194

Biological response modifier, 151, 152, 175 Biological therapy, 151, 170 Biopsy, 16, 43, 65, 107, 152, 186 Biosynthesis, 19, 23, 104, 152, 194 Biotechnology, 37, 38, 116, 127, 152 Biotinylation, 36, 152 Biphasic, 26, 152 Bladder, 91, 152, 177, 201 Blastocyst, 152, 158, 188 Blood Coagulation, 152, 153, 198 Blood pressure, 110, 114, 133, 152, 173, 181, 189, 195 Blood vessel, 104, 152, 155, 159, 164, 171, 178, 195, 196, 197, 198, 201 Body Composition, 44, 152 Body Fluids, 152, 153, 162, 167, 184, 195 Body Mass Index, 67, 152 Bone Marrow, 15, 152, 160, 168, 170, 178, 179, 182, 197 Bone Marrow Cells, 15, 152, 179 Bone Resorption, 19, 152 Boron, 152, 160 Bowel, 23, 108, 148, 152, 153, 161, 164, 174, 175, 176, 197, 200 Bowel Movement, 153, 161, 197 Bradycardia, 153, 166 Bradykinin, 153, 183, 188 Breeding, 31, 153 Broad-spectrum, 147, 153 Bronchi, 153, 198 Bronchial, 114, 153, 198 Bronchiectasis, 114, 153 Bronchitis, 114, 153, 156 Bypass, 76, 153 C Calcium, 6, 10, 19, 48, 104, 153, 157, 191, 195 Calcium Channel Blockers, 48, 153 Calcium Signaling, 19, 153 Canaliculus, 75, 153 Carbimazole, 40, 153 Carbohydrate, 133, 153, 159, 169, 189 Carbon Dioxide, 153, 188, 193 Carcinogen, 36, 153 Carcinogenic, 154, 175, 190, 196 Carcinoma, 109, 154 Cardiac, 104, 146, 148, 154, 159, 182, 196 Carrier Proteins, 36, 154, 188 Case report, 7, 46, 57, 58, 69, 76, 89, 95, 154, 156 Caspase, 22, 154 Catalase, 31, 145, 154

207

Catalogs, 133, 154 Catheter, 154, 164, 177 Cathode, 148, 154, 163 Cations, 31, 154, 176 Causal, 7, 154, 171 Cause of Death, 10, 17, 31, 104, 154 Caveolae, 23, 24, 154 Caveolins, 154 Celiac Artery, 154, 171 Cell Death, 16, 30, 149, 154, 182 Cell Division, 150, 154, 155, 170, 181, 188 Cell membrane, 33, 153, 154, 176, 179, 187 Cell Membrane Structures, 154 Cell motility, 154, 171 Cell proliferation, 74, 154, 195 Cell Respiration, 155, 181, 193 Cell Size, 155, 167 Cell Survival, 22, 155, 170 Cell Transplantation, 15, 42, 155 Central Nervous System, 145, 155, 187, 194, 198 Centrifugation, 155, 180 Ceramide, 20, 155 Cerebellar, 150, 155, 192 Cerebral, 150, 155, 158, 165 Cerebral Cortex, 150, 155, 165 Cerebrospinal, 155, 195 Cerebrospinal fluid, 155, 195 Cerebrovascular, 151, 153, 155, 198 Chelation, 90, 155 Chemoembolization, 14, 155 Chemotactic Factors, 155, 157 Chenodeoxycholic Acid, 104, 155, 201 Cholangiography, 48, 50, 68, 79, 155 Cholangitis, 46, 67, 108, 109, 155 Cholecystectomy, 13, 155 Cholelithiasis, 25, 38, 155 Choleretic, 15, 84, 89, 90, 102, 103, 155, 201 Cholestanol, 93, 156 Cholesterol Esters, 156, 177 Choline, 121, 156, 187 Chromatin, 149, 156, 178 Chromosome, 15, 64, 68, 146, 156, 177, 200 Chronic Disease, 108, 156 Chronic Obstructive Pulmonary Disease, 114, 156 Chylomicrons, 156, 177 Cirrhosis, 10, 34, 38, 64, 65, 87, 96, 108, 109, 110, 112, 114, 132, 133, 156, 170, 189, 190 CIS, 13, 30, 156 Clavulanic Acid, 63, 156

Clinical study, 156, 158 Clinical trial, 4, 13, 110, 127, 156, 158, 160, 192 Cloning, 25, 110, 152, 156, 177 Cofactor, 156, 191, 198 Colchicine, 90, 110, 156, 200 Colitis, 156 Collagen, 16, 78, 151, 156, 166, 188, 190 Collapse, 66, 157 Colloidal, 146, 157, 186 Colon, 23, 75, 100, 101, 156, 157, 174, 176, 200 Combination Therapy, 110, 157 Common Bile Duct, 10, 13, 29, 157, 160, 171 Complement, 37, 148, 157, 168, 178, 188 Complementary and alternative medicine, 87, 88, 96, 157 Complementary medicine, 88, 157 Computational Biology, 127, 157 Computed tomography, 107, 109, 158 Computerized axial tomography, 158 Computerized tomography, 158 Conception, 158, 166 Congenita, 65, 158 Congestion, 100, 158, 164 Conjugated, 5, 6, 27, 151, 155, 158, 160, 183 Connective Tissue, 152, 157, 158, 166, 178, 197 Consciousness, 148, 158, 162, 171, 191 Conserved Sequence, 147, 158 Consultation, 11, 158 Contamination, 17, 158, 171 Continuum, 42, 158 Contraceptive, 72, 158 Contraindications, ii, 110, 133, 158 Controlled clinical trial, 13, 84, 158 Controlled study, 50, 158 Convulsions, 158, 162, 189 Cor, 159, 173 Corneum, 159, 164, 173 Coronary, 159, 182 Coronary Thrombosis, 159, 182 Corpus, 159, 178, 190 Corpus Luteum, 159, 178, 190 Cortex, 159, 192 Corticosteroid, 159, 189 Cortisol, 146, 159 Coumarins, 159, 191 Cryoelectron Microscopy, 6, 159 Curative, 159, 198 Curcumin, 91, 160

208

Cholestasis

Cyclic, 16, 21, 160, 170, 183, 198 Cyclosporine, 45, 91, 160 Cystic Duct, 157, 160, 171 Cytochrome, 30, 84, 89, 92, 160 Cytokine, 11, 17, 27, 34, 160 Cytomegalovirus, 55, 62, 73, 160, 167 Cytomegalovirus Infections, 160, 167 Cytoplasm, 149, 153, 154, 160, 170, 178, 193 Cytoskeleton, 160, 181 Cytostatic, 18, 160 Cytotoxic, 16, 160, 195 D Danazol, 47, 78, 160 Data Collection, 7, 88, 160 Decidua, 160, 188 Decompression, 110, 161 Decompression Sickness, 161 Degenerative, 161, 171, 184 Deletion, 35, 149, 161 Delivery of Health Care, 161, 170 Demography, 110, 161 Dendrites, 161, 183 Dendritic, 19, 161, 179 Dendritic cell, 19, 161 Detergents, 23, 161 Detoxification, 32, 161 Diabetes Mellitus, 67, 161, 169, 170 Diagnostic procedure, 99, 116, 161 Diarrhea, 22, 26, 72, 84, 161 Diastolic, 161, 173 Diathesis, 18, 161 Diffusion, 161, 174, 176 Digestion, 34, 36, 46, 101, 108, 146, 151, 152, 161, 175, 177, 186, 196, 201 Digestive system, 108, 161 Dihydrotestosterone, 161, 192 Dilation, 114, 153, 162 Direct, iii, 13, 21, 23, 25, 28, 29, 49, 108, 119, 162, 192 Disinfectant, 162, 165 Dissociation, 146, 162 Distal, 162, 168 Diuresis, 162, 198 Drive, ii, vi, 22, 83, 84, 133, 162, 176 Drug Design, 5, 120, 121, 162 Drug Interactions, 120, 162 Drug Resistance, 24, 162 Drug Tolerance, 162 Duct, 6, 11, 14, 21, 28, 30, 33, 34, 35, 42, 43, 79, 88, 100, 110, 147, 151, 153, 155, 157, 162, 163, 165, 171, 193, 196, 197

Duodenal Ulcer, 55, 162 Duodenum, 100, 101, 112, 151, 162, 163, 164, 171, 185, 186, 197 Dysplasia, 117, 162 E Eclampsia, 162, 189 Edema, 162, 178, 189, 201 Effector, 22, 145, 157, 163 Efficacy, 9, 14, 50, 77, 88, 100, 162, 163 Elastin, 157, 163 Electrolysis, 148, 154, 163 Electrolyte, 53, 108, 159, 163, 167, 184, 189, 195, 201 Electrons, 149, 151, 154, 163, 176, 185, 192 Embryo, 152, 163, 174 Embryology, 108, 163 Emphysema, 114, 156, 163 Emulsion, 92, 163 Endemic, 163, 196 Endocrine System, 163, 183 Endocytosis, 154, 163 Endogenous, 6, 16, 20, 163, 190, 199 Endometriosis, 160, 163 Endoscope, 163 Endoscopic, 13, 48, 64, 110, 163, 164 Endoscopic retrograde cholangiopancreatography, 13, 110, 163 Endoscopy, 13, 48, 55, 64, 67, 108, 109, 110, 164 Endothelial cell, 11, 164, 198 Endothelium, 164, 183 Endothelium-derived, 164, 183 Endotoxic, 164, 177 Endotoxin, 25, 94, 164 Enhancer, 164, 193 Enterocolitis, 69, 164 Enterocytes, 26, 164 Enterohepatic, 29, 164 Enteropeptidase, 164, 200 Environmental Health, 84, 126, 128, 164 Enzymatic, 49, 153, 157, 164, 179 Epidemic, 164, 196 Epidemiological, 9, 164 Epidermis, 159, 164, 173 Epigastric, 164, 185 Epithelial, 6, 8, 21, 23, 33, 35, 145, 160, 164, 169, 171, 185 Epithelial Cells, 6, 8, 21, 23, 33, 164, 171 Epithelium, 15, 151, 164 Erythema, 40, 164 Erythema Nodosum, 40, 164 Erythrocytes, 148, 152, 165, 171, 192

209

Esophageal, 165, 168 Esophagitis, 165, 168 Esophagus, 150, 161, 165, 168, 177, 186, 187, 192, 197 Estradiol, 14, 88, 92, 165 Estrogen, 4, 15, 68, 69, 89, 92, 165, 179, 190 Estrogen receptor, 68, 69, 165 Ethanol, 11, 18, 165 Ethnic Groups, 4, 165 Eukaryotic Cells, 165, 174, 184, 200 Evoke, 165, 196 Excitation, 165, 167, 183 Excrete, 17, 165, 193 Exocrine, 165, 185 Exogenous, 20, 163, 165, 168, 186, 190 Exon, 36, 165 Extracellular, 16, 23, 158, 163, 165, 166, 195 Extracellular Matrix, 16, 158, 165, 166 Extracellular Space, 165 Extracorporeal, 47, 165 Extraction, 110, 165 Extravasation, 166, 170 Eye Infections, 145, 166 F Failure to Thrive, 114, 132, 166 Family Planning, 127, 166 Fat, 5, 17, 32, 80, 114, 117, 133, 146, 151, 152, 155, 159, 166, 177, 195 Fatigue, 54, 110, 166 Fatty acids, 23, 146, 166, 169, 179, 187 Fatty Liver, 109, 166 Feces, 156, 166, 197 Fetal Distress, 4, 166 Fetal Growth Retardation, 40, 166 Fetus, 166, 179, 188, 201 Fibrinogen, 166, 188, 191, 198 Fibroblasts, 29, 166 Fibronectin, 16, 166 Fibrosis, 8, 12, 24, 33, 34, 46, 48, 53, 65, 66, 69, 76, 80, 90, 93, 100, 101, 102, 103, 104, 110, 166, 194 Filtration, 117, 166 Fine-needle aspiration, 166, 182 Fixatives, 159, 166 Flatus, 166, 167 Flow Cytometry, 35, 166 Fluid Therapy, 167, 184 Fluorescence, 15, 19, 20, 25, 31, 36, 167 Fluorescent Dyes, 167 Fluoxetine, 40, 167 Fold, 23, 167, 180, 184 Forearm, 152, 167

Free Radicals, 149, 162, 167 Fulminant Hepatic Failure, 18, 109, 167 G Galactosides, 151, 167 Gallbladder, 101, 108, 109, 145, 151, 155, 160, 161, 163, 167, 171, 177 Gamma-interferon, 167, 175 Ganciclovir, 55, 73, 167 Gas, 48, 147, 153, 161, 166, 167, 172, 183, 197 Gastric, 55, 64, 100, 101, 150, 154, 167, 168, 184, 186 Gastric Acid, 100, 101, 167, 184 Gastric Juices, 168, 186 Gastric Outlet Obstruction, 64, 168 Gastrin, 168, 172 Gastroesophageal Reflux, 14, 168 Gastroesophageal Reflux Disease, 14, 168 Gastrointestinal, 13, 22, 31, 56, 67, 93, 94, 95, 108, 112, 153, 165, 168, 194, 196, 197 Gastrointestinal tract, 22, 108, 165, 168, 194, 196 Gene Expression, 8, 11, 17, 26, 30, 35, 47, 91, 168, 196 Gene Targeting, 35, 168 Gene Therapy, 19, 32, 145, 168 Genetic Code, 168, 183 Genetic Engineering, 152, 156, 168 Genetics, 22, 23, 24, 39, 52, 57, 60, 65, 66, 68, 74, 168 Genomics, 9, 24, 168 Genotype, 168, 187 Gestation, 168, 186, 188 Gestational, 39, 67, 166, 169 Gland, 146, 169, 178, 185, 187, 194, 196, 197, 199 Glomerular, 169, 193 Glucocorticoid, 169, 189 Glucose, 10, 33, 58, 161, 169, 170, 175, 194 Glucose Intolerance, 10, 161, 169 Glucose tolerance, 169 Glucose Tolerance Test, 169 Glutamate, 169, 187 Glutathione Peroxidase, 169, 194 Glycerol, 169, 187 Glycerophospholipids, 169, 187 Glycine, 104, 151, 155, 169, 183, 194 Glycogen, 33, 169 Glycoprotein, 20, 166, 169, 198 Glycosylation, 36, 169 Goblet Cells, 164, 169 Gonadal, 169, 196

210

Cholestasis

Gout, 156, 170 Governing Board, 170, 189 Graft, 42, 74, 110, 170 Graft-versus-host disease, 42, 74, 170 Granulocytes, 170, 176, 195, 202 Growth factors, 35, 170 Guanylate Cyclase, 170, 183 H Half-Life, 15, 170 Haptens, 146, 170 Health Care Costs, 13, 170 Health Expenditures, 170 Heart attack, 104, 170 Hematology, 44, 107, 109, 170 Hematoma, 50, 170 Hemochromatosis, 133, 170 Hemoglobin, 148, 165, 170, 171, 176 Hemoglobinopathies, 168, 171 Hemolysis, 80, 171 Hemolytic, 54, 171 Hemorrhage, 84, 171, 187, 197 Hepatic Artery, 107, 109, 171 Hepatic Duct, Common, 163, 171 Hepatic Encephalopathy, 107, 109, 133, 171 Hepatic Veins, 109, 171 Hepatitis, 7, 8, 59, 63, 69, 75, 79, 96, 100, 108, 109, 114, 133, 167, 171, 181, 202 Hepatitis A, 8, 171, 181 Hepatitis C, 59, 79, 171 Hepatobiliary, 10, 12, 25, 29, 48, 56, 59, 62, 65, 108, 111, 112, 171 Hepatocellular, 14, 24, 30, 40, 59, 94, 103, 107, 114, 133, 171 Hepatocellular carcinoma, 14, 114, 133, 171 Hepatocyte, 14, 15, 16, 18, 22, 24, 30, 33, 36, 55, 89, 171 Hepatocyte Growth Factor, 16, 171 Hepatoma, 25, 171 Hepatotoxic, 18, 22, 171 Hepatotoxicity, 27, 38, 48, 84, 89, 171 Hepatovirus, 171 Hereditary, 12, 40, 55, 57, 60, 61, 108, 170, 171 Heredity, 64, 168, 171 Heterogeneity, 51, 57, 66, 146, 172 Histology, 65, 108, 172 Homeostasis, 23, 26, 112, 172 Homogeneous, 158, 172 Homologous, 168, 172, 200 Hormonal, 17, 150, 159, 172, 180

Hormone, 11, 17, 25, 159, 165, 168, 172, 175, 179, 180, 188, 190, 193, 195, 196, 198 Hormone therapy, 172, 179 Humoral, 25, 172 Humour, 172 Hybrid, 5, 32, 172 Hydrogen, 145, 151, 153, 154, 169, 172, 177, 181, 183, 185, 186, 191, 198 Hydrogen Peroxide, 154, 169, 172, 177 Hydrolysis, 24, 29, 151, 172, 176, 187, 189, 191, 200 Hydrophilic, 22, 161, 172 Hydrophobic, 22, 161, 169, 172, 177 Hydroxylysine, 157, 172 Hydroxyproline, 157, 172 Hyperbilirubinemia, 4, 27, 79, 172, 176 Hypercholesterolemia, 20, 23, 25, 26, 28, 65, 91, 172 Hyperplasia, 70, 172 Hypersensitivity, 29, 173, 193 Hypertension, 67, 110, 153, 159, 173, 187, 189, 201 Hypertrophy, 15, 159, 173 Hypoglycemia, 45, 173 Hypopituitarism, 45, 173 Hypoplasia, 117, 173 Hypothalamus, 173, 188 I Iatrogenic, 103, 173 Ichthyosis, 41, 173 Idiopathic, 173, 194 Ileal, 6, 26, 29, 61, 76, 173 Ileitis, 26, 173 Ileostomy, 173, 182 Ileum, 26, 35, 173 Imidazole, 153, 173 Immune response, 149, 150, 159, 170, 173, 174, 178, 197, 202 Immune system, 108, 149, 151, 173, 174, 202 Immunofluorescence, 5, 173 Immunogenic, 173, 177 Immunoglobulins, 34, 173, 188 Immunohistochemistry, 35, 173 Immunologic, 9, 16, 155, 174 Immunology, 19, 20, 24, 32, 33, 47, 146, 167, 174 Immunosuppressant, 110, 174, 180 Impairment, 37, 103, 150, 166, 174 In situ, 8, 15, 32, 35, 174 In Situ Hybridization, 8, 15, 32, 35, 174 In vitro, 19, 20, 25, 34, 37, 62, 168, 174

211

In vivo, 19, 20, 27, 32, 37, 89, 91, 168, 174 Incision, 174, 176 Incompetence, 168, 174 Incubation, 10, 174 Induction, 28, 91, 148, 174, 190 Infancy, 31, 55, 60, 84, 108, 109, 111, 174 Infantile, 47, 48, 62, 66, 69, 174 Infarction, 173, 174 Infiltration, 62, 174 Inflammatory bowel disease, 108, 174 Infusion, 174, 199 Ingestion, 87, 100, 101, 169, 175 Initiation, 175, 190, 199 Insecticides, 175, 202 Insight, 5, 21, 27, 34, 89, 175 Insomnia, 175, 200 Insulin, 102, 103, 169, 175 Insulin-dependent diabetes mellitus, 175 Insulin-like, 102, 103, 175 Intensive Care, 79, 175 Intercellular Adhesion Molecule-1, 61, 175 Interferon, 75, 90, 167, 175 Interferon-alpha, 175 Internal Medicine, 6, 11, 19, 21, 28, 34, 170, 175 Interstitial, 53, 165, 175, 193 Intestinal, 26, 34, 68, 155, 164, 169, 175, 178, 179, 185 Intestinal Mucosa, 164, 175 Intestine, 21, 26, 34, 101, 151, 152, 164, 175, 176, 202 Intoxication, 175, 202 Intracellular, 6, 12, 22, 30, 31, 153, 174, 175, 179, 183, 189, 194, 195 Intrahepatic bile ducts, 29, 34, 109, 175 Intramuscular, 175, 185 Intravenous, 18, 30, 84, 92, 174, 176, 185 Intrinsic, 146, 151, 176 Invasive, 13, 176, 178 Ion Transport, 29, 176 Ions, 151, 162, 163, 172, 176, 191 J Jaundice, 3, 48, 64, 79, 92, 100, 108, 109, 110, 112, 114, 132, 172, 176, 182 K Kb, 126, 176 Kinetics, 12, 15, 176 L Labile, 157, 176 Lacrimal, 153, 176 Lactation, 176, 190 Laparoscopy, 13, 176

Large Intestine, 161, 175, 176, 192, 195, 202 Latent, 176, 189 Laxative, 146, 155, 176 Lectin, 93, 176, 180 Lens, 158, 176 Lesion, 31, 176, 177, 200 Lethal, 32, 150, 176 Leucine, 79, 176 Leucocyte, 147, 176 Leukemia, 62, 168, 177 Life cycle, 152, 177 Ligands, 25, 103, 177 Ligase, 12, 177 Ligation, 10, 29, 177 Linkage, 32, 64, 177, 187 Lipid, 6, 16, 20, 24, 31, 32, 40, 74, 91, 112, 117, 149, 154, 156, 169, 175, 177, 185 Lipid A, 20, 177 Lipid Peroxidation, 91, 177, 185 Lipopolysaccharides, 177 Lipoprotein, 6, 24, 46, 65, 73, 104, 177 Lithotripsy, 110, 177 Liver cancer, 52, 114, 133, 177 Liver Regeneration, 18, 177 Liver Transplantation, 7, 8, 9, 14, 18, 38, 44, 46, 62, 72, 75, 95, 108, 132, 133, 177 Localization, 78, 173, 177 Localized, 27, 34, 55, 147, 170, 174, 177, 188, 200 Low-density lipoprotein, 177 Lower Esophageal Sphincter, 168, 177 Luciferase, 26, 29, 178 Lutein Cells, 178, 190 Lymph, 164, 172, 178, 194 Lymph node, 178, 194 Lymphatic, 164, 174, 178, 196, 199 Lymphatic system, 178, 196, 199 Lymphedema, 51, 178 Lymphocytes, 47, 149, 161, 167, 176, 178, 196, 199, 202 Lymphoid, 148, 176, 178 Lymphoma, 79, 178 Lysine, 172, 178, 200 M Magnetic Resonance Imaging, 76, 107, 109, 178 Major Histocompatibility Complex, 81, 91, 178 Malabsorption, 80, 178 Malformation, 117, 178, 193 Malignancy, 87, 178

212

Cholestasis

Malignant, 58, 67, 79, 108, 110, 145, 149, 177, 178, 179, 182 Malignant tumor, 179, 182 Malnutrition, 146, 150, 179 Manometry, 110, 179 Meconium, 42, 166, 179 Mediate, 5, 14, 15, 33, 179 Mediator, 18, 179, 194 Medical Records, 179, 193 MEDLINE, 127, 179 Medullary, 117, 179 Megakaryocytes, 152, 179 Megestrol, 92, 179 Megestrol Acetate, 92, 179 Melanocytes, 179 Melanoma, 67, 179 Membrane Lipids, 179, 187 Membrane Microdomains, 24, 179 Membrane Proteins, 154, 179, 191 Menstrual Cycle, 180, 190 Mental, iv, 4, 126, 128, 155, 162, 166, 174, 180, 194, 201 Mentors, 12, 180 Mercaptopurine, 27, 180 Mercury, 167, 180 Mesenteric, 180, 189 Metabolic disorder, 32, 109, 113, 132, 170, 180 Metabolite, 45, 180, 189 Metastasis, 180 Metastatic, 67, 173, 180 Methimazole, 153, 180 Methotrexate, 110, 180 Methyltestosterone, 95, 180 Microbe, 180, 199 Microbiology, 19, 20, 32, 67, 145, 150, 180 Microorganism, 156, 180, 185, 202 Microscopy, 5, 19, 21, 23, 24, 25, 30, 36, 151, 159, 180 Microsomal, 28, 36, 180 Microspheres, 100, 101, 181 Microtubules, 25, 181 Migration, 175, 181 Milk Thistle, 87, 96, 181, 195 Miscible, 88, 181 Mitochondria, 30, 181, 184 Mitochondrial Swelling, 181, 182 Mitosis, 149, 181, 196 Mitotic, 181, 202 Mobility, 30, 181 Mobilization, 5, 153, 181 Mode of Transmission, 13, 181

Modeling, 162, 181 Modification, 21, 93, 109, 168, 181, 192 Molecule, 28, 149, 151, 157, 162, 163, 164, 165, 171, 172, 176, 181, 185, 188, 192, 195, 201 Monitor, 15, 78, 181, 183 Morphology, 43, 170, 181 Motility, 25, 108, 181, 194 Mucilaginous, 179, 181 Mucins, 164, 169, 181 Mucosa, 93, 181, 190, 197 Multidrug resistance, 12, 17, 38, 68, 69, 88, 91, 94, 181 Multiple Myeloma, 44, 182 Multivariate Analysis, 72, 182 Mutagenesis, 23, 182 Mutagens, 182 Mydriatic, 162, 182 Myocardial infarction, 104, 159, 182 Myocardium, 182 N Naloxone, 182 Naltrexone, 50, 55, 182 Narcotic, 182 NCI, 1, 125, 156, 182 Necrosis, 18, 30, 58, 61, 74, 77, 84, 149, 174, 182, 187, 194 Necrotizing Enterocolitis, 34, 182 Needle biopsy, 109, 166, 182 Neonatal, 7, 8, 12, 23, 30, 39, 43, 49, 55, 60, 62, 65, 68, 69, 76, 78, 80, 182 Neonatal Hepatitis, 7, 8, 182 Neoplasm, 182, 200 Nervous System, 155, 179, 182, 183, 197 Networks, 5, 183 Neural, 172, 183 Neuroendocrine, 47, 183 Neurologic, 55, 183 Neuromuscular, 53, 145, 183, 201 Neurons, 19, 161, 183 Neuropathy, 80, 183 Neurotransmitter, 145, 153, 169, 183, 195, 197 Neutrons, 147, 183, 192 Neutrophil, 132, 175, 183 Nitric Oxide, 30, 183 Nuclear, 11, 18, 21, 22, 25, 27, 28, 33, 65, 71, 103, 150, 163, 165, 182, 183, 201 Nuclear Proteins, 18, 183 Nuclei, 18, 147, 163, 168, 178, 181, 183, 191 Nucleic acid, 105, 168, 174, 182, 183 Nucleoproteins, 183

213

Nucleotidases, 29, 184 Nucleus, 149, 151, 156, 160, 165, 178, 183, 184, 191, 198 Nutritional Support, 108, 132, 184 O Omentum, 171, 184 Omeprazole, 184, 191 Oncogene, 171, 184 Oogenesis, 19, 184 Opiate, 71, 76, 77, 182, 184 Opium, 184 Organelles, 73, 155, 159, 160, 179, 184, 188 Osmolarity, 5, 184 Osmoles, 184 Osmotic, 146, 181, 184 Osteoarthritis, 88, 184 Osteodystrophy, 58, 184 Osteoporosis, 67, 110, 184 Ovary, 159, 165, 184, 197 Overdose, 167, 184 Ovulation, 179, 184 Ovum, 159, 160, 168, 177, 184, 190 Oxidation, 18, 145, 149, 160, 169, 177, 180, 185 Oxidative Stress, 27, 30, 185 P Palliative, 179, 185, 198 Pancreas, 48, 108, 109, 145, 161, 170, 171, 175, 185, 196, 200 Pancreatic, 62, 75, 84, 110, 163, 168, 185 Pancreatic cancer, 84, 185 Pancreatic Ducts, 164, 185 Pancreatic Juice, 168, 185 Pancreatitis, 40, 108, 185 Paneth Cells, 164, 185 Panniculitis, 114, 185 Papilla, 67, 163, 185 Parenteral, 34, 61, 65, 67, 69, 70, 71, 72, 74, 77, 78, 85, 89, 90, 92, 93, 115, 185 Parenteral Nutrition, 34, 61, 65, 67, 69, 70, 74, 77, 78, 85, 89, 92, 93, 115, 185 Parotid, 185, 194 Particle, 185, 199 Parturition, 185, 190 Pathogen, 174, 185 Pathologic, 18, 26, 145, 149, 152, 159, 166, 172, 173, 185, 186 Pathologic Processes, 149, 186 Pathophysiology, 6, 108, 112, 186 Patient Education, 132, 138, 140, 144, 186 Penicillin, 147, 148, 186 Pepsin, 186

Peptic, 108, 168, 186 Peptic Ulcer, 108, 168, 186 Peptide, 20, 164, 186, 189, 190, 191, 196 Perception, 14, 186, 194 Percutaneous, 177, 186 Perforation, 186, 202 Perinatal, 7, 29, 61, 63, 77, 109, 186 Peripheral blood, 105, 175, 186 Peripheral stem cells, 170, 186 Peritoneal, 150, 186 Peritoneal Cavity, 150, 186 Peritonitis, 186, 202 Peroxide, 80, 186 Petrolatum, 163, 186 PH, 19, 48, 60, 186 Pharmacokinetics, 162, 186 Pharmacologic, 12, 170, 187, 199 Pharynx, 168, 187 Phenobarbital, 27, 100, 187 Phenolphthalein, 163, 187 Phenotype, 31, 34, 35, 187 Phorbol, 187, 191 Phorbol Esters, 187, 191 Phosphatidic Acids, 187 Phosphatidylcholines, 25, 187 Phospholipids, 31, 95, 166, 177, 179, 187, 191 Phosphorus, 153, 187 Phosphorylates, 187, 191 Phosphorylation, 10, 11, 16, 17, 21, 22, 187 Physiologic, 10, 18, 23, 29, 37, 87, 152, 170, 180, 187, 192 Physiology, 5, 12, 19, 22, 24, 26, 31, 56, 93, 95, 108, 170, 187 Pigment, 6, 151, 179, 187 Pilot study, 31, 33, 78, 187 Pituitary Apoplexy, 173, 187 Pituitary Gland, 159, 173, 187, 188 Pituitary Hormones, 17, 188 Pituitary Neoplasms, 173, 188 Placenta, 41, 62, 165, 188, 190 Plant sterols, 89, 188 Plants, 147, 153, 156, 169, 176, 181, 188, 193, 199 Plaque, 104, 188 Plasma, 20, 22, 24, 29, 36, 146, 148, 154, 156, 166, 169, 170, 182, 188, 191 Plasma cells, 148, 182, 188 Plasma protein, 146, 188, 191 Plastids, 184, 188 Platelet Aggregation, 148, 183, 188 Platelets, 179, 183, 188, 194

214

Cholestasis

Pneumonia, 158, 188 Point Mutation, 105, 188 Polymorphic, 64, 188 Polypeptide, 147, 156, 158, 166, 189, 190, 203 Polysaccharide, 149, 189 Porphyria, 132, 189 Portal Hypertension, 89, 107, 108, 109, 110, 114, 133, 189 Portal Vein, 114, 133, 189 Posterior, 148, 150, 185, 188, 189 Postmenopausal, 184, 189 Postnatal, 29, 189, 196 Postoperative, 3, 189 Post-translational, 16, 189 Potassium, 117, 189 Practice Guidelines, 128, 189 Pravastatin, 45, 189 Precursor, 156, 163, 164, 189, 191, 200, 201 Predisposition, 4, 7, 189 Prednisolone, 103, 189 Preeclampsia, 68, 189 Prevalence, 4, 189 Primary Biliary Cirrhosis, 3, 57, 79, 100, 103, 108, 109, 110, 190 Primary Sclerosing Cholangitis, 3, 7, 42, 103, 190 Probe, 15, 190 Problem Solving, 108, 190 Progeny, 34, 190 Progesterone, 4, 42, 179, 190, 196 Progression, 16, 30, 55, 148, 190 Prolactin, 29, 52, 190 Proline, 157, 172, 190 Promoter, 11, 13, 17, 21, 25, 26, 28, 30, 36, 190 Promotor, 190, 193 Prospective study, 48, 58, 74, 79, 190 Protease, 23, 157, 190 Protective Agents, 153, 190 Protein Binding, 17, 190 Protein C, 36, 146, 147, 149, 177, 190, 201 Protein Kinase C, 22, 191 Protein S, 23, 33, 152, 168, 191, 193 Proteinuria, 182, 189, 191 Proteolytic, 147, 157, 164, 166, 191 Prothrombin, 18, 191, 198 Prothrombin Time, 18, 191 Proton Pump, 14, 184, 191 Proton Pump Inhibitors, 14, 191 Protons, 147, 172, 191, 192

Pruritus, 4, 14, 50, 51, 66, 70, 71, 76, 77, 81, 93, 110, 191, 201 Psychoactive, 191, 202 Public Policy, 127, 191 Publishing, 37, 108, 134, 191 Pulmonary, 44, 62, 152, 159, 191 Pulmonary Artery, 152, 191 Pulse, 181, 191 Pupil, 162, 182, 192 Q Quality of Life, 14, 88, 114, 192 R Radiation, 15, 32, 110, 167, 173, 192, 203 Radioactive, 170, 172, 183, 192, 198, 201 Radiofrequency ablation, 14, 192 Radiological, 13, 186, 192 Radiology, 58, 62, 68, 108, 109, 110, 192 Randomized, 9, 13, 14, 163, 192 Reactive Oxygen Species, 30, 192 Reagent, 178, 192, 198 Receptor, 10, 11, 20, 23, 24, 25, 27, 28, 33, 72, 103, 145, 149, 171, 187, 191, 192, 194, 195 Recombinant, 32, 192, 201 Recombination, 168, 192 Rectum, 149, 153, 157, 161, 166, 167, 174, 176, 192 Recurrence, 110, 192 Red blood cells, 165, 171, 192, 194, 195 Red Nucleus, 150, 192 Reductase, 23, 58, 180, 189, 192 Refer, 1, 157, 177, 183, 192, 199 Reflux, 14, 168, 192 Refraction, 192, 196 Regeneration, 15, 66, 192 Regimen, 163, 193 Regurgitation, 168, 193 Remission, 192, 193 Renal agenesis, 117, 193 Renal failure, 44, 45, 193, 201 Renal tubular, 41, 117, 193 Renal tubular acidosis, 117, 193 Resection, 18, 26, 35, 193 Respiration, 153, 181, 193 Response Elements, 11, 193 Retrograde, 48, 110, 193 Retrospective, 79, 193 Retrospective study, 79, 193 Retroviral vector, 168, 193 Rheumatoid, 53, 193 Rheumatoid arthritis, 53, 193 Ribosome, 193, 200

215

Risk factor, 67, 72, 74, 114, 190, 193 S Salivary, 160, 161, 185, 193 Salivary glands, 160, 161, 193 Saponins, 193, 196 Sarcoidosis, 3, 46, 194 Schizoid, 194, 202 Schizophrenia, 194, 202 Schizotypal Personality Disorder, 194, 202 Screening, 9, 28, 37, 39, 49, 57, 78, 80, 104, 105, 114, 117, 156, 194 Secretory, 6, 16, 34, 35, 37, 173, 184, 194 Secular trends, 9, 194 Selenium, 4, 194 Senile, 184, 194 Sepsis, 3, 17, 18, 50, 56, 58, 67, 75, 194 Sequencing, 32, 36, 194 Serine, 191, 194, 200 Serotonin, 75, 167, 183, 194, 200 Serum, 4, 8, 9, 20, 32, 36, 49, 61, 67, 74, 75, 79, 80, 85, 93, 146, 148, 157, 177, 186, 194 Shock, 177, 194, 200 Shunt, 6, 195 Side effect, 27, 103, 119, 121, 146, 151, 195, 199 Signal Transduction, 154, 195 Silymarin, 89, 93, 181, 195 Skeletal, 85, 148, 182, 195 Skeleton, 195 Skull, 195, 198 Sludge, 105, 195 Small intestine, 155, 156, 160, 162, 164, 168, 172, 173, 175, 195, 200 Smooth muscle, 148, 153, 195, 197 Social Environment, 192, 195 Sodium, 17, 26, 36, 45, 117, 170, 195, 197 Soft tissue, 152, 195 Solvent, 165, 169, 184, 195 Soma, 195, 196 Somatic, 35, 172, 181, 196 Somatotropin, 173, 196 Specialist, 134, 162, 196 Species, 26, 155, 156, 158, 172, 181, 192, 196, 197, 200, 202, 203 Specificity, 26, 146, 196 Spectrum, 94, 114, 117, 132, 160, 196 Sperm, 148, 156, 196, 200 Spinal cord, 155, 156, 182, 183, 196 Spleen, 147, 160, 178, 194, 196 Splenic Vein, 189, 196 Sporadic, 37, 196 Steatosis, 18, 72, 133, 166, 196

Stellate, 11, 196 Stem Cells, 15, 34, 186, 196 Stenosis, 117, 196, 197 Stent, 64, 196 Steroid, 28, 37, 50, 62, 100, 151, 159, 160, 193, 196 Stimulus, 14, 162, 165, 196, 198 Stool, 47, 80, 157, 176, 197 Stress, 28, 159, 185, 189, 193, 197 Stricture, 108, 109, 196, 197 Stroke, 104, 126, 197 Stromal, 152, 163, 197 Stromal Cells, 152, 197 Subacute, 174, 197 Subclinical, 174, 197 Subcutaneous, 114, 162, 185, 197 Subspecies, 196, 197 Substance P, 180, 194, 197 Substrate, 15, 26, 88, 197 Suction, 166, 197 Supplementation, 90, 91, 92, 94, 197 Suppression, 76, 110, 159, 197 Survival Rate, 18, 197 Sweat, 53, 197 Sweat Glands, 197 Symptomatic, 88, 185, 197 Synergistic, 190, 197 Systemic, 17, 108, 109, 147, 152, 173, 174, 189, 194, 197, 201 Systemic disease, 108, 109, 173, 197 Systolic, 173, 197 T Tachycardia, 166, 198 Taurine, 94, 104, 151, 155, 198 Technetium, 65, 198 Temporal, 9, 19, 33, 198 Testis, 165, 198 Testosterone, 192, 198 Thalamic, 150, 198 Thalamic Diseases, 150, 198 Theophylline, 85, 198 Therapeutics, 25, 120, 198 Thioacetamide, 89, 198 Thoracic, 88, 198 Threonine, 191, 194, 198 Threshold, 146, 173, 198 Thrombin, 166, 188, 190, 191, 198 Thrombomodulin, 190, 198 Thromboplastin, 191, 198 Thrombosis, 191, 197, 198 Thymoma, 91, 199 Thymus, 178, 199

216

Cholestasis

Thyroxine, 146, 199 Tomography, 199 Tone, 199 Tonicity, 171, 199 Tonus, 199 Tooth Preparation, 145, 199 Topical, 165, 172, 186, 199 Toxaemia, 189, 199 Toxic, iv, 15, 16, 18, 22, 27, 30, 53, 101, 150, 171, 183, 186, 194, 199 Toxicity, 15, 30, 101, 162, 180, 199 Toxicology, 14, 27, 76, 84, 128, 199 Toxin, 87, 164, 199 Transcription Factors, 17, 19, 21, 103, 193, 199 Transduction, 32, 153, 195, 199 Transfection, 17, 29, 36, 152, 168, 199 Transferases, 169, 199 Transfusion, 51, 171, 199 Translation, 15, 19, 25, 200 Translational, 8, 15, 35, 200 Translocating, 20, 200 Translocation, 6, 20, 22, 30, 200 Transmitter, 145, 179, 200 Transplantation, 44, 45, 48, 58, 62, 65, 66, 68, 74, 75, 95, 108, 109, 110, 178, 200 Trauma, 108, 109, 151, 165, 182, 185, 198, 200 Triazolam, 53, 200 Trypsin, 33, 164, 200, 203 Tryptophan, 157, 194, 200 Tubulin, 181, 200 Tumour, 61, 74, 200 Tunica, 181, 200 U Ubiquitin, 12, 200 Ulcer, 55, 162, 200 Ulceration, 186, 200 Ulcerative colitis, 174, 190, 200 Ultrasonography, 48, 200 Untranslated Regions, 15, 200 Uraemia, 185, 201 Uranium, 198, 201 Urea, 197, 201 Uremia, 193, 201 Ureters, 201 Urethra, 201 Urinary, 49, 78, 117, 201 Urinary tract, 117, 201 Urine, 49, 78, 117, 152, 162, 191, 201

Ursodeoxycholic Acid, 21, 39, 41, 42, 49, 52, 54, 61, 63, 70, 75, 100, 101, 103, 110, 115, 201 Uterus, 159, 160, 190, 201 V Vaccines, 201, 202 Vacuoles, 163, 184, 201 Vascular, 109, 117, 147, 153, 164, 174, 183, 188, 201 Vascular Resistance, 147, 201 Vasculitis, 185, 201 Vasodilators, 183, 201 Vector, 33, 199, 201 Vein, 108, 176, 183, 185, 189, 196, 201 Venous, 107, 109, 191, 202 Ventricular, 147, 159, 202 Venules, 152, 202 Vesicular, 20, 24, 31, 180, 202 Veterinary Medicine, 127, 202 Vinblastine, 94, 200, 202 Vinca Alkaloids, 202 Viral, 3, 9, 16, 18, 79, 87, 100, 103, 108, 133, 199, 202 Viral Hepatitis, 3, 18, 88, 100, 108, 133, 202 Viral vector, 19, 202 Virulence, 24, 150, 199, 202 Virus, 18, 32, 45, 59, 108, 109, 164, 168, 171, 175, 188, 193, 199, 202 Viscera, 196, 202 Vitro, 19, 202 Vivo, 202 Volvulus, 34, 202 W War, 3, 202 White blood cell, 132, 148, 178, 183, 188, 202 Withdrawal, 55, 71, 77, 202 X Xenobiotics, 32, 112, 202 Xenograft, 148, 203 X-ray, 154, 158, 163, 167, 183, 192, 203 Y Yeasts, 187, 203 Z Zebrafish, 32, 203 Zymogen, 190, 203

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