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

HEART TRANSPLANT A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES J A...

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HEART

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

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., 1960Heart Transplant: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84446-1 1. Heart Transplant-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 heart transplant. 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 HEART TRANSPLANT ................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Heart Transplant .......................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 60 The National Library of Medicine: PubMed ................................................................................ 64 CHAPTER 2. NUTRITION AND HEART TRANSPLANT .................................................................... 113 Overview.................................................................................................................................... 113 Finding Nutrition Studies on Heart Transplant ....................................................................... 113 Federal Resources on Nutrition ................................................................................................. 119 Additional Web Resources ......................................................................................................... 119 CHAPTER 3. DISSERTATIONS ON HEART TRANSPLANT................................................................ 121 Overview.................................................................................................................................... 121 Dissertations on Heart Transplant ............................................................................................ 121 Keeping Current ........................................................................................................................ 121 CHAPTER 4. CLINICAL TRIALS AND HEART TRANSPLANT .......................................................... 123 Overview.................................................................................................................................... 123 Recent Trials on Heart Transplant ............................................................................................ 123 Keeping Current on Clinical Trials ........................................................................................... 125 CHAPTER 5. PATENTS ON HEART TRANSPLANT .......................................................................... 127 Overview.................................................................................................................................... 127 Patents on Heart Transplant ..................................................................................................... 127 Patent Applications on Heart Transplant.................................................................................. 134 Keeping Current ........................................................................................................................ 138 CHAPTER 6. BOOKS ON HEART TRANSPLANT .............................................................................. 139 Overview.................................................................................................................................... 139 Book Summaries: Online Booksellers......................................................................................... 139 Chapters on Heart Transplant ................................................................................................... 141 CHAPTER 7. MULTIMEDIA ON HEART TRANSPLANT ................................................................... 143 Overview.................................................................................................................................... 143 Video Recordings ....................................................................................................................... 143 CHAPTER 8. PERIODICALS AND NEWS ON HEART TRANSPLANT ................................................ 145 Overview.................................................................................................................................... 145 News Services and Press Releases.............................................................................................. 145 Academic Periodicals covering Heart Transplant...................................................................... 148 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 151 Overview.................................................................................................................................... 151 U.S. Pharmacopeia..................................................................................................................... 151 Commercial Databases ............................................................................................................... 152 Researching Orphan Drugs ....................................................................................................... 152 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 157 Overview.................................................................................................................................... 157 NIH Guidelines.......................................................................................................................... 157 NIH Databases........................................................................................................................... 159 Other Commercial Databases..................................................................................................... 161 APPENDIX B. PATIENT RESOURCES ............................................................................................... 163 Overview.................................................................................................................................... 163 Patient Guideline Sources.......................................................................................................... 163 Finding Associations.................................................................................................................. 171 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 175

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Overview.................................................................................................................................... 175 Preparation................................................................................................................................. 175 Finding a Local Medical Library................................................................................................ 175 Medical Libraries in the U.S. and Canada ................................................................................. 175 ONLINE GLOSSARIES................................................................................................................ 181 Online Dictionary Directories ................................................................................................... 182 HEART TRANSPLANT DICTIONARY.................................................................................... 183 INDEX .............................................................................................................................................. 249

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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 heart transplant 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 heart transplant, 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 heart transplant, 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 heart transplant. 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 heart transplant, 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 heart transplant. The Editors

1

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

3

CHAPTER 1. STUDIES ON HEART TRANSPLANT Overview In this chapter, we will show you how to locate peer-reviewed references and studies on heart transplant.

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

Dental Management of the Heart Transplant Patient Source: General Dentistry. 40(2): 126-131. March-April 1992. Summary: This article brings readers up to date on the dental management of heart transplant patients. Topics include the historical development of heart transplantation, including survival rates, postoperative care, and patient selection; complications following heart transplantation, including graft rejection, immunosuppression, accelerated atherosclerosis of the graft coronary arteries, side effects of agents used for immunosuppression, and excess bleeding as a result of anticoagulation medicine; dental management of these patients, including the pretreatment dental evaluation, retention of teeth, treatment of patients with valvular disease, and preventive techniques; and managing invasive dental treatment for posttransplant patients, including the need for antibiotic prophylaxis, handling excessive bleeding and reactions to stress, the use of

4

Heart Transplant

steroids, and myocardial infarction. The authors conclude that the two most important roles for dentistry in managing heart transplant patients are to be involved before the transplant, so areas of active infection can be identified and treated before the start of immunosuppressive therapy, and to initiate an aggressive preventive dentistry program for the patient. 7 tables. 22 references. •

Reversion of Gingival Hyperplasia in a Heart Transplant Patient Upon Interruption of Cyclosporine Therapy Source: SCD. Special Care in Dentistry. 16(1): 18-21. January-February 1996. Summary: This article presents a case of reversion of gingival hyperplasia in a heart transplant patient upon interruption of cyclosporine therapy. A heart transplant patient undergoing a combined cyclosporine and prednisone treatment was monitored during the 18 months following transplantation. Complete oral and dental examinations were performed on a set schedule; data collected included gingival hyperplasia secondary to cyclosporine use, and clinical and periodontal variables. Cyclosporine treatment was replaced by azathioprine treatment in month 10 because the patient was experiencing nephrotoxicity. Between months 9 and 18, gingival hyperplasia regressed by 26.5 percent due to reductions in the fibrous connective tissue mass, fibroblasts, and inflammatory infiltration. A control group included 13 heart transplant patients subject to equivalent conditions except for discontinuance of cyclosporine treatment. Seven of these patients had developed hyperplasia by month 9. Results provide further evidence for the causal relationship between cyclosporine therapy and gingival hyperplasia and suggest that this side-effect is reversible. 7 figures. 7 references. (AA-M).

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

Project Title: ADENOVIRAL/LENTIVIRAL MODIFICATION

VECTORS

FOR

GENETIC

Principal Investigator & Institution: Mc Gregor, Christopher G.; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 2 Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

Studies

5

Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: The broad long-term objectives of this proposal are to achieve targeted, efficient and durable gene transfer to the transplanted heart and, using biologically relevant genes for isoforms of nitric oxide synthase (NOS), to normalize coronary arterial vasoreactivity and reduce cardiac allograft vasculopathy (CAV) after allotransplantation in both a small and large animal model. The central hypotheses of this proposal are that, using the unique transplant setting, targeted, efficient and durable gene transduction of blood vessels of the heart or the myocardium can be achieved and that abnormalities in coronary vascular relaxation and the development of CAV after heart transplantation can be reduced by efficient cardiac transduction with endothelial or inducible NOS (eNOS or iNOS). CAV is the greatest obstacle to long-term patient survival after cardiac transplantation. Gene therapy may be particularly applicable in the setting of transplantation as the donor organ is uniquely available for genetic modification ex vivo prior to implantation into a recipient. Major challenges to successful clinical gene genetic modification ex vivo prior to implantation into a recipient. Major challenges to successful clinical gene therapy include the need for optimal vectors and delivery systems to transfer genetic material to tissues in vivo. Recently, for the first time, physical and chemical conditions of gene delivery to the heart have been shown to allow selective targeting of the vector to the media of the coronary arteries of the myocardium. Using a normothermic perfusion system, the usual period of storage of the donor heart before transplantation can be transformed into a period for optimal gene delivery without affecting the viability of the graft. The first aim of transformed into a period for optimal gene delivery without affecting the viability of the graft. The first aim of the current proposal is to identify the most suitable vector (adenovirus or lentivirus) and delivery system using chemical modification of a normothermic perfusion system for efficient, targeted and durable gene delivery in the heterotopic rat heart transplant model. The second aim is to study, using the most suitable vector and same delivery system from Specific Aim 1, the effects of eNOS or iNOS gene transfer to either the coronary vasculature or myocardium of the donor heart on coronary arterial vascular reactivity and on CAV after heterotopic pig heart allotransplantation. NOS will be studied as the gene of choice as reduced nitric oxide bioavailability is characteristic of vessels undergoing CAV. Abnormal endothelium dependent relaxation precedes CAV, so that successful NOS gene transfer might be expected to impact on the early stages of the disease. Before gene transfer technology to the transplanted heart can progress to the clinic, satisfactory experience in a large animal model will be necessary. The porcine model is particular suitable from a physiological and pathological viewpoint and is also the animal of choice for future clinical xenotransplantation. Success in achieving the specific aims of this proposal opens up the potential for clinical gene therapy to avoid CAV after heart transplantation. Implications also exist for the application of these techniques for the modification of non-allograft arteriosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AIF-1 EXPRESSION IN VSMC GROWTH AND ARTERIOPATHY Principal Investigator & Institution: Autieri, Michael V.; Assistant Professor; Physiology; Temple University 406 Usb, 083-45 Philadelphia, Pa 19122 Timing: Fiscal Year 2002; Project Start 20-MAR-2001; Project End 28-FEB-2005 Summary: (Applicant's abstract): Vascular restenosis induced by arterial trauma is one of the most critical factors which limits the success o solid organ transplantation and coronary interventional procedures. A popular hypothesis is that the cytokine-induced

6

Heart Transplant

activation and proliferation of VSMC in the media, culminating in intimal hyperplasia, is the most critical cellular event in formation of both cardiac allograft vasculopathy (CAV) and balloon angioplastyinduced restenosis. Identification and functional characterization gene products involved in VSMC activation is a promising approach for the identification of targets to combat proliferative arteriopathy observed in vascular proliferative disorders. Our hypothesis is that allograft inflammatory factor-I (AIF-1) promotes development of vascular proliferative disease based on its ability to respond to inflammatory cytokines and participate in the growth stimulatory pathways leading to proliferation of VSMC. We have recently shown that modulation of AIF- 1 levels in human VSMC impacts the growth of these cells. The first aim of this project will determine the mechanism of AIF-l growth promoting effects in human VSMC through a combination of flow cytometric analysis and investigation of expression and turnover of cell cycle-associated proteins. We will also identify regions that mediate these effects by site-specific modification of the AIF- 1 protein. We have determined that AIF- 1 partners with several cytoplasmic proteins, including a newly described growth factor-activated lipid kinase termed LCBK5. The second aim of this proposal will determine the functional significance of the AIF- 1-LCBK5 interaction and characterize the other AIF-1interacting peptides we have identified. Expression of AIF- 1 transcript is induced in mitogen-stimulated peripheral blood lymphocytes (PBL), and its expression in endomyocardial biopsies from transplanted hearts correlates with ISHLT rejection scores. A final aim of this proposal will correlate AIF-1 transcript levels in endomyocardial biopsies and PBL from heart transplant recipients with development of arteriopathy as determined by several clinical and imaging indices. It is anticipated that completion of these studies will implicate expression of this novel protein as a target of anti-restenotic therapy and a surrogate marker of transplant restenosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APOPTOSIS

ALLOGRAFT

TOLERANCE

WITH

FAS/FASL-MEDIATED

Principal Investigator & Institution: Shirwan, Haval; Associate Professor; Microbiology and Immunology; University of Louisville University of Louisville Louisville, Ky 40292 Timing: Fiscal Year 2002; Project Start 15-DEC-2001; Project End 30-NOV-2005 Summary: Transplantation of vascularized allografts is an effective therapeutic alternative for patients with end-stage organ failure. Transplantation of organs between genetically different individuals, however, is limited by our ability to control the immunological rejection of the graft by the recipient. Immunosuppressive drugs may reduce the severity of rejection, but fail to create a state of permanent specific tolerance to the graft. We herein propose an immunomodulatory approach using a modified form of FasL with potent apoptotic activity to eliminate alloreactive T cells for the prevention of cardiac allograft rejection and induction of tolerance. FasL-induced apoptosis is the main mechanism of activation-induced cell death that is responsible for immune homeostasis and self-tolerance. The use of wild type (wt)FasL to prevent allograft rejection has been controversial. FasL is initially synthesized as a membranous molecule that induces apoptosis when prevention the cell surface. wtFasL is also shed from the cell surface by metalloproteinases within minutes of expression and the soluble form is antiapoptotic and chemotactic for neutrophils. We hypothesize that FasL can be used as an immunomodulatory molecule if its apoptotic activity is separated from anti-apoptotic and chemotactic functions. We generated modified forms of FasL with potent apoptotic activity and developed a novel approach to express FasL at the protein level on the surface of antigen- presenting cells (APCs) and vascular endothelium within 1 hour. In

Studies

7

preliminary experiments, we demonstrated that delivery of FasL on donor APCs blocked alloreactive responses in naive and presensitized animals and prevented islet allograft rejection. Expression of FasL protein on vascular endothelium under conditions adapted from clinical settings prolonged survival of cardiac allografts. In this proposal, rats and mice will be immunized with allogeneic APCs expressing FasL at various times pre-and post- transplantation. FasL will also be expressed on the surface of heart endothelium for immune evasion and prevention of rejection. Several mutant and transgenic animals will be used to test whether apoptosis induced by FasL is the main mechanism of the observed immune nonresponsiveness. This protein-based approach may be readily applied to the clinic and may provide a significant advantage because of its safety and simplicity as compared with immunomodulatory approaches using DNAbased expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AN ETHICAL ANALYSIS OF ORGAN ALLOCATION POLICIES Principal Investigator & Institution: Fox, Mark D.; Pediatrics; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): The purpose of this career development award is to enable Dr. Fox to develop the requisite skills to become an independent investigator, scholar, and resource in transplant ethics and policy. Through a structured program of didactic training and mentored research, the applicant proposes to develop an "evidence-based" ethical analysis of organ allocation policy, with specific reference to heart transplantation. This ethical analysis will be predicated on the development of skills in health services/outcomes research relevant to transplantation. The overall goal of this project is to provide an evidence-based ethical analysis of allocation policy informed by data regarding cardiac transplantation outcomes, and to determine if the impact of the policy changes enacted matches the stated goals of allocation policy. The fundamental hypothesis to be tested is that the changes in the allocation policy for heart transplantation have not produced outcomes consistent with the stated goals for transplantation. This hypothesis will be systematically pursued through the following five specific aims: 1) to develop methods for analyzing clinical outcomes for patients listed for cardiac transplantation in the United States, using the Scientific Registry of Transplant Recipients database; 2) to examine changes over time in the allocation policy regarding heart transplantation, with particular attention to how criteria defining medical urgency impact allocation decisions; 3) to evaluate the impact of changes in heart allocation policies with respect to various outcomes (pretransplant mortality, posttransplant survival, and the need for re-transplantation); 4) to examine differences in value assigned to possible outcomes, as reflected in preferences for allocation strategies, among patients and non patients, transplant professionals and other health care providers; and 5) to develop a policy analysis of other potential models for heart allocation to determine their clinical, political, and moral viability. Upon completion of the career development award, Dr. Fox will be able to function as an independent investigator in the interface between ethics and health services research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ANGIOGENESIS AND CHRONIC REJECTION Principal Investigator & Institution: Briscoe, David M.; Children's Hospital (Boston) Boston, Ma 021155737

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Heart Transplant

Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIMHC ANTIBODY EFFECTS ON ENDOTHELIUM AND MUSCLE Principal Investigator & Institution: Reed, Elaine F.; Professor; Pathology and Laboratory Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 01-JAN-1999; Project End 31-DEC-2007 Summary: (provided by applicant): Accelerated transplant arteriosclerosis (TA), a manifestation of chronic rejection, is the leading cause of graft failure. The development of anti-HLA antibodies to donor HLA antigens is a major risk factor associated with TA. The overall goal of this proposal is to elucidate the signal transduction pathways that mediate HLA class I induced cell proliferation and the development of TA. Under specific aim #1, we will establish whether anti-HLA antibodies induce tyrosine phoshphorylation of focal adhesion proteins and assembly of signaling complexes via an actin cytoskeleton dependent pathway in endothelium and smooth muscle. For this, we will establish whether exposure of cultured endothelial cells (EC) and smooth muscle cells (SMC) to monoclonal anti-HLA antibodies and anti-HLA antibodies from transplant patients with chronic rejection is accompanied by FAK phosphorylation and the generation of FAK/Src/Paxillin signaling complexes. We will determine if the phosphorylation of focal adhesion proteins is accompanied by alterations in the organization of the actin cytoskeleton and in the assembly of focal adhesions. We will explore the role of ROK, MLC phosphatase and ERK as upstream components of the class I signaling pathway. We will also determine if class I signaling stimulates antiapoptotic signals by inducing tyrosine phosphorylation of PI3-kinase, Akt and Bad. Under specific aim #2, we will identify the signaling pathways leading to MHC class I induced FGF receptor translocation in EC and SMC. For this, we will determine the role of the actin cytoskeleton, phosphorylation of FAK, Src, paxillin and assembly of focal adhesions in class I mediated FGFR translocation to distinct subcellular locations using flow cytometry and confocal microscopy. We will also assess the importance of ROK, ERK, MLC phosphatase in class I mediated FGF receptor translocation. The contribution of the FGF receptor tyrosine kinase activity and ERK phosphorylation to class I induced cell proliferation will be established. Under aim #3, we will assess the expression of class I induced tyrosine phosphorylation, FGF receptors and anti-apoptotic proteins in clinical biopsy specimens from cardiac allografts with and without evidence of transplant arteriosclerosis. We will determine the correlation between protein phosphorylation events and protein expression with the incidence and time of onset of transplant arteriosclerosis and development of anti-HLA antibodies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: APCS IN CHRONIC HEART REJECTION Principal Investigator & Institution: Rosengard, Bruce R.; Assistant Professor; Surgery; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-MAY-2001; Project End 30-APR-2004 Summary: (Verbatim from the Applicant's Abstract): Cardiac transplantation is established therapy for the treatment of end-stage heart failure. However, chronic rejection in the form of accelerated arteriosclerosis remains the primary cause of late

Studies

9

death after heart transplantation. Despite the development of several new drugs to combat rejection, the incidence of this form of chronic rejection has not changed. We have hypothesized that endothelial cells, which line coronary arteries, are capable of directly activating CD8+ T cells, which may play an important role in the development of graft vascular disease. We have established both in vitro and in vivo mouse models to study this process. The broad objective of this grant proposal is to define the differences in the ability of murine endothelium to activate CD4+ and CD8+ T cells in vitro and then to use analogous in vivo models to define the allorecognition pathways and effector mechanisms responsible for graft vascular disease. To achieve this goal, we will: 1. Test the hypothesis that endothelium activates both unprimed and primed CD8t T cells preferentially due to a less stringent requirement for costimulation. 2. Test the hypothesis that endothelium is a suitable target for CD8+ T cell cytotoxicity predominantly via the Fas/FasL pathway. 3. Test the hypothesis that graft vascular disease is a CDK about-dependent process. In summary, this proposal will determine whether endothelium has the capacity to stimulate CD8F T cells and the ability to act as targets for CD8+ cytotoxic T cells, which is sufficient to induce graft vasculopathy in a mouse model. Insights from this study will undoubtedly provide information that will lead to rational strategies to help prevent this lethal complication of human heart transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APPLIED GENOMICS IN CARDIOPULMONARY DISEASE Principal Investigator & Institution: Haponik, Edward F.; Professor of Internal Medicine; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2004 Summary: The Clinical Core will serve as the coordinating center for patient recruitment, specimen procurement and data base management. It is the mission of this Core to identify and provide disease-specific candidate genes from patients with such clinical disorders as acute lung injury, COPD, cystic fibrosis, asthma, pulmonary hypertension, pulmonary fibrosis, ischemic heart failure and both lung and cardiac transplant rejection. This core will also be responsible for the establishment of a Cardiopulmonary Tissue Repository that will maintain an archive of cryopreserved tissues and maintain an accurate data base of patient demographic and clinical data for correlation with biological end points produced by cDNA microarray. Following patient consent and registration, tissue samples and peripheral blood are delivered to the Core laboratory. The freezing facility will also serve as a repository for cyropreserved human lung and cardiac specimens. The Core Investigators will meet regularly to review all diagnostic materials on each specimen procured including histochemical stains and biopsies in order to determine a precise diagnosis and relevant demographic and clinical data for entry into the Project's data base which will include critical variables for the analysis of the biological data obtained. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: BIORAD ASPERGILLOSIS

GALACTOMANNAN

EIA

FOR

DIAGNOSIS

OF

Principal Investigator & Institution: Marr, Kieren A.; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 29-FEB-2008

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Heart Transplant

Summary: (provided by applicant): The Bio-Rad galactomannan enzyme immunoassay (GM EIA) will soon be submitted to the FDA for approval as an aid to diagnose aspergillosis, a frequent cause of infectious death in immunosuppressed patients. Our preliminary studies suggest that the assay may also be used as a screening test to enable early diagnoses; however, the optimal cut-offs for positivity have not been determined. Defining cut-offs to optimize performance is critical for patients who have different manifestations of infection (endobronchial vs. invasive), such as in solid organ transplant recipients, and in children, who appear to have frequent false-positive results. The studies proposed in this project will define parameters to use the GM EIA in multiple different patient populations, using clinical samples obtained from a large ongoing FHCRC longitudinal protocol in adult allogeneic hematopoietic stem cell transplant (HSCT) recipients, and samples obtained from multicenter trials sponsored by the NIH. Aim 1 will define parameters for use of the GM EIA as an early diagnostic test for aspergillosis in adult allogeneic HSCT patients. Studies will be performed to determine the lower limit of GM detection, identify clinical factors that impact levels of circulating GM, and to determine the role of GM EIA applied to non-blood fluids (bronchoalveolar lavage fluid and urine). Aim 2 will define appropriate cut-offs for positivity and characterize performance of the GM EIA as a diagnostic assay for aspergillosis in high-risk solid organ transplant recipients. To do this, longitudinal sample collection will be performed in a protocol conducted as a companion to an ongoing CDC-sponsored multicenter surveillance study. Aim 3 will define parameters for use of the GM EIA as an early diagnostic test for aspergillosis in neutropenic children. To determine the appropriate cut-offs for positivity in children, GM EIAs will be performed on serial sera obtained from children at high risk for aspergillosis after treatment with induction chemotherapy for AML, and after cord blood transplant. Companion protocols will be performed to collect sera as part of ongoing multicenter studies performed by the Children' s Oncology Group and the NHLBI Cord Blood Transplantation Study. Studies will be performed to determine if false-positivity of the GM EIA in children corresponds with gut translocation of GM during periods of mucositis, by measuring surrogate markers for GI integrity in a case-control study. This project is enabled by the cooperative activities of FHCRC investigators, Bio-Rad Laboratories, and several multicenter networks supported by the CDC, NIAID, and NHLBI. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CASPASE INHIBITION OF APOPTOSIS, INFANT CARDIAC SURGERY Principal Investigator & Institution: Mcgowan, Francis X.; Associate Professor; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2002; Project Start 01-JAN-2001; Project End 31-DEC-2005 Summary: (Verbatim from Applicant's Abstract): A major limitation to successful outcome of the repair of congenital heart lesions is the development of ventricular dysfunction. While the etiology is undoubtedly multifactorial, evidence suggests that it in large part may be due to myocyte loss resulting from chronic cyanosis, prolonged exposure to abnormal hemodynamic loads, and one or more episodes of ischemiareperfusion required for cardiac surgery. Death of myocytes can occur by either necrosis or apoptosis. In contrast to necrosis, apoptosis is the orderlv disassemblv of the cell by specific enzymatic pathways that are triggered by a wide variety of genetic, environmental and toxic stimuli. Recently, human and animal studies have shown that hypoxia, ischemia-reperfusion, abnormal mechanical loading, and inflammation can

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cause significant cardiomyocyte apoptosis. This occurs during myocardial ischemia, infarction, hypertrophy, and heart failure. The role of apoptosis in infants undergoing cardiac surgery is not known. Based upon this information and preliminary data from our laboratory, we believe that myocyte apoptosis is a significant problem in infants with normal and hypertrophied myocardium subjected to surgical ischemiareperfusion. This loss of myocytes will be particularly injurious to the infant myocardium because of the loads imposed by future growth and residual hemodynamic abnormalities. Because the pathways triggering apoptosis in this setting are multiple, we have chosen to focus on the role of the caspase enzymes. Caspases are the focal point of propagation and execution of apoptosis, and are directly responsible for the proteolytic cleavage of specific proteins required for the process to occur. Experiments in Aim I will be the first to l)define which caspases are expressed, activated, and what key intracellular proteins are thereby cleaved in normal and hypertrophied myocardium exposed to surgical ischemia-repercusion, 2)quantify the amount of apoptosis that occurs in this setting, and 3)determine the effects of specific caspase inhibition on these events. Using a novel working heart transplant model with normal and hypertrophied infant hearts, Aim II will answer a question of critical importance, namely what is the effect of inhibition of caspases and apoptosis on long-term myocardial inflammation, fibrosis, and recovery of function? These experiments will be the first to study the beneficial versus harmful roles of apoptosis in myocardial ischemia-reperfusion injury. Overall, these studies will provide valuable new insights into therapeutic targets and strategies to preserve myocardial function in these patients. The results are also likely to be applicable to patients with ischemia, myocardial infarction, and heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CCR2 AND CCR5--ATHEROSCLEROSIS AND CONTROL OF EXPRESSION Principal Investigator & Institution: Charo, Israel F.; Professor of Medicine; J. David Gladstone Institutes 365 Vermont St San Francisco, Ca 94103 Timing: Fiscal Year 2002; Project Start 15-JUL-1994; Project End 30-JUN-2003 Summary: (Adapted from the application) The overall goal of this proposal is to determine the role of chemokine receptors in vascular disease. Chemokines (chemotatic cytokines) specifically attract leukocytes by activating G-protein-coupled receptors. The investigators have focused their efforts on two of these receptors, CCR2 and CCR5, which were cloned in this laboratory and which are the major chemokine receptors on monocytes. During the first funding period, the investigators examined the structure/activity relationships of these two receptors with regard to ligand binding and signaling. The work proposed in the current application will extend these in vitro studies to in vivo models, taking advantage of our recent creation of a CCR2 knockout mouse. The first goal of the proposal is to determine the role of CCR2 in two forms of vascular disease: atherosclerosis and the accelerated arteriosclerosis of allogeneic cardiac transplants. The investigators will cross the CCR2-/- mice with apoE-/- mice and perform detailed atherosclerosis studies. The investigators will also perform heterotopic transplants of allogeneic hearts into the CCR2-/- mice and determine whether CCR2 plays a role in chronic myocardial rejection and transplant arteriosclerosis. The second goal is creating CCR2/CCR5 double-knockout mice. The investigators will selectively delete these receptors and simultaneously "knock in" lacZ under the control of the CCR2 promoter and green fluorescent protein (GFP) under the control of the CCR5 promoter. This approach will generate chemokine receptor knockout animals, as well as provide a sensitive means for detecting the endogenous in

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Heart Transplant

vivo expression of CCR2 and CCR5. Differential regulation of chemokine receptors clustered on chromosome 3 (3p21.3-24) may provide specificity in inflammation and immunity. The third goal is to determine the tissue-specific expression and transcriptional regulation if selected CC receptors. The investigators will use the hemizygous CCR2/CCR5 double-knockout mice (CCR2+/LacZ, CCR5=/GfP), as well as transgenic mice created with large fragments of human genomic DNA, to follow the expression of these two receptors in models of human disease. the experiments proposed in this grant will utilize novel and complementary approaches to provide the first detailed information on the role of chemokines and chemokine receptors in vascular disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CD28/B7 COSTIMULATION BLOCKADE-RESISTANT GRAFT REJECTION Principal Investigator & Institution: Hancock, Wayne W.; Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 15-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Failure to stem the incidence of chronic rejection continues to diminish the long-term benefits of transplantation. Experimental data suggest the importance of tolerance induction as a means to prevent chronic rejection and minimize drug toxicity, and blockade of CD28/B7 and/or CD154/CD40 can markedly prolong allograft survival, in some cases leading to permanent engraftment. However, costimulation blockade-resistant allograft rejection can still occur. This application is based around recently recognized CD28 and B7 homologs whose ligands are broadly expressed in peripheral tissues, and which likely regulate effector T and B cell responses. We will study the roles of ICOS/B7RP-1 and PD-1/PD-L1/PD-L2 in host alloresponses using murine models of cardiac and islet allograft rejection, thereby allowing consideration of rejection in primarily revascularized vs. non-revascularized grafts, as well as validation of heterotopic cardiac graft data in the more stringent, lifesupporting islet allograft system. Aim 1 will determine the mechanisms by which the ICOS/B7RP-1 costimulatory pathway can regulate T and B cells responses in allograft recipients in vivo, such that targeting of this interaction can diminish chronic rejection and promote tolerance induction. We will dissect the contributions of ICOS and B7RP-1 to T and B cell responses in wild-type as well as CD28- and CD154-independent responses. We anticipate these studies will provide key mechanistic insights into the importance of ICOS/B7RP-1 in ongoing host alloresponses, and how targeting of this pathway can best promote allograft tolerance. Aim 2 hypothesizes that tissue-specific immune responses are regulated by the PD-1/PD-L1/PD-L2 pathway, and we propose to analyze the extent to which manipulation of this pathway can facilitate long-term allograft survival. Our preliminary data show that stimulation of a negative signal through ligation of PD-1 can dampen host alloresponses, including those underlying costimulation blockade-resistant allograft rejection. We will expand these studies to dissect how interactions of PD-1 with its ligands can be promoted to achieve therapeutic effects in allograft recipients. Success in this work would provide a rationale for testing in non-human primates, and may ultimately improve the management and long-term results seen in patients undergoing organ transplantation or receiving islet allografts by promoting graft tolerance and decreasing the incidence of chronic rejection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CD4 T CELL DEPENDENT ACUTE CARDIAC ALLOGRAFT REJECTION Principal Investigator & Institution: Pietra, Biagio A.; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-AUG-2005 Summary: Numerous studies indicate that CD4 T cells are required for acute cardiac allograft rejection. However, the precise role for CD4 T cells in this response has remained ambiguous due to the multi-potential properties of this T cell subpopulation. We have recently demonstrated the capacity of CD4 T cells to serve as direct effector cells of cardiac allograft rejection. CD4 T cells are both necessary and sufficient for acute graft rejection as indicated by adoptive transfer experiments in immune-deficient SCID and rag-/- recipients. Acute CD4 T cell-mediated rejection requires MHC class II expression by the allograft, implicating the importance of direct graft recognition in this response. While CD4 T cells can serve as effector cells for primary acute cardiac allograft rejection via direct donor recognition, they can also serve as helper cells via the indirect response leading to the function of other graft-reactive lymphoid populations. The difficulty in examining the relative contribution of these CD4-dependent pathways to acute allograft rejection is that these responses normally occur simultaneously. In the adoptive transfer model systems proposed, the consequence of direct (donor MHCrestricted) and indirect (host MHC-restricted) CD4 reactivity can be studied independently. Thus, the overall goals of this proposal are to: (1) Clarify the nature of acute CD4-mediated cardiac allograft rejection via direct donor recognition, and (2) Clarify the pathway of 'indirect' CD4 reactivity that results in help for other graftreactive CD8 T cells and/or B cells. These general goals will be examined through the following specific aims: I) Define the recognition and costimulatory requirement(s) of direct CD4-dependent cardiac allograft rejection. This aim will test the novel hypothesis that antigen recognition and costimulation can be delivered by different APCs in vivo. II) Determine the effector mechanism(s) of CD4-dependent direct cardiac allograft rejection. This aim will test the hypothesis that direct, CD4-mediated rejection is cytokine-dependent in vivo. III) Determine the nature of indirect CD4 T cell 'help' for cardiac allograft rejection. This aim will test the hypothesis that indirect CD4 T cells can provide 'unlinked' T cell help for graft reactive CD8 T cells. The information obtained will be useful in understanding the basic immune mechanisms of human cardiac transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CD40 COSTIMULATION AND TRANSPLANTATION Principal Investigator & Institution: Perkins, David; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: (adapted from applicant's abstract) Following transplantation, acute rejection is recognized as the most frequent serious complication and the best predictor of chronic rejection, a major cause of long term graft loss. T cells are essential for initiating and maintaining acute rejection. Early intervention in transplant rejection necessitates understanding the mechanisms of T cell activation, as related to allograft survival. The principal investigator and others have found that blockade of CD40 signals prolongs graft survival. The goal of this proposal is to determine which CD40 regulated functions mediate graft rejection. CD40 signals are transduced by both NF-kB-dependent and independent mechanisms. The PI has found that in vivo inhibition of NF-kB activation

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Heart Transplant

with a dominant negative transgene or by deletion of c-Rel prolongs allograft survival. Thus, one focus will be on the role of CD40-regulated actions that are NF-kB-dependent. The investigators propose the hypothesis that blockade of the CD40/CD40L costimulatory pathway prolongs allograft survival by NF-kB-dependent mechanisms. To test this hypothesis, they will employ an adoptive transfer model of cardiac transplantation using double transgenic lines that express the DO11 TCR transgene, which is cross-reactive with I-Ab, plus null alleles of either CD40, CD40L, c-Rel, or IkBa (DN), a dominant negative inhibitor of NF-kB. Transfer of cells from these animals into Balb/c recipients of C57Bl6 cardiac grafts will provide a means to examine in vivo and in vitro the molecular mechanisms governing CD40/CD40L costimulatory effects. Aim 1 will determine the role of CD40 ligand signals on T cell activation, proliferation, unresponsiveness, and cytokine secretion. Aim 2 will determine the cellular mechanisms by which CD40 expressed on T cells regulates allograft rejection by mechanisms of activation and apoptosis involving FasL and TNF-a signals. Aim 3 will investigate the molecular mechanisms by which activation of NFkB controls allograft survival. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELLULAR BASIS OF CMV ACCELERATED VASCULOPATHY Principal Investigator & Institution: Nelson, Jay A.; Director & Professor; Molecular Microbiology and Immunology; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): The long-term goal of this project is to determine the role of viral pathogens in the development of vascular diseases such as atherosclerosis, restenosis, and transplant vascular sclerosis (TVS). All of these diseases are the result of either mechanical or immune related injury followed by inflammation and subsequent smooth muscle cell (SMC) proliferation and/or migration from the vessel media to the intima, which culminates in vessel narrowing. Clinical studies have directly associated human cytomegalovirus (HCMV) with the acceleration of TVS and restenosis as well as atherosclerosis. However, the mechanism(s) involved in the acceleration of vascular disease by HCMV is unknown. Studies by our group and others have implicated endothelial cells (EC), macrophages (MDM) and SMC as potential reservoirs of the virus in the host. Unfortunately, an animal model for HCMV is unavailable. However, mouse cytomegalovirus (MCMV) provides an ideal system to study mechanisms of pathogenesis and cellular tropism in the mouse model. Recently, we have developed a mouse heart transplantation model of TVS, which exhibits all of the hallmarks of human disease. We have also shown that CMV accelerates the progression and severity of TVS. Therefore, in this project we will utilize the mouse TVS model in combination with MCMV to assess the role of viral infection of MDM and EC on the acceleration of disease. In the first specific aim, we will utilize MCMV EC and MDM tropic mutants, which inhibit growth of virus in these cell types to assess the contribution of viral infection of these cells in the acceleration of TVS. In the second specific aim, we will utilize mice which specifically express Cre recombinase in EC and MDM in combination with recombinant MCMV that contain Lox sites which inactivate the virus in the presence of Cre enzyme to assess the role of MCMV replication in MDM and EC in the acceleration of TVS. In the last specific aim, we will examine viral mechanisms which accelerate TVS through ablation of MCMV genes which mediate inflammatory events. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CELLULAR MECHANISMS OF PTLD IN TRANSPLANT RECIPIENTS Principal Investigator & Institution: Martinez, Olivia M.; Associate Professor; Surgery; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-MAY-1997; Project End 19-SEP-2003 Description (provided by applicant): Post-transplant lymphoproliferative disease (PTLD) is a morphologically complex disorder that ranges from benign B cell hyperplasia to malignant lymphoma. Epstein-Barr virus (EBV) B cell lymphomas are the hallmark of PTLD and are associated with significant morbidity and mortality. During the previous funding period we identified specific signaling pathways that confer a survival advantage to EBV-infected B cells despite significant frequencies of EBVspecific CD8+ T cells in the circulation of transplant recipients. We also established that the immunosuppressive sirolimus (RAPA) can directly inhibit the growth of EBVinfected B cells. The objective of this research is to defme the immune alterations that contribute to the autonomous growth of EBV-associated B cell lymphomas. To accomplish this objective we propose four Specific Aims. In Specific Aim 1 we will determine the requirement for IL- 10 and its associated Jak/STAT signal transduction pathway in sustaining the growth of EBV-infected B cells. Dominant negative (DN) forms of the 1L-lO receptor (IL-1OR), STAT1 and STAT3 will be transduced into EBVinfected B cells using a lentivirus-based retroviral transduction system to evaluate the effect on cell growth. A SCID mouse model of EBV+ B cell lymphoma will be used to test the effect of blockade of IL-lO on tumor growth. Specific Aim 2 will examine the mechanism by which EBV-infected B cells are resistant to death receptor-induced apoptosis. The proximal events in the Fas and TRAIL-DR4/DR5 cell death pathways will be characterized by two-dimensional gel electrophoresis and DNA microarray. The role of the decoy receptors DcR1 and DcR2 in resistance to TRAIL cytotoxicity will be examined. The contribution of the EBV latent genes LMP1 and EBNA2 to resistance to apoptosis will also be determined. In Specific Aim 3 MHC/peptide tetramers containing immunodominant epitopes of EBV antigens will be used to identify EBV-specific CD8+ T cells in transplant recipients and the functional properties of these T cells will then be assessed. The effects of immunosuppression on the generation of functional EBVspecific CD8+ T cells will be determined in the SCID/EBV B cell lymphoma model. Aim 4 will determine the mechanism by which RAPA inhibits growth of EBV-infected B cells with specific focus on apoptosis, cell cycle proteins and the JakISTAT pathway. Elucidation of the immune mechanisms involved in PTLD will provide novel opportunities for treatment of this serious disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMPARATIVE APPROACH TO GENOMICS OF COMPLEX TRAITS Principal Investigator & Institution: Goldschmidt-Clermont, Pascal J.; Professor and Chair; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant) The determinants of genetic susceptibility for most common traits are complex, likely to involve contributions from multiple gene variants. These variations in gene function that affect critical phenotypes can represent amino acid replacements as well as extragenic differences that might affect expression levels; in most instances, these are single nucleotide polymorphisms (SNPs). Although one would like to assay for these gene variants in a completely unbiased fashion, ultimately measuring the contribution of every variant of every gene, this is obviously impractical at this point in time. An alternative strategy is to identify those genes most likely to

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Heart Transplant

make contributions to disease variation, identify the variations within this group of genes, and then conduct association studies to link gene variants with disease phenotype. Using cardiovascular disease as a model system, this proposal describes a multi-dimensional approach to this overall problem. In particular, we will use multiple methods for the identification of candidate genes most likely to make contributions to disease variation within populations of patients. This work will take advantage of three unique clinical resources here at Duke. First, we have begun the collection of a large series of aorta samples from heart transplant donors as a source of vascular tissue for gene expression analysis. These samples are unique in the volume of the samples (hundreds) as well as the range of phenotype: early stages of atherosclerosis to advanced forms of the disease. As such, it provides an opportunity to match gene expression profiles with the development of disease in a very unique way. This will be the focus of work in Component 1 as well as statistical efforts in Component 5. Second, a large study of the genetics of early onset cardiovascular disease, representing a collaboration between Duke investigators and GlaxoSmith-Kline, offers the opportunity to identify loci that are linked with the development of disease. This provides a mechanism for the identification of additional candidate genes without any bias whatsoever, including whether the gene actually functions within cardiovascular tissue or not. This represents the focus of Component 2, and bioinformatic efforts in Component 6. The combined efforts of Component I and 2, taking different approaches to the identification of candidate genes, will then be the source of substrate to discover SNPs within this group of genes (Component 3). Much of this work will take advantage of existing information regarding SNPs as well as other major studies directed at cardiovascular disease. But, it will also necessitate efforts within this component to identify as exhaustively as possible those sequence variants that can then be the subject for assays in clinical populations. Third, and possibly the most important asset of this program, is the Duke Cardiovascular Database, an effort initiated some thirty years ago at Duke to follow the clinical course of every cardiovascular disease patient. As such, we now have access to over 40,000 patients who are being followed on a regular basis, creating a clinical dataset that is unmatched. This clinical dataset provides a completely unique resource for this study, both from the quantity as well as the quality of patient clinical data to allow the validation of candidate gene variants with disease variation. Thus, the SNPs identified in Component 3 will go into an expansive genotyping program (Component 4), to bring these candidate genes to a point of validation. A major challenge in an undertaking of such magnitude will be the statistical power to find associations in complex situations. Component 5, will develop the methodologies for understanding the complex gene expression datasets, will also develop the statistical approaches to the analysis of the complex genotyping studies. The program will also enhance and integrate with existing and developing educational programs in bioinformatics and genome technology at Duke (Component 6). This synergy will be of clear benefit to the program, bringing in talented investigators from multiple disciplines in each area critical for the program. Hence, our project will advance the frontiers of genome sciences and technology in the field of common traits. The culmination of our program will provide essential tools to clinicians to improve risk stratification of patients and to design novel preventive and therapeutic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--CLINICAL AND PATHOLOGY Principal Investigator & Institution: Rodriguez, Rene E.; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008

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Summary: (provided by applicant) The Clinical/Pathology Core will continue to coordinate the collection of tissue and blood samples at the time of transplantation and at the time the allograft is biopsied. Tissues from the explanted hearts and from selected endomyocardial biopsies will be collected. Blood/plasma samples will be collected from donor, recipient, blood bank, and from the spouse of the recipient at the time of transplantation. In addition, this core will act as the repository for all the relevant clinical data in support of these tissue samples. This core will examine the collected tissue and blood samples using general histology, routine immunohistochemistry and specialized coagulation assays in support of individual projects. Finally, this core will provide non-routine noninvasive analyses. Cardiac surgeons at Johns Hopkins have transplanted 337 hearts into human recipients during the last 18 years (to 8/31/01) and the demographics of these recipients are: by gender-93 female, and 244 male; by race- 39 African American, 291 Caucasian, and 7 other; and by age-29 children and 308 adults. During the current period of this program project 86 hearts were successfully transplanted (by gender-29 female, and 57 male; by race-23 African American, 57 Caucasian, and 6 other; and by age-4 children and 82 adults). After transplant, surveillance endomyocardial biopsies are performed every 10 days for the first month, every 14 days for second month, every month for months 3 to 6, and every 4 to 6 months, thereafter. Additional endomyocardial biopsies are performed when the symptoms dictate. 180 heart transplant patients were followed during the most recent year (9/1/00-8/31-01) and 600 endomyocardial biopsies were performed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--HISTOPATHOLOGY Principal Investigator & Institution: Sedmak, Daniel D.; Professor and Chair; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: Chronic allograft rejection is the leading cause of renal and cardiac allograft failure. The Long term goal of this core is to assist investigators in acquiring the experimental data necessary for the successful investigation of this disease process. In this program project human cardiac biopsies will be extensively utilized, as well as murine cardiac grafts, for the investigation of chronic rejection; however, meaningful studies with model will require the use of standardized tissue sections, special stains, and quantitative morphometric measurements. Therefore, the short term goals of the Histopathology core are to provide a centralized and standardized histology, immunohistochemistry, and automated morphometric analysis service for all projects. As a central core service it will guarantee a high level of uniformity, consistency and quality that will facilitate comparison of experimental results between the three program projects. The Specific Aims are to (1) provide a central histopathology laboratory for all projects, (ii) provide a central immunohistochemistry laboratory for the detection of disease-related antigens in frozen or formalin-fixed tissues, (iii) provide an automated image analysis and morphometrics service that will provide consistent and uniform measurements of transplant vascular sclerosis and myocardial fibrosis in murine heterotopic heart transplants and human explanted heart autopsy specimens, and (IV) provide a laser capture microdissection (LCM) service that will provide morphometric-like cell populations from thin sections of formalin fixed paraffinembedded or frozen tissues of both animal and human tissues for molecular analysis. The core will be located in The Ohio State University Medical Center and utilize the preexisting Department of Pathology laboratories. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--HUMAN CARDIAC TISSUE REPOSITORY Principal Investigator & Institution: Rodriguez, E Rene.; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: Human Cardiac Tissue Repository Core. To study the immunopathogenesis of human cardiac allograft arteriosclerosis (GA), the Human Cardiovascular Tissue Repository will continue to build on the highly successful existing tissue bank established at Hopkins. The functions of the core will be: 1. To banked fresh-frozen tissues include sections of myocardium and coronary arteries. The number of hears from patients undergoing a re-transplantation have steadily been in the range of 5-15% of all hearts transplanted (average 30 hearts per year) at Hopkins during the last 10 years. The infrastructure in place for this core allows for procurement of human hearts at the time of surgery. Cardiac tissues are triaged and processed immediately as needed by the different projects in this proposal (e.e. freezing, cell culture, organ culture) by a cardiac pathologist as part of the evaluation of the specimen. In addition to the fresh and frozen tissue repository, there is formalin-fixed paraffin- embedded tissue from human heart transplant recipients, which currently includes over 6,000 heart biopsies, 54 autopsies and 223 explanted hearts, including 24 explanted from heart transplant recipients who were re- transplanted because of allograft vasculopathy in their first grafts. 2. Another function of this core be to provide clinical data striped from any identifies to individual investigators. These database is supported by departmental funds and are provided free to the Core. 3. Comprehensive pathologic examination of the tissues will be performed with advanced pathologic techniques in our facilities at Hopkins Molecular Pathology, tissues will be performed with advanced pathologic techniques in our facilities at Hopkins Molecular Pathology, Research Immunohistochemistry, and Research Histology laboratories. 4. Cardiac allograft arteriosclerosis lesions will be microdissected and analyzed with an array of ProteinChips/TM to identify protein expression alterations in the allograft important mechanism in the pathogenesis of cardiac allograft arteriosclerosis. Accordingly, the proteomics core will focus on the role of IFN-gamma and the molecules that both, regulate IFN-gamma and are regulated by IFN-gamma, leading to proliferation of TH1 cells. The proteomics core will correlate expression of molecules identified in projects 1, 2 and 3 taking advantage of phage-peptide-display libraries and candidate gene sequences identified in core E (RNA microarrays). Core D will microdissect cells from human coronary arteries. Microdissection will allow the comparison of the proliferative cell component present in the intima of GA vessels with musculopathy and smooth muscle cells from the media of transplant arteries and controls. The power of the proteomics analysis with the ProteinChipTM technology is that femtomolar amounts of proteins can be identified, thus requiring only a few hundred to a few thousand cells from human arteries to obtain protein expression information. The integration of this core with the projects in this proposal will provide scientific basis to develop effective approaches to early diagnosis of GA and provide information of possible targets for early therapeutic intervention, which is crucial to lengthen the longevity of the allograft. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RECIPIENTS

COSTIMULATORY

PATHWAYS

IN

SENSITIZED

GRAFT

Principal Investigator & Institution: Kupiec-Weglinsky, Jerzy W.; Professor; Surgery; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024

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Timing: Fiscal Year 2002; Project Start 01-APR-1988; Project End 31-MAR-2007 Summary: (provided by applicant) Transplant patients sensitized to allo-Ag may undergo "accelerated" rejection (AccR), which combines cell and humoral immune mechanisms. We have developed a model of cardiac allograft rejection in skin sensitized mice (B/c- B6; rejection in <36h). We will study the role and mechanisms of CD154CD4O T cell costimulation in host sensitization. These studies are important for: (i) further understanding the allograft rejection cascade in sensitized hosts; and (ii) defining novel mechanisms that may improve the long-term effects of CD154 blockade. We propose the following specific aims: (1). Analyze mechanisms by which CD154 blockade prevents AccR. Hypothesis: Inhibition of CD8+ T cell activation represents the principal mechanism of the CD154 blockade in sensitized hosts. First, we will use 2C TCR Tg system to dissect the mechanisms by which CD154 blockade prevents CD8+ T cell activation in sensitized hosts. Then, to test the functional significance of CD8+ T cell defect, we will compare the rejection process in sensitized WT hosts with or without CD4/CD8 effector branch depletion. Using T cell subsets or APCs alone or in combination from WT mice will test the restoration of graft rejection in CD154 KO recipients. We will determine whether activated CD8+ effectors (CD44high CD62Llow) alone can trigger accelerated rejection in naive CD154 KO hosts. We will delineate in vitro cross-talk between cell subsets after CD154 blockade that prevents CD8 T cell activation/differentiation. (2). Determine mechanisms by which CD1 54 blockade fails to prevent graft vasculopathy leading to chronic rejection. Hypothesis: Long-term allograft survival after CD154 blockade may be impaired by: (i) CD4-dependent afloreactive B cells, andior (ii) CD154-resistant or preexisting memory CD8 T cells. First, we will analyze serum alloreactive Ab levels and intragraft Ab deposition. The functional role of anti-donor Abs will be assessed in passive transfer studies (SCID). Then, we will determine the function of alloreactive B cells in vitro (ELISPOT) and in vivo (CD154 blockade in WT vs. B cell KO mice). The requirement of CD4 help for alloreactive B cells will be addressed in CD4 KO/CD4 mAbtreated WT mice. In parallel, we will study activation of resistant CD8+ and preexisting memory CD8+(CD44high CD62Llow T cells during the C0154 blockade by using GM1 marker and 2C ICR Tg system, respectively. (3). Investigate STAT4 vs STAT6 mediated mechanisms and the role of regulatory CD4+ T cells in CD154 blockade. Hypothesis: STAT6 signaling is important for the generation of regulatory CD4+ T cells to inhibit alloreactive residual CD8+ T and B cell responses after CD154 blockade. We will analyze the ability of CD154 blockade to affect early/ late allograft loss in WT, STAT4 vs. STAT6 KO mice. Proliferation, differentiation, and cytokine production by CD4+ and CD8+ I cells will be examined. We will establish the identity of regulatory CD4+ T cells, and determine their function in adoptive transfer experiments. STAT6-dependent mechanism will be further delineated after administration of regulatory CD4+ T cells into: (i) WT host + neutralizing lL-4/IL-10 mAb, and (ii) untreated STAT4 KO or STAT6 KO test mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOKINE TRANSPLANTATION

REGULATION

IN

MURINE

CARDIAC

Principal Investigator & Institution: Bucy, R Pat.; Professor; Pathology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-JAN-1994; Project End 31-DEC-2003 Summary: (Adapted from the applicant's abstract) The broad objective of this application is to examine the population dynamics of individual antigen-specific T cells during the rejection of a cardiac allograft and the development of allograft tolerance.

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Heart Transplant

The application plans detailed examination of the allograft and lymphoid tissues in recipient mice using conventional morphologic examination, a series of immunohistochemical studies using monoclonal antibody staining, an extensive panel of in situ hybridization studies focused on cytokine gene expression, and correlative analysis of cytokine gene expression using QC-RT-PCR. The primary system for analysis will be adoptive transfer of CD4 positive T cells with single antigen-specificity into immunodeficent syngeneic mice, such as SCID or rag knockout animals, that are transplanted with an alloantigenic cardiac graft. The first specific aim is to determine whether the mechanisms of rejection vary dependent on cytokine expression pattern and TCR-specificity and avidity in adoptive transfers of T cells into transplanted mice. Both T cell clones and TCR-transgenic T cells using alloreactive TCRs will be used for these studies. The roles of precise TCR specificity in the cytokine gene expression pattern by particular T cells can be distinguished using adoptive transfer of TCR transgenic cells differentiated in vitro into distinct functional subsets. The second specific aim is to produce several transgenic mice which express an immunoregulatory molecule under the control of a cardiac-specific promoter to probe the role of the allograft histological microenvironment on the progress of the immune response mediated by different kinds of T cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOKINES AND COMPLEMENT IN NEPHRITIS AND COLITIS Principal Investigator & Institution: Lin, Feng; Pathology; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 31-JAN-2006 Summary: (provided by applicant):This proposal is for a three year training program at Case Western Reserve University (CWRU) for the development of a career in academic experimental immunology. The principal investigator, a Ph.D. in molecular biology who is now completing postdoctoral training in molecular immunology, will expand upon his skills and transition to independent research through an integrated program involving further work with his mentor and other investigators.The program will expand knowledge in the interplay of complement activation and cytokine generation in the settings of digestive and particularly renal diseases and in therapeutics in animal models. Dr. Edward Medof will mentor the PI's scientific development. He is a recognized leader in complement regulatory proteins that protect self tissues from complement attack, and pioneered research in the decay accelerating factor (DAF), the first of these to be described. He is a Professor in Pathology, is Associate Director of the CWRU Immunology Postdoctoral and Predoctoral Training Programs, and has trained numerous postdoctoral fellows and graduate students. To enhance the training, the program will include Dr. Steven Emancipator, Professor of Pathology, an authority in immunological diseases of the kidney, Dr. Alan Levine, Associate Professor of Medicine, a recognized expert in cytokines and inflammatory bowel disease, Dr. David Salant, Chief of Nephrology at Boston University, a world renowned expert in antibodyinduced renal diseases, and Dr. Peter Heeger, an expert of cellular immune mechanisms. Additional faculty will provide scientific and career advice.Research will focus on inflammatory mediators that are generated in experimental models of inflammatory bowel disease and particularly nephritis. The applicant has generated a DAF knockout mouse and shown that in the absence of DAF, tissue injury is greatly enhanced in nephrotoxic serum-induced nephritis and dextran sulfate sodium-induced colitis and in delayed, possibly NK cell-mediated allograft rejection. Specific aims are to 1) define the patterns and site(s) of cytokine production in the two disorders and characterize the

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mechanism of allograft rejection, 2) investigate these issues in related diseases, and 3) explore the effects of targeted recombinant DAF modules on disease pathogenesis. The results will constitute the first in vivo analysis of the interplay between complement activation and cytokine production, and could have therapeutic benefits.The integrated research activities at CWRU encompassing Pathology, Medicine, and the Biomedical Sciences Training Program incorporate diverse expertise and a full range of state-of-theart facilities that provide an ideal setting for training in specific programs. It should maximize the opportunity for a promising young scientist to develop a niche for an independent career. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEFINING THE MECHANISM OF DELAYED XENOGRAFT REJECTION Principal Investigator & Institution: Chong, Anita S.; Associate Professor; Rush University Medical Center Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-JUN-1999; Project End 31-AUG-2002 Summary: (adapted from the applicant's abstract) The inadequate supply of human organs has created a strong interest in the use of non- primate organs for clinical transplantation, but vigorous immune reactions prevent their current use in humans. Recent genetic approaches have generated porcine organs that are significantly resistant to complement-mediated hyperacute rejection. Nonetheless, they elicit a significant immune response in primates or humans and are ultimately rejected in a process labeled delayed xenograft rejection (DXR) or acute vascular rejection (AVR). DXR/AVR is predominantly mediated by xenoreactive antibodies (XAbs) that bind to and cause endothelial cell activation in the xenograft. Remarkably, the natural and the elicited XAbs that mediate the rejection of porcine grafts in human and Old World monkeys are directed predominantly against a single carbohydrate epitope, galactose-alpha1,3galactose (alphaGal). Opportunities to study the immunological basis of anti-alphaGal antibody production in a xenotransplantation setting have been limited, historically, to humans and Old World monkeys, since all other mammals do not make anti-alphaGal Abs. However, the recent generation of alpha1,3galactosyltransferase knockout (GT-KO) mice, which do not express the alphaGal epitope and can spontaneously make antialphaGal Abs, has provided a new model system for a reductionist approach to studying alphaGal-mediated xenotransplant rejection. Using these mice, the investigators propose (1) to use in vivo and ex vivo approaches to define the B cell subsets producing natural and elicited anti-alphaGal Ab responses; (2) to define the role of cytokines in regulating anti-alphaGal Ab responses and xenograft rejection; and (3) to control anti-alphaGal Ab responses and xenograft rejection using pharmacological and biological immunosuppressants, then use in vivo and ex vivo approaches to define the immunological basis for the successful control. The investigators propose that these studies will lead to an improved understanding of the immune regulation of antialphaGal responses and of xenograft rejection, and ultimately to the development of new genetic and/or immunosuppressive strategies that allow xenografts to survive and function in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DENDTRITIC CELLS, APOPTOTIC BODIES & TRANSPLANT TOLERAN* Principal Investigator & Institution: Morelli, Adrian E.; Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260

22

Heart Transplant

Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant): Acute allograft rejection occurs mainly because recipient T lymphocytes mount a vigorous specific immune reaction against donor allogeneic (allo) antigens (Ag). DC are the professional Ag presenting cells (APC) that as "passenger leukocytes" present the allo-Ag to recipient naive T cells and trigger graft rejection. However, DC are also involved in the induction/maintenance of Ag-specific self-tolerance. There is evidence that certain APC (macrophages and likely DC) increase production of the immunoregulatory cytokines interleukin (IL)-10 and transforming growth factor (TGF)beta1 after ingestion of apoptotic bodies. We propose to test the hypothesis that recipient DC, after interaction with donor major histocompatibility complex (MHC)+ apoptotic bodies in the appropriate extracellular environment, are able to generate T cells with regulatory function. We propose to employ this approach to induce Ag-specific tolerance in heart allograft recipients as an alternative to pharmacological treatments that induce generalized immunosuppression and severe side effects. To reach these goals we propose the following aims. AIM 1: To investigate the effect of apoptotic bodies on the phenotype, synthesis of cytokines, and T helper (Th)-driving capacity of DC in vitro. We will develop a phagocytosis assay of apoptotic bodies for mouse DC to analyze the phenomenon and molecules involved. We will analyze the phenotype and pattern of cytokines synthesized by DC under such conditions and the impact on the subset of Th lymphocytes induced. AIM 2: To characterize the T cell stimulator's function and the Th-driving capacity in vivo of DC exposed to apoptotic bodies. Our purpose is to learn how DC exposed to apoptotic bodies can regulate, in vivo, the outcome of a T cell response from Ag-specific immune reactivity to potential Ag-specific tolerance. AIM 3: To evaluate the effect of recipient DC exposed to donor MHC+ apoptotic bodies on heart allograft survival. After focusing on the influence of DC exposed to apoptotic bodies on alloimmune responses in normal hosts, we will investigate their role in allogeneic heart graft recipients. The results may provide new insight into how apoptotic bodies can modulate the Th-driving capacity of DC and determine the therapeutic potential of DC and apoptotic bodies in transplant tolerance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DONOR CELL FACILITATION OF TOLERANCE Principal Investigator & Institution: Strober, Samuel; Professor of Medicine; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 15-MAR-1995; Project End 31-MAY-2005 Summary: (Adapted from the Investigator's abstract): In the first four years of this project, the investigators have shown that rat ACI vascularized heart allografts are accepted by Lewis hosts with a combination of TLI, ATG, and intravenous injections of donor cells. With one model, the results showed that donor cells, such as monocytes and dendritic cell precursors, with surface expression of class II MHC molecules but with incomplete expression of co-stimulatory molecules such as B7-1 and B7-2, were potent facilitators of nonchimeric tolerance, based on immune deviation rather than on clonal anergy or clonal deletion. In a second model, donor cell infusions containing hematopoietic stem cells, such as bone marrow, were potent facilitators of chimeric tolerance, which was best explained by clonal anergy or deletion. Tolerance required both an alteration of the host immune system by the preparatory regimen and the injection of an appropriate donor cell population in both models. Additional data show that NK1.1+ T-cells are an important component of the host tolerance response. In particular, these cells seem to be important for the production of IL-4 that is required for

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tolerance. The studies proposed here will test the hypothesis that TLI causes an increase in NK1.1+ T-cells, such that they become the predominant subset of T-cells in the spleen; that activation of the host NK1.1+ T-cells, and their secretion of IL-4, is required for the induction of tolerance; and that donor cells that facilitate tolerance activate host NK1.1+ T-cells by donor cell expression of CD1. In order to test the hypothesis further, they will use mice that lack NK1.1+ T-cells (CD1 or Jalpha281 KO) or lack specific cytokines (IL-4 KO, IL-10 KO, IFNgamma KO). In addition, they will use donor mice that lack specific antigen presenting molecules (CD1 KO, MHC Class II KO). They propose to study the role of NK1.1+ T-cells and their IL-4 secretion in tolerance by TLI, TLI plus ATG, and a depleting anti-CD4 mAb in a heart transplant model. They will also study GVHD using similar hypotheses and models. Mice tolerant of their allografts will be observed for evidence of immune deviation, clonal anergy or deletion, chimerism, and allograft expression of cytokine mRNA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DONOR-SPECIFIC T CELL MEMORY: BARRIER TO TOLERANCE Principal Investigator & Institution: Pearson, Thomas C.; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): Transplantation has emerged as the preferred method of treatment for many forms of end-stage organ failure. While short-term results have, improved long-term outcomes remain inadequate. The development of strategies to promote the long-term acceptance of allogeneic tissues without the need for chronic immunosuppression, which defines transplantation tolerance, could greatly expand the application of organ, tissue and cellular transplantation for diseases such as the hemoglobinopathies, genetic immunodeficiencies, and possibly autoimmune diseases. However, transplantation tolerance has remained an elusive goal in clinical transplantation. It has been known for many years that mixed hematopoietic chimerism induces a state of specific immunological tolerance, and in recent years it has been shown that this goal can be achieved in mouse models using clinically relevant costimulation blockade based strategies. While there are many practical issues that must be addressed for tolerance induction to become a clinical reality, we believe that the strategy must provide a means to control the existing population of donor-specific T cells in the periphery. This includes the control of memory cells that may persist in an individual as a result of previous antigen exposure. An understanding of the memory cell population is critical; both to prevent these cells from being a barrier to tolerance induction, as well as maintaining their function posttolerance induction to prevent infectious complications in transplant recipients. The specific aims of this study are to: (1) To characterize the number, distribution, phenotype and function of allospecific memory T cell subsets generated after skin or cardiac transplantation in the mouse; (2) To determine the number, subset and phenotype of allospecific memory T cells that prevents, the induction of chimerism and tolerance using the CD2B/CD40 blockade and micro-conditioning tolerance induction protocol; (3) To define strategies to tolerize allospecific CD4 and CDB memory populations by (a) blockade of alternative costimulatory pathways, or (2) manipulation of the signal 3 pathway. The results of this study will be critical for the development of safe strategies for the induction of transplantation tolerance to address the great clinical need. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Heart Transplant

Project Title: FUNCTION

ECHOCARDIOGRAPHIC

EVALUATION

OF

ENDOTHELIAL

Principal Investigator & Institution: Villanueva, Flordeliza S.; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-AUG-1997; Project End 30-JUN-2006 Summary: (provided by applicant): Coronary artery disease is the major cause of mortality in the United States. Although many patients come to medical attention because of hemodynamically significant coronary lesions, over one-half who die suddenly from coronary disease have had no pre-existing symptoms. It has been hypothesized that critical abnormalities in the coronary endothelial lining provide a milieu that ultimately promotes acute thrombotic occlusion in the absence of significant prior coronary stenoses. Moreover, in patients with angina due to severe stenoses, endothelial abnormalities likewise promote the development and progression of atherosclerotic plaques that culminate in acute ischemic syndromes. Aberrations in endothelial function in coronary disease involve the microcirculation and occur in other cardiovascular disease states such as heart transplant rejection and ischemiareperfusion. Endothelial dysfunction is thus a critical mediator of the total burden of atherosclerotic heart disease and a major component of other cardiovascular pathologies, and the identification and treatment of this phenomenon would confer significant health benefits. Unfortunately, methods to identify patients with early endothelial dysfunction are limited. Studies have shown that endothelial overexpression of leukocyte adhesion molecules such as intercellular adhesion mnolecule-1 (ICAM1) promotes the development of the earliest lesions of atherosclerosis, suggesting that ICAM1 can serve as a marker of incipient endothelial disease. Using perfused cultured human coronary artery endothelial cells (ECs), we recently proved the principle that gas-filled microbubbles conjugated to a ligand that binds specifically to ICAM1 adhere to interleukin1a-activated ECs overexpressing ICAM1. Because these bubbles are acoustically active in the presence of ultrasound, we hypothesize that in vivo ultrasound imaging of bubbles targeted to specific cell surface markers of endothelial activation such as ICAM1 will permit non-invasive identification of pre-clinical endothelial dysfunction. To test this hypothesis, in vitro and in vivo models of endothelial activation will be used to address three Specific Aims with respect to bubbles engineered to bind to cell surface markers of endothelial disease: (1) Define shear conditions under which ICAM1-targeted bubbles attach to ECs and optimize bubble characteristics for binding; (2) Identify other EC surface proteins specific for endothelial dysfunction, including selectins, vascular adhesion molecule-1, or vascular endothelial growth factor receptors, evaluate their suitability as imaging targets, and design microbubbles for these targets; and (3) Image and quantify targeted bubble adhesion in vivo under clinically relevant conditions. The ultimate goal of this proposal is to develop targeted ultrasound imaging in order to enhance the early diagnosis of ischemic heart disease or other cardiovascular disease states associated with endothelial dysfunction. Principles gleaned from these studies can be extended to function-specific ultrasound imaging of other targets such as angiogenic markers, and may also provide a basis for targeted therapeutic approaches using microbubble carriers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT OF FOLIC ACID AND VITAMIN B6 ON HOMOCYSTEINE Principal Investigator & Institution: Schirch, Laverne G.; Biochemistry; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 01-MAY-2000; Project End 31-JAN-2005

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Summary: Elevated homocysteine (Hcy) in the blood is an established risk factor for cardiovascular disease. Increases in dietary folate and B6 have been shown to lower Hcy levels. There are however, certain groups with other health problems where Hcy remains elevated, these include heart transplant recipients, diabetics, women with preclampsia or retarded fetal growth, end stage renal disease and Parkinson's disease. The aim of this proposal is to elucidate how nutritional insufficiency of folate and B6 affect the pathways of Hcy metabolism in mammalian cells. There are four specific aims: (1) the development of rapid enzyme-based assays for 5,10-methyleneTHF, B6 vitamers and homocysteine; (2) to determine the direction of flux of 1-carbon (1-C) groups in the cytosol and mitochondria of cells in culture, with special emphasis on serine hydroxmethyltransferase (SHMT); (3) to determine the role of mitochondria in the supply of 1-C groups to the cytosol; and (4) to determine the relationship of folate pools and metabolic levels of homocysteine with several different cell lines when either folate or B6 are limiting growth factors. Three hypotheses will be tested, which are: (1) that the role of cytosolic SHMT is not to generate 1-C units but to regulate the levels of glycine and 5,10-methyleneTHF in the cytosol; (2) that 1-C groups used by the cytosol are generated by the mitochondria as formate; and (3) Hcy levels are related to the level of 5,10-methyleneTHF in the cytosol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FAS LIGAND+ BLOOD CELLS TO REDUCE TRANSPLANT REJECTION Principal Investigator & Institution: Civin, Curt I.; Professor of Cancer Research; Oncology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant): The ability to stably transduce lymphohematopoietic stem-progenitor cells (HSCs) and progeny cells allows us to genetically engineer HSCs and progeny, especially dendritic cells (DCs), to serve as cellular tools to improve transplantation. Allogeneic (allo) blood and marrow transplantation (BMT) will continue to be an important treatment option in patients with many inherited and acquired diseases. Our recent Preliminary Results indicate that ex vivo or in vivo treatment with transduced FasL+ allog mouse DCs or HSCs suppressed the response to that alloantigen and increased engraftment of allo cells, without immunoablation or evident toxicity to the recipient mice. In Aims 1-2 of this proposal, we propose studies to test the concept and elucidate the principal mechanisms by which transduced DCs or HSCs constitutively expressing Fas ligand (FasL) appear to reduce the T (and NK) cells that mediate graft rejection without overwhelming organ toxicity or general immunologic impairment. Aims 1-2 attempt to accelerate and enhance the natural homeostatic role of FasL during the course of the alloimmune response, with the potential outcome that alloimmune T cells may be killed earlier in their activation/expansion, or killed more potently later during activation-induced cell death (AICD), by transduced FasL+ DCs (Aim 1) or HSCs/progeny (Aim 2), respectively. As we investigate this, we will examine the apoptotic pathways in alloimmune cells. In addition, since we expect that transduced FasL+ HSCs might potentially be toxic in vivo, we will in parallel investigate technologies to limit potential FasL toxicity, eg by transducing only a small percent of high quality HSCs, by employing a FasL deletion mutant that cannot be cleaved to release soluble FasL (sFasL), by eliminating the transduced cells themselves or their FasL expression after tolerance to HSCs has been generated, or by using lineage/stage-specific promoters to restrict FasL expression. A novel FasL+ cell therapy approach to reduce graft rejection may

26

Heart Transplant

eventually be used in clinical allo BMT. Furthermore, achievement of stable lymphohematopoietic chimerism would also be predicted to generate tolerance for transplanted allo organs or pluripotent stem cells. Therefore, in Aim 3, we will assess tolerance to cardiac allografts in hematopoietic macro-chimeras, generated by this FasL strategy, with or without other immunosuppressive methodologies such as costimulatory blockade. SPECIFIC AIM 1: Assess whether FasL+ DCs specifically reduce an alloimmune response and enhance engraftment of allo HSCs SPECIFIC AIM 2: Determine whether FasL+ HSCs generate specific tolerance in allo BMT. SPECIFIC AIM 3: Evaluate tolerance to cardiac allografts in hematopoietic chimeras generated using FasL+ DCs/HSCs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUEL CELL POWER PACKS FOR LEFT VENTRICULAR ASSIST DEVICE Principal Investigator & Institution: Sarangapani, Srinivasan; Vice President; Innovative Chemical/Environmental Tech Environmental Technologies, Inc Norwood, Ma 02062 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 30-JUN-2004 Summary: (Unedited Applicant's Abstract):The end-stage cardiac patients, who cannot undergo heart transplantation owing to age limitation, lack of donor hearts or complications in using immunosuppressive drugs are essentially salvaged by LVAD and TAH devices. An estimated 40-70,000 American cardiovascular patients under age 65 could benefit from a heart transplant each year, whereas only 2,400 patients actually receive such transplants. These patients can benefit from the LVAD type devices both as a bridge to transplant as well as an alternative treatment option. Of the -900 patients who have received the LVAD system, a growing number are surpassing the three-yearmark of continuous support with their LVAD device. With such growing number of people on LVAD, there is a need for a reliable power system that could support the devices for longer hours without interruption. In Phase I program, we demonstrated the feasibility of producing a low fuel cell stack assembly, weighing -225 g and stack volume of 0.19 L. The performance of single cell matched those of the state-of-the-art while some performance degradation was observed when single cells were assembled into a stack. The cause for such degradation has been identified and since corrected. The Phase II proposal concentrates on the engineering development of the power pack. Further weight/volume reduction, heat and water management issues, optimization of the membrane electrode assemblies, evaluation of the hydrogen source, failure analysis and initial hazard analysis are the objectives of the Phase II program. At the end of Phase II, a prototype unit with integrated hydrogen storage will be fabricated and tested at the Artificial Organ Development Center of the University of Pittsburgh. PROPOSED COMMERCIAL APPLICATION: Not Available Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE TRANSFER TO ALTER TRANSPLANTED HEART FUNCTION Principal Investigator & Institution: Koch, Walter J.; W.W. Smith Professor of Cardiology; Surgery; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2004 Summary: (Verbatim from the applicant's abstract) This represents a competing renewal application to study gene transfer as a means to alter the function of transplanted hearts. Cardiac transplantation is limited by the limited supply of donor hearts and perioperative ventricular dysfunction. Ventricular dysfunction (including RV

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dysfunction due to recipient pulmonary hypertension) and allograft vasculopathy are major causes of cardiac transplant failure. Understanding signaling mechanisms may be important to improve graft function and survival. Signaling through G-protein coupled receptors (GPCR), especially BAR, is important for normal cardiac and vascular smooth muscle cell physiology. BAR signaling is often compromised in the transplanted human heart, and several agents implicated in allograft vasculopathy can signal through G proteins. Transgenic mice have been developed with altered BAR and G protein signaling, including mice in which BAR-kinase (BARK1) is overexpressed. Increased expression of a BARK1 inhibitor improves cardiac performance in heart failure and transplant models. The plans are to use viral-mediated gene transfer in rat and rabbit models and transgenic mice models to investigate mechanisms by which GPCR signaling affects graft function. The Aims are (1) to characterize BAR signalling in brain dead rabbit hearts and to try to improve function with adenoviral delivery of BAR signalling/inhibitory molecules; (2) to characterize BAR signalling and elucidate molecular defects in murine cardiac grafts, to use transgenic BAR signaling mutants to determine effects on graft function, and to use a rabbit model of heterotopic cardiac transplantation to study the effects of acutely manipulating BAR signalling; (3) to use a pulmonary artery banding model in rabbits to produce RV stress, as a condition to test BAR signalling and as a means to improve posttransplant RV dysfunction; and (4) to study the role of G protein signalling in mediating vascular smooth muscle (VSM) cell proliferation, and to use a rat aortic allograft model to test strategies to limit VSM hyperplasia in transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC DETERMINATION OF ALLOGRAFT VASCULOPATHY Principal Investigator & Institution: Benza, Raymond L.; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2002 Summary: (Adapted from applicants' abstract) Dr. Benza will become an Assistant Professor of Medicine in April 1997, in the Division Cardiovascular Diseases (DCD) at the University of Alabama (UAB). Dr. Benza's subspecialty training is in the area of Cardiac Transplantation with a research interest in vascular biology. He has won several distinguished departmental awards for his research in endothelial cell-mediated fibrinolysis and has presented his research at several national and international meetings. He received an American Heart Association/Alabama Affiliate Award during his first year of fellowship to fund his work in endothelial cell-mediated fibrinolysis and has several publications in peer reviewed journals. His proposed studies will define the relationship between impaired fibrinolytic activity and the development of cardiac allograft vasculopathy (Tx CAD), a frequent and costly problem post transplantation. The premise of these studies is that the development of Tx CAD may be related to the presence of certain fibrinolytic protein (t-PA, PAI-1, u-PA) gene polymorphisms (FPGP) in both the donor graft and recipient. Specifically, the expression of these genes may be affected in a genotype-specific manner by certain factors (hypertriglyceridemia) which develop as a result of the transplant. This altered expression of fibrinolytic proteins (FPs) will then lead to fibrin deposition and the development of Tx CAD analogous to the development of native CAD. In this context, FPGPs for t-PA, PAI-1, u-PA and fibrinogen will be determined by Southern blot and PCR techniques for 150 donor/recipient pairs. These patients will then be followed for a period of 4 years to determine if these FPGP are predictive for the development of Tx CAD. In addition, plasma levels (recipient) and tissue levels (biopsy specimens) of FPs will be determined

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Heart Transplant

by ELISA and immuncytochemical fluorescent staining, respectively, to determine whether a link exists between the expression of these proteins, fibrinolytic genotypes and TX CAD. UAB, Department of Medicine and DCD will provide the research space, facilities, resources (secretarial support and office space) and appropriate time commitment (80%) to allow the candidate to conduct and accomplish the research goals set forth in this application. He will have no administrative or teaching duties during the period of this application. If his faculty mentor were to leave the institution, a new mentor will be appointed and his continued development toward becoming a independent physician scientist supported and encouraged. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GRAFT RECOGNITION

REJECTION

AND

DIRECT

VERSUS

INDIRECT

Principal Investigator & Institution: Heeger, Peter S.; Associate Staff and Co-Director of Trans; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2003; Project Start 01-AUG-1998; Project End 30-NOV-2003 Summary: (provided by applicant): Alloreactive T cells, central mediators of graft rejection, can recognize donor MHC: peptide complexes expressed on donor cells through the direct pathway of allorecognition and can recognize processed donorderived peptide determinants expressed on recipient APCs in the context of recipient MHC molecules (the indirect pathway. While it is clear that CD4 + T cells responding through the indirect pathway participate in graft rejection, the presence and contribution of indirectly primed CD8 T cells to allograft rejection has not been addressed. We hypothesize that placement of an allogeneic transplant indirectly primes CD8 T cells, that these T cells comprise a significant portion of the indirect alloimmune response and that they migrate to the target organ. We further hypothesize that indirectly primed CD8 T cells contribute to the pathologic destruction of the transplanted organ through local effects at the graft site and by influencing the development of the remainder of the alloimmune T cell repertoire. We will test this hypothesis through the following specific aims. Aim 1. To compare the induction of the indirect CD8+ T call repertoire with the other components of the alloreactive T cell response to allografts. In these studies we will use complementary approaches to determine the contribution of indirectly primed CD8 T cells to the peripheral and intragraft alloimmune repertoire following skin or heart transplantation. Aim 2. To define the in vivo effector functions of indirectly primed CD8 T cells. In these studies we will use skin graft and heart transplant models to determine the in vivo effector functions and mechanisms of indirectly primed CD8 T cells and to fully assess their ability to mediate and/or contribute to graft pathology. Aim 3. To determine the in vivo requirements for indirect priming of CD8 T cells to transplant antigens. This aim will address the cellular and costimulatory requirements for priming CD8 T cells through the indirect pathway in vivo and will assess how eostimulatory blockade based interventions affect the function of these CD8 cells. The proposed studies will address an issue in transplantation immunology that has been ignored--whether and how indirectly primed CD8 T cells contribute to organ rejection. The design of effective therapies aimed at preventing rejection and improving human allograft survival depend on a complete understanding of the recipient alloimmune response. The findings derived from the work will define the role for indirectly primed CD8 T cells in allograft rejection and have the potential to guide future therapies aimed a prolonging graft survival. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HLA DERIVED PEPTIDES IN TRANSPLANTATION Principal Investigator & Institution: Clayberger, Carol A.; Associate Professor; Cardiovascular Surgery; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 30-JUN-2005 Summary: There is no text on file for this abstract. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNE REGULATION IN LUNG TRANSPLANTATION Principal Investigator & Institution: Burlingham, William J.; Associate Professor; Surgery; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 30-JUN-2004 Summary: Adapted from Investigator's abstract): Rapamycin inhibits obliterative fibrosis in a rat tracheal transplant model and promotes tolerance induction in mouse heart transplant models. Because it can spare the use of calcineurin inhibitors, rapamycin also promises to help eliminate the numerous side effects of cyclosporine and FK506. An ongoing multi-center, prospective, randomized, double-blinded clinical trial including patients from the UW-Madison is underway to see if a form of rapamycin (RAD) can prevent bronchiolitis obliterans syndrome (BOS) while improving long-term outcome in lung transplants. The clinical trial sponsored by Novartis relies on biopsy histology and pulmonary function tests to determine the primary endpoints; no immune function tests are funded. This proposal addresses not only surrogate markers of disease and therapeutic effects, but also aims, for the first time, to provide useful surrogate markers for the dynamic process of development and maintenance of allograft tolerance. We believe that such markers are essential for rational adjustment of maintenance immune suppressive therapy in a given patient. We also believe that tolerance is the best solution to the long-term problem of allograft obliterative airway disease, a problem that currently affects virtually all lung transplants. Specifically we will: 1) monitor the development of both systemic and local immune regulation of delayed type hypersensitivity (DTH) responses in all UW/Madison lung transplant recipients, including those receiving RAD-based vs. conventional IS therapy; 2) monitor the systemic and local release of soluble forms of donor HLA antigen in lung transplant patients, determine which soluble donor HLA antigens can trigger regulation of DTH, and analyze the role of metalloproteinase therein; and 3) monitor the persistence of donor T cells (including CMV-specific CD8+ cells), and alveolar macrophages, using flow cytometry of BAL cells. This research project will be conducted in conjunction with the current clinical trial, but will not exclude any lung transplant patients not enrolled in the trial. Our study has a high likelihood of providing clinical correlation of outcomes (acute & chronic rejection, infection) with surrogate markers of tolerance, alloreactivity and pathogen reactivity. We will determine how the sensitivity, specificity, and predictive value of each test would be clinically useful in the management of lung transplant patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNOLOGICAL MONITORING OF HEART ALLOGRAFT RECIPIENTS Principal Investigator & Institution: Suciu-Foca, Nicole; Professor; Pathology; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 28-FEB-2007

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Heart Transplant

Summary: (provided by applicant): The long term success of cardiac transplantation is currently limited by the high incidence of coronary artery disease, a manifestation of chronic rejection. This complication is principally related to antecedent episodes of high grade allograft rejection and/or ongoing alloreactivity. Daclizumab, a humanized antiCD25 antibody has been added to conventional immunosuppression to block and delete alloreactive T cells which express the high affinity IL-2 receptor alpha, CD25. At low doses this antibody prevents rejection in some but not all patients, suggesting that higher doses may be necessary particularly for poorly matched recipients who are at increased risk of rejection. However, Daclizumab may affect, not only the population of CD25+ alloreactive T helper cells (TH) but also the population of CD25+ regulatory/suppressor T cells which are believed to be crucial to allograft survival. The overall goal of this project is to study the mechanism which determines whether a graft will be rejected or tolerated and to develop a reliable strategy for tailoring the type and amount of immunosuppression to the patient's needs. The specific aims are: (1) To evaluate the frequency and characteristics of allospecific helper, cytotoxic and regulatory/suppressor T cells in heart allograft recipients treated with conventional immunosuppressive therapy and without (n=53) or with high doses of Daclizumab (n=53). (2) To establish the relationship between T cell alloreactivity, antibody production, acute and chronic rejection (3) To examine whether Daclizumab at 2mg/kg can reduce the frequency of acute and chronic rejection. To meet these objectives we will characterize alloreactive T cells within the graft and periphery with respect to direct or indirect activity and cytokine production. The generation of suppressor and regulatory T cells will be monitored by flow cytometry and functional studies. Anti-HLA class I and II antibodies will be monitored using both lymphocytotoxicity and ELISA methods. Statistical analysis will be performed to determine the relationship between the observed immunological changes and rejection in patients treated with conventional immunosuppressive therapy and with or without high doses (2mg/kg) of Daclizumab. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOMODULATION BY MHC CLASS II PEPTIDES Principal Investigator & Institution: Murphy, Barbara T.; Associate Professor; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (Verbatim from the applicant's abstract) The success of improved graft survival over the last decade has heightened the awareness of the long-term complication of classical immunosuppression, hence focusing future research on the development on tolerogenic strategies. It has become apparent that peptides play a central role in determining T cell responses to alloantigen. This has lead to an increasing interest in the potential use of synthetic peptides to manipulate T cell responses to foreign antigen. Peptides derived from both polymorphic and non-polymorphic regions of the MHC have been shown to significantly impact allograft survival in animals models, and clinical trials using non-polymorphic MHC peptides in humans are currently underway. Our preliminary data demonstrates that non-polymorphic MHC class II derived peptides inhibit the proliferative response to autoantigen, and alloantigen presented by both direct and indirect pathways. These immunomodulatory effects are mediated through the deletion of antigen presenting cells and T cell unresponsiveness. We hypothesize that the inhibitory peptides mediate their effects through binding to MHC class II, disrupting the interaction of the TCR with the MHC+peptide complex and thereby modulating the immune response. The aims of the research proposal are to investigate the mechanism of action mediating the

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immunomodulatory effects of these peptides and to determine their role in preventing allograft rejection. We will define the pathways leading to the induction of apoptosis in antigen presenting cells and determine the relative susceptibility of the different professional antigen presenting cells to deletion. T cell signaling patterns in unresponsiveness T cells will be investigated, and studies performed to determine whether the lack of T cell response to subsequent stimulation is mediated by anergy, deletion or immune deviation. The sequence specific nature of inhibition by the peptides will be evaluated by amino acid substitutions. Binding studies will performed to determine both the site of binding, and the relative binding affinity of the original and altered peptides. The ability of non-polymorphic MHC class II peptides to prolong allograft survival and induce tolerance will be evaluated in a mouse cardiac transplant model. Gene transfer of peptide constructs to cardiac allografts will be performed to investigate the benefits of local versus systemic delivery on graft survival. The mechanisms mediating long-term allograft survival will be investigated in vitro and in vivo. Peptides will be combined with other immunomodulators to develop novel tolerogenic strategies. These studies will help elucidate the potential role of MHC class II peptides in the prevention of transplant rejection and the induction of tolerance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INDUCIBLE NO SYNTHASE IN CARDIAC ALLOGRAFT REJECTION Principal Investigator & Institution: Cannon, Paul J.; Professor of Medicine (With Tenure); Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-MAY-1996; Project End 30-JUN-2003 Summary: (adapted from the applicant's abstract): The general objective of the proposed research in this renewal application is to investigate the role of the inducible isoform of nitric oxide synthase (iNOS) in the biochemistry and pathobiology of cardiac allograft rejection. The central hypothesis to be tested is that NO produced by iNOS in macrophages infiltrating the myocardium and in the cardiac myocytes augments the myocardial inflammation and contributes to the death of cardiac myocytes. We have demonstrated: 1) that iNOS mRNA, protein, and enzyme activity are induced in endothelial cells, infiltrating macrophages and cardiomyocytes in rejecting cardiac allografts, and 2) that iNOS induction is accompanied by impaired ventricular function and death of heart muscle cells which occurs both by necrosis and by apoptosis. We now propose to investigate mechanisms responsible for necrosis, apoptosis, and iNOS expression during heart transplant rejection. Aim #1 is to investigate, using cultured cardiomyocytes and rat and mouse heterotopic cardiac transplantation models, the hypothesis that activation of polyadenosine 5' -diphosphoribose synthetase (PARS) by nitric oxide contributes to the necrosis of cardiac myocytes in vitro and during cardiac allograft rejection. Aim #2 is to investigate the hypothesis that myocardial inflammation, necrosis and apoptosis during cardiac allograft rejection are ameliorated using mice as allograft donors and recipients that are unable to express iNOS (iNOS-ko mice). Aim#3 is to investigate the hypotheses that apoptosis of cardiomyocytes triggered by NO can be inhibited by sem-selective iNOS inhibitors, by transfection with Bcl-2, and by administration of caspase inhibitors. Aim #4 is to investigate the interplay between iNOS and COX-2 in modulating prostaglandin and thromboxane synthesis during cardiac allograft rejection, the role of CD154-CD40 interaction in the expression of iNOS and COX-2 in cardiomyocytes and the effect of COX-2 expression on cardiomyocyte apoptosis in cardiac allograft rejection. The proposed experiments may provide new insights concerning the role of iNOS in pathobiology and potential therapy of cardiac

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Heart Transplant

allograft rejection and they may also be relevant to other cardiac diseases in which iNOS is expressed such as myocardial infarction and dilated cardiomyopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERLEUKIN-10 IMMUNOSUPPRESSION Principal Investigator & Institution: Bromberg, Jonathan S.; Surgical Director; Center for Gene Therapy & Molecular Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2005 Summary: (adapted from applicant's abstract): Interleukin-10 (IL-10) causes suppression or down modulation of T cell, B cell, and antigen presenting cell (APC) functions. However, cellular IL-10 (cIL-10), derived from mammalian cells, also has immunostimulatory properties. Conversely, viral IL-10 (vIL-10), encoded by the BCRF I open reading frame of the Epstein Barr virus, is almost exclusively immunosuppressive. The structural and physiological basis for these key characteristics and differences have not been defined. The applicant's preliminary data now demonstrate that a defined structural change can convert vIL-10 to cIL-10-like activity, or cIL-10 to vIL-10-like activity, by interchanging a single amino acid between the viral and cellular ligands. This structural change correlates with IL-10 binding to the previously described IL-10R1 chain and may correlate with the function of a newly described IL-10R2 chain. The applicant hypothesizes that cIL-10 and vIL-10 differentially bind IL-10 receptors, activate second messenger pathways, and induce immunosuppressive or immunostimulatory responses. Dr. Bromberg also hypothesizes that IL-10R1 and IL10R2 and/or their associated second messengers are differentially distributed on different cell types. He proposes that elucidation of these differences will increase understanding of how IL-10 regulates immunity and allow the manipulation of IL-10 responses for immunosuppressive therapy in transplantation. The specific aims of the proposed research are: 1) Demonstrate the structural basis of the binding to and activation of the IL-10R complex by IL-10 ligand constructs. Binding and competition assays will be performed between various cIL-10 and vIL-10 constructs and IL-10R1 and IL-10R2 chains. Additional studies will assay second messenger pathways through Western blotting and electrophoretic mobility shift assays for JAK-STAT activation. 2) Demonstrate the immunologic activity of IL-10 constructs on T cell, B cell, and APC function. The differential distribution of IL-10R1 and IL-10R2 on T, B, and APC subsets will also be characterized. 3) Demonstrate the in vivo immunological activity of IL-10 constructs in a transplant model. Gene transfer of IL-10 constructs to cardiac allograft will be performed and the effect on graft survival and immune activation of T, B, and APC functions evaluated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIVER TRANSPLANTATION: THE ROLE OF DENDRITIC CELLS Principal Investigator & Institution: Thomson, Angus W.; Professor; Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-MAY-1996; Project End 30-NOV-2005 Summary: (adapted from the applicant's abstract): The precise role of donor dendritic cells in the inherent tolerogenicity of hepatic allografts remains unresolved. We have shown, however, that poorly stimulatory, immature liver dendritic cells, or dendritic cells whose co-stimulatory function is blocked, can strikingly enhance activationinduced death in allogeneic T cells. Moreover, infusion of such immature donor

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dendritic cells plus co-stimulatory blockade augments apoptotic death of host immunoreactive T cells and markedly enhances graft survival. These data support our hypothesis that liver dendritic cells have potential to promote the development of tolerance in allogeneic recipients by mediating the apoptotic death of allospecific T cells. Aim 1 is to elucidate the role of apoptosis in the outcome of liver dendritic cellallogeneic T cells interactions and the factors that influence this activity. These studies will test whether myeloid and lymphoid dendritic cells exhibit functional differences in their interaction with T cells and whether they have equal potential to mediate apoptosis in activated T cells and whether Th1 and Th2 cells are equally susceptible. The role of critical co-stimulatory pathways and of IL-2 in the regulation of T cell death will be examined. Aim 2 will ascertain the death regulatory pathways that may determine T cell apoptosis by liver dendritic cells. Contribution of the Fas pathway and the role of TNF families, in particular TRAIL, will be examined. Cell survival factors and death resistance molecules will also be examined for the possible differential resistance of Th1/Th2 subsets to dendritic cell induced death. Aim 3 studies will examine the ability of liver dendritic cells to delete alloreactive cells in vivo and will examine factors that modulate this activity. These studies will involve quantitative assessment of proliferation and apoptosis of CD4 and CD8 T cells in vivo. The impact of blockade of specific co-stimulaory pathways and whether antigen specific T cells are deleted selectively will be ascertained. Finally, Aim 4 studies will assess and maximize the therapeutic potential of liver dendritic cell induced alloantigen-specific T cell apoptosis in organ transplant recipients. In these clinically-relevant studies, emphasis will be placed on targeting specific costimulatory pathways, including use of novel blocking agents. The results will provide new insight into how liver dendritic cells can modulate survival of alloreactive T cells, and determine the potential of donor dendritic cells to delete allospecific T cells to facilitate transplant tolerance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MACROPHAGES IN REMODELING AND REJECTION OF SOLID ORGAN TRANSPLANTS Principal Investigator & Institution: Marsh, Clay B.; Vice Chair for Research; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: This project will explore the role of macrophages in the pathogenesis of chronic in organ transplantation. We hypothesize that HLA class I and/or II antigens are expressed by cells in the graft serve as the ligand for anti- donor MHC antibodies to be deposited. We speculate that recipient macrophages are stimulated by these antibodies to produce and secreted TGF-beta that appears to be important in organ acceptance. Consistent with this hypothesis, we found that deposited IgG stimulates human monocytes to produce TGF-beta, although whether this TGF-beta is activated is not clear. Thus, we will seek to define how monocyte production of TGF-beta induced by deposited IgG is regulated, determine the biochemical pathways modulating this production, determine if these in vitro data apply to endomyocardial biopsies from patients with heart transplants and test "proof of concept" studies in animal models. This project will interact with the other two projects in the proposal in a manner that will provide additional opportunities for discovery. Through these studies we hope to define the molecular mechanisms by which monocytes, macrophages and IgG may facilitate the generation of chronic rejection in organ transplantation and define new molecular targets to direct new strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Heart Transplant

Project Title: MECHANISMS OF ACCELERATED GRAFT ARTERIOSCLEROSIS Principal Investigator & Institution: Baldwin, William M.; Associate Professor; Pathology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 06-MAY-1997; Project End 31-MAR-2008 Summary: (provided by applicant): This multidisciplinary research program project is focused on chronic rejection of heart transplants. Although advances in immune suppression and improvements in the diagnosis and treatment of acute rejection and infection have improved the survival for heart transplant recipients the first year, longterm survival is limited by chronic rejection. The lesion that ultimately causes chronic rejection is accelerated graft arteriosclerosis (AGA). The only treatment currently available for AGA is retransplantation, but retransplantation entails increased patient risk, and it exacerbates the increasing shortage of donor hearts. Although the gross and microscopic features of AGA have been well characterized, the cellular and molecular mechanisms leading to AGA need to be determined. It is clear that AGA is a complex and multifactorial process. This program project focuses antigen-independent and antigen-dependent responses that causes of vascular injury leading to AGA. The 3 projects will investigate the following interactive mechanisms of vascular injury and response to injury: 1) complement and antibody-mediated injury; 2) regulation of Weibel-Palade body secretion by endothelial cells; and 3) granzyme B-induced proteolysis of smooth muscle cell targets. We hypothesize that these mechanisms occur in the initial phases of AGA and represent potential novel targets for intervention before AGA is irreversible. Each of the 3 projects makes use of the extensive clinical material from human cardiac transplant recipients in the Clinical/Pathology Core to verify experimental data from animal models developed in the Animal Core. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF ALLOGRAFT TOLERANCE Principal Investigator & Institution: Orosz, Charles G.; Professor; Surgery; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: Long-term allograft survival is readily achieved in murine cardiac allograft recipients, but very little is known about the mechanisms by which this allograft acceptance is induced or maintained. We have developed a testable, working paradigm of cardiac allograft acceptance. This paradigm holds that allograft acceptance involves immune processes that actively protect allografts. We believe that one manifestation of this alloprotective process, the phenomenon of linked antigen non-responsiveness, holds the key to understanding allograft acceptance. The proposed studies will investigate important aspects of the alloprotective responses that develop in allograft recipients. Specific Aim 1: To evaluate the contributions of three intriguing cell types to the initiation of allograft acceptance responses. These are addressed as the "memory hypothesis", the "gamma/delta hypothesis", and the "NKT hypothesis". In general, we will use cell transfer studies with SCID mice to determine the role of memory T cells, gammadeltaT cells or NKT cells in the generation of alloprotective activity, ie., linked DTH non-responsiveness or cardiac allograft acceptance. Specific Aim 2: To evaluate two non-competing mechanisms by which allograft acceptance is maintained. These are addressed as the "cytokine synergy hypothesis" and the "protected compartment hypothesis". In general, we will use cytokine knock-out mice and anti-cytokine antibodies to dissect the roles of TGFbeta, IL10 and IL4 in the expression of alloprotective activity (linked DTH non-responsiveness and cardiac allograft

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acceptance). We will also determine whether new alloprotective mechanisms independent of these cytokines are installed in accepted allografts over time. Specific Aim 3: To identify the cytokine environment necessary for the in vitro generation of alloprotective T cells that can be transferred into allograft recipients to promote cardiac allograft acceptance. Initially, these studies will use IL10 to drive alloantigen- stimulated splenic T cells towards alloprotective behavior. Specific Aim 4: To evaluate and optimize the experimental system in which tolerization to BSA, a foreign protein unrelated to an allograft, can be used to promote linked non-responsiveness to graft alloantigens, and thus educate an allograft recipient toward allograft acceptance. This represents a novel therapeutic approach that uses BSA as a "vaccine" for transplant recipients. Routine molecular genetic methods would allow us to explore the potential of this vaccine strategy for use as a potential gene therapy in transplant recipients. Finally, we will evaluate the effects of concurrent infection with murine influenza virus on he survival of the graft and recipient in mice that are being educated with BSA for allograft acceptance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REJECTION

MECHANISMS

OF

ANTIBODY

MEDIATED

ALLOGRAFT

Principal Investigator & Institution: Wasowska, Barbara A.; Pathology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 24-JUL-2000; Project End 30-JUN-2004 Summary: Numerous clinical observations indicate that in certain patients alloantibodies probably contribute to rejection. Although some investigators have attributed a causal relationship to this association, there are still insufficient data to evaluate critically the mechanisms of such antibody-mediated acute allograft injury. Presently, the availability of inbred "knock out" mice, monoclonal antibodies to critical mediators, and soluble recombinant receptors provide the means to establish a causative role of antibody in the in vivo pathogenesis of acute graft rejection. Recent in vitro studies have demonstrated that antibodies and complement can initiate dynamic interactions among endothelial cells, macrophages and platelets that are mediated by adhesion molecules and their ligands. The potential role of these receptors and their ligands has not been examined in acute alloantibody-mediated rejection. The hypothesis to be tested in this proposal is that alloantibody and complement mediate acute cardiac rejection by activating endothelial cells, macrophages and platelets through ,expression of P-selectin and von Willebrand factor. The proposed studies are based upon our extensive preliminary data from cardiac allograft models in complement deficient rats as well as immunoglobulin knock out (IgKO), C4, C3 and CR2 KO mice. The specific aims of this project will test our hypothesis by demonstrating that: 1. Passive transfer of complement-activating classes and subclasses of mAbs specific for donor MHC antigens can reconstitute cardiac allograft rejection in IgKO mice and cause the upregulation of Pselectin, von Willebrand factor, and MCP-l in endothelial cells. 2. Passive transfer of non-complement-fixing subclasses of mAbs specific for donor MHC antigens will modulate in a dose-dependent manner cardiac allograft rejection induced in IgKO mice by complement-activating subclasses of mAbs with the same specificity. 3. Activation of endothelial cells, B-cells, platelets and macrophages by antibody mediated acute rejection is inhibited in C4, C3 and CR2 KO mice resulting in prolonged cardiac allograft survival. 4. P-selectin augments activation of endothelial cells, platelets and macrophages in allograft rejection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Heart Transplant

Project Title: MESENCHYMAL PROGENITORS OF INTRAGRAFT FIBROBLAST Principal Investigator & Institution: Wu, Gordon D.; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 90027 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2004 Summary: Recent observations indicate that fibroblasts of recipient origin may actively participate in the development of chronic allograft rejection. Recipient-derived fibroblasts have been showed to contribute to fibrosis in human renal transplants as well as rodent heart allografts. These exciting findings could impact human health care in a positive way: if the progenitors of graft-proliferating fibroblasts are identified, new strategies aiming at inhibition of these cells will become possible for the treatment of chronic rejection. In order to appreciate this potential, the scientific community must determine the phenotype(s) of the mesenchymal stem cells (MSC) that give rise to intragraft fibroblasts, and must understand the mechanisms that control their homing to allografts. The central hypothesis for the research proposal is that proliferating intragrafl fibroblasts are derived from mesenchymal progenitors of host origin, which are committed de novo in the bone marrow, released into blood circulation, attracted by local factors to home to allograft during chronic rejection. Three Specific Aims will be pursued: (1) Identify the progenitor cells of intragrafl fibroblasts. The proliferative hierarchy of the fibroblastic lineage of MSC will be determined using MSC differentiation cultures, immunophenotyping and fibroblast functional assays. Vectormarked syngeneic MSCs of defined phenotype will then be engrafted into rat recipients of cardiac allograft for assessment of their capacity to home to allografts. Clonal integration analysis will determine if the progeny of vector-marked MSC is originated from the same precursor, or discrete stem cell. (2) Determine the mechanism that is responsible for the recruitment and proliferation of fibroblast progenitors in allografts. Studies are designed to test a hypothesis that homing of MSC to allograft is mediated by binding of CD44 expressed by the progenitors to extracellular matrix hyaluronan (HA); MCP-1 promotes MSC migration by up-regulating expression of selected CD44v isoforms and supports fibroblast proliferation by stimulating macrophage production of fibrogenic factors. (3) Determine the feasibility of using fibroblast progenitors as a vehicle for gene delivery to allografls. Mesenchymal progenitors will be transduced with retroviral vectors containing a hepatocyte growth factor (HGF) gene and then engrafted into allograft recipients. Studies are designed to examine the distribution of the engrafted MSC in allograft and bone marrow, kinetics of HGF production, its impact on bone marrow cell biology and the development of graft fibrosis. Our studies will provide definitive proof that mesenchymal progenitors of recipient origin play a pathogenic role in the development of graft fibrosis, and will determine the phenotype of fibroblast progenitors, the recruitment mechanism, and the feasibility of using MSC for gene therapy of chronic rejection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR EPIDEMIOLOGY OF DILATED CARDIOMYOPATH Principal Investigator & Institution: Mestroni, Luisa; Director and Associate 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-JAN-2002; Project End 31-DEC-2005 Summary: This proposal addresses the molecular epidemiology of dilated cardiomyopathy by determining the frequency of disease gene mutations, and the genotype/phenotype correlations in the patient population, and their clinical relevance.

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Idiopathic dilated cardiomyopathy (DCM) is a disease affecting the cardiac muscle and is a primary cause of heart failure leading to heart transplant. The etiology of DCM is mainly unknown, but the disease is frequently inherited and genetically heterogeneous. Linkage studies have identified 17 FDC disease loci including a locus mapped by the P.I.'s laboratory on chromosome 9 in a large kindred with autosomal dominant FDC. Thus far, 8 disease genes have been identified: the P.I.'s laboratory has contributed to the discovery of mutations in dystrophin gene leading to X-linked FDC, and more recently, has discovered lamin A/C gene mutations in patients with FDC and variable skeletal muscle involvement. Other investigators have reported mutations in cardiac actin, deltasarcoglycan, desmin, tafazzin, beta-myosin heavy chain and troponin T leading to FDC. However, the prevalence, type and clinical relevance of cytoskeletal gene mutations in FDC, and in the overall DCM population are unknown. This application proposes a series of experiments designed to test the following hypotheses: 1) gene mutations are a frequent cause of FDC, 2) different gene mutations may have different frequency, different prognostic value, and different clinical relevance, 3) several FDC genes are still unidentified, and they are likely to encode cytoskeletal proteins. The Specific Aims of this proposal are: 1) to investigate of a cohort of patients with FDC and to evaluate their relatives to determine the inheritance pattern, the phenotype, the natural history, and recruit for molecular genetics studies; 2) to identify and characterize novel genes causing FDC using a candidate gene approach and a positional candidate cloning approach; 3) to analyze the molecular epidemiology of known and novel disease genes by studying the prevalence, type, and genotype/phenotype correlation of the FDC gene mutations in a large patient population with or without a familial trait. Clinical data, DNA and, in the case of FDC, lymphoblastoid cell lines have already been collected from 478 subjects, and we anticipate the enrollment of 20 to 30 new families/year. The experimental methods include mutation screening of known and novel candidate genes, positional cloning of the FDC gene on chromosome 9 by linkage and association studies, analysis of the frequency and genotype/phenotype correlations using a large database designed for these studies. The identification of the genes and mutations responsible for DCM will greatly increase the understanding of the molecular basis of this disease and will allow for the development of new molecular- based diagnostic and therapeutic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR TARGETS OF NITRIC OXIDE IN CARDIAC TRANSPLANTS Principal Investigator & Institution: Pieper, Galen M.; Surgery; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2005 Summary: (Verbatim from the application): While nitric oxide (NO) is believed to contribute to cardiac allograft rejection, me precise mechanism is not understood. We will examine the intracellular molecular mechanisms for the actions of excess NO on cardiac allograft contractile dyskinesis relating to a paradigm which includes both oxidative and nitrosative stress. We will examine the regulation of inducible NO synthase (iNOS) gene expression by the oxidant-sensitive NF-kB transcription factor and examine key candidate cytosolic and mitochondrial proteins as molecular targets of NO. These proteins include myoglobin and aconitase. In vitro nitrosylation of these proteins are known to inhibit enzyme activity and 02 binding, thus, interfering with efficient 02 utilization by this O2-demanding organ. Hypothesis: [NO derived from iNOS targets certain cellular proteins for nitrosylation within cardiac grafts that contribute to

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Heart Transplant

myocardial contractile dysfunction. Furthermore, reactive oxygen plays a role in regulating iNOS gene expression at the transcriptional level via activation of the oxidant-sensitive transcription factor (NF-KB).] The applicant will use advanced, stateof-the-art molecular and biophysical techniques including: transcription factor regulation of iNOS gene (gel shift assays; Northern and Western analysis); in situ sonomicrometry; measures of nitrosyl protein and function (EPR, electron paramagnetic resonance spectroscopy and immunoprecipitation); assay for apoptosis; quantitation of reactive oxygen (EPR spin trapping; salicylate trapping); evaluation with iNOS knockout and SOD1 or SOD2 transgenic mice. The applicant will show that following allogeneic cardiac transplantation: Aim #1: [Induction of iNOS leads to iron-nitrosyl complex formation within myocardium and contractile dysfunction during allogeneic cardiac transplantation.]; Aim #2: [Certain candidate proteins are molecular targets of nitrosylation by excess NO in allogeneic transplantation.]; Aim #3: [iNOS gene deletion prevents nitrosyiprotein formation and prolongs graft survival. ]; Aim #4: [iNOS gene expression during allogeneic transplantation is regulated by activation of NF-KB.]; Aim #5: [Antioxidants inhibit activation of NF-KB, induction of iNOS, formation of nitrosyl complexes and enhance contractile function.]; Aim #6: [Antioxidant transgene overexpression inhibits activation of NF-kB, induction of iNOS, formation of nitrosyl complexes and enhances contractile function during allogeneic cardiac transplantion.] These studies will provide a novel mechanism to explain the pathogenesis of dyskinesis and graft failure during cardiac transplant rejection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSPLANT

MYOFIBROBLASTS

AND

FIBROSIS

AFTER

CARDIAC

Principal Investigator & Institution: Strauch, Arthur R.; Professor; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: Chronic rejection in the transplanted heart is associated with interstitial fibrosis and progressive neointimal lesion formation in the coronary arterial bed that impairs tissue perfusion to the point of functional disruption. Our intention in Project 3 is to examine wound repair processes in the transplanted heart that specifically involve activated stromal myofibroblasts. We propose that alloantigen-independent ischemia/reperfusion injury during the early post-operative period as well as chronic, alloantigen-dependent release of TGFbeta1 in long-term accepted grafts promote myofibroblasts activation and histogenic remodeling via a common signaling pathways based on reactive oxygen species (ROS). Myofibroblasts accumulate in the coronary adventitia and cardiac interstitium of heart grafts where they express several injuryresponse genes that are regulated by MSYI, a cold-shock domain (CSD) transcriptional regulatory protein. MSY1 and related proteins are important mediators of the transcriptional response to tissue stress and redox imbalance. The goal of the proposed research is to examine TGFbeta1- and ROS-dependent changes in MSY1 protein complexes that govern VSM alpha-actin promoter activity. Mis-regulation of VSM alpha-actin expression during chronic rejection is associated with accumulation of myofibroblasts, fibrocontractile scar tissue, neointimal smooth muscle cells, and poorly differentiated cardiomyocytes. VSM alpha-actin is encoded by a prototypical injury response gene that shares MSY1 control elements with other genes required for wound repair. Analysis of interactions between MSY1 and other TRPs required for injuryresponse gene expression in human stromal myofibroblasts should provide new information about molecular control points in chronic rejection. In human pathology

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and intramyocardial biopsy samples, assessment of MSY1:TRP structure and function may provide new prognostic indicators for evaluating and staging chronic rejection in transplant patients before the development of graft-destructive fibrosis. From the standpoint of transplant vascular sclerosis, studiers of stromal myofibroblasts are especially relevant given the demonstrated importance of adventitial fibroblasts in neointima formation as well as the establishment of new microvascular perfusion circuits that are critical for long-term heart graft survival. Finally, TGFbeta1 and/or ROS may modulate expression of other MSY1-dependent, chronic rejection- associated genes such as those encoding MHC class II molecules which compliments Project 1 and 2 aims pertaining to alloantibody production, monocyte/macrophage FcR engagement, and the role of TGFbeta1 in graft acceptance vs. fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REJECTION

NF-KAPPABETA

ACTIVATION

T

CELL

FUNCTION/GRAFT

Principal Investigator & Institution: Alegre, Maria-Luisa; Assistant Professor; Medicine; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): T cell activation via TCR ligation and CD28 costimulation results in the nuclear translocation of several transcription factors, an event thought necessary for cytokine production, proliferation, survival etc. In particular, CD28 costimulation markedly potentiates TCR-induced activation of NF-kB. However, whether NF-kB is in fact necessary for CD28 and TCR-mediated functions in vitro and in vivo is not fully understood. The global aim of this study is to determine whether activation of NF-kB is necessary for defined T cell functions driven by ligation of TCR and CD28. Specific Aim 1. To determine whether activation of NF-kB is necessary and/or sufficient for CD28-mediated costimulation of T cells in vitro. We hypothesize that NF-kB activation is selectively required for a subset of T cell functions promoted by CD28 costimulation. To address this issue, T cells from 2 strains of mice deficient in NF-kB activation will be utilized. To address whether NF-kB activation is sufficient to bypass a need for CD28 costimulation, T cells from CAR transgenic mice will be transduced with an adenoviral construct expressing a constitutively active form of IKKb. In all cases, effects on T cell survival, cytokine production, and differentiation into effector cells will be examined. Specific Aim 2. To investigate whether lack of NF-kB activation prevents the lymphoproliferative disease observed in CTLA-4-deficient mice. CTLA-4, a molecule with marked homology with CD28, is a negative regulator of T cell responses that also inhibits NF-kB activation. We hypothesize that the lymphoproliferation occurring in CTLA-4-deficient mice is due, in part, to unopposed NF-kB activation in T cells. To address this possibility, CTLA-4-deficient mice will be interbred with mice expressing the IkBa transdominant gene on T cells, and life span, numbers of T cells in peripheral lymphoid organs and in solid organs, and T cell function will be monitored. Specific Aim 3. To determine whether NF-kB activation is necessary for acute allograft rejection. To address the requirement for NF-kB activation in acute allograft rejection, skin and heart allografts will be transplanted into mice with deficient NF-kB activation in T cells. Graft survival, T cell priming, migration, and effector function will be analyzed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Heart Transplant

Project Title: OPTIMIZING TRANSPLANTATION

OUTCOME

AFTER

PEDIATRIC

HEART

Principal Investigator & Institution: Webber, Steven A.; Pediatrics; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2004; Project Start 15-FEB-2004; Project End 31-JAN-2009 Summary: (provided by applicant): Over the last 15 years, significant improvements in patient outcome have occurred such that heart transplantation is now considered an established therapy with a high likelihood for short-term success. However, the emotional, financial, social and medical burdens placed on patients and families remain enormous and heart transplantation therapy remains palliative. Indeed, most children transplanted in infancy and childhood are not predicted to survive to adulthood. The immunosuppressive regimens have many inherent risks including infections, malignancy and multiple end-organ toxicities. Furthermore, these agents have had little impact on the development of chronic rejection, the leading cause of death late after transplantation. The central paradigm driving this integrated SCCOR proposal is that further improvements in clinical outcome following pediatric heart transplantation depend upon novel strategies that link basic science advances with evidence-driven modifications in clinical protocols. This SCCOR proposal will bring together experts in the fields of pediatric cardiology (cardiac transplantation) and cardiac surgery, immunology, infectious disease, molecular genetics, and biostatistics to advance the common goal of developing novel approaches to the management of pediatric heart transplant recipients. Our long-term goals are to: 1. Develop strategies that result in long-term graft acceptance without requiring immunosuppression. 2. Develop strategies to reduce the morbidities related to non-specific immunosuppressive protocols. 3. Identify genetic markers that predict disparities in transplant outcomes in children after transplantation, including racial disparities. 4. Develop non-invasive diagnostic strategies for rejection surveillance that reduce cost and improve quality and length of life. This Pediatric CV SCCOR proposal addresses each of these areas with novel, hypothesis driven projects to rapidly and significantly advance the state-of-the-art care for pediatric heart transplant recipients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OXIDATIVE STRESS SIGNALING IN GRAFT CORONARY DISEASE Principal Investigator & Institution: Robbins, Robert C.; Assistant Professor; Cardiothoracic Surgery; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (Verbatim from the applicant's abstract) We propose to investigate the role that early myocardial oxadative stress signaling pathways have in the development of graft coronary artery disease (GCAD) following cardiac transplantation. In the established PVG donor to ACI recipient rat model, expression of bcl-2 decreases and nuclear factor kappa-B (NFkB) activity increases in the early reperfusion period. Inhibition of NFkB reduces reperfusion injury and GCAD in this model. In other models of ischemia and reperfusion BCL-2 has been shown to regulate NFkB activity. The overall hypothesis of this proposal is that myocardial oxidative stress following cardiac transplantation contributes to the development of graft coronary artery disease via a bcl2 associated mechanism. The specific aims of the proposed work are: 1) To delineate the dependence of early myocardial oxidative stress and NFkB activity on bcl-2 expression following cardiac transplantation; 2) To determine the effects of decreased or increased myocardial oxidative stress on bcl-2 expression and NFkB activity following cardiac

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transplantation; and 3) To determine the role that early post-transplantation myocardial bcl-2 expression and intracellular localization plays in the later development of graft coronary artery disease. This proposal utilizes transgenic mice to more clearly characterize the role that bcl-2 plays in NFkB activation and in the development of myocardial oxidative stress following cardiac transplantation. The knowledge gained in the transgenic experiments will contribute to the overall understanding of the effects of bcl-2 overexpression on the development of GCAD in the PVG to ACI model. Upon completion of this study, we will have demonstrated the potential of altering the signaling pathways of oxidative stress by graft specific modulation, which may have applicability for other solid organ transplantation and as a myocardial protection strategy for routine cardiac surgical procedures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PARS INHIBITOR FOR CARDIAC ALLOTRANSPLANTATION Principal Investigator & Institution: Jagtap, Prakash; Corporation 100 Cummings Ctr, Ste 419E Beverly, Ma 01915

Inotek

Pharmaceuticals

Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 31-OCT-2004 Summary: Immune-mediated rejection is the principal obstacle to the use of heart transplantation for the treatment of end-stage cardiac failure. Current immunosuppressive regimens have limited efficacy and are associated with substantial toxicity. A recently discovered mechanism of inflammatory injury, the "Poly (ADPribose) Synthetase (PARS) Pathway", has now been implicated in the pathogenesis of allograft rejection. Triggered by peroxynitrite-induced DNA single strand breaks, PARS catalyzes an energy-consuming polymerization of ADP-ribose, resulting in NAD depletion, inhibition of glycolysis and mitochondrial respiration, and the ultimate reduction of intracellular high energy phosphates. PARS activation also strongly upregulates expression of the transcription expression of the transcription factor AP-1 and AP-1 dependent genes, including ICAM-1. In this proposal, we present experimental evidence that pharmacologic inhibition of PARS activity has potent anti-inflammatory effects and prolongs cardiac allograft survival. The specific aim of the present proposal has to determine the benefit of PJ-34, a novel, non-toxic, and highly potent PARS inhibitor, in the prevention of organ dysfunction and cellular injury in an experimental rodent model of cardiac transplant rejection. Demonstration that PJ-34 prevents tissue injury and prolongs graft survival would represent a breakthrough in the design of novel anti- inflammatory regimens to prolong allograft survival. PROPOSED COMMERCIAL APPLICATIONS: The domestic marker for a novel, effective therapy for cardiac allograft rejection is estimated at $100 million per annum. Global markets are estimated at $400 million. Current market entrants such as cyclosporine A and FK506, have substantial toxicity. Funding of SBIR Phases I and II would allow for market entry in 4 years. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENESIS AND TREATMENT OF CHRONIC REJECTION Principal Investigator & Institution: Murase, Noriko; Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2003 Summary: (Adapted from the applicant's abstract): This investigation postulates that chronic rejection of allografts is caused by the elimination of donor antigen presenting cells residing in the graft, and that through retention of these cells, promotes low grade

42

Heart Transplant

stimulation of the recipient s immune system leading to prevention of CR. An animal model as been developed to test this hypothesis. Animals are pretreated with donor bone marrow or a hepatic allograft in concert with Tacrolimus. Donor microchimerism persists for at least 100 days, and then, the animals are challenged with a heterotopic cardiac allograft (CCA). The PI has found that animals previously receiving a liver allograft do not experience CR while those that receive bone marrow do. The hypothesis is advanced that the liver provides the stromal elements for survival of donor hematopoietic stem cells which protect cardiac allografts from CR. In contrast, with animals receiving donor bone marrow, there is induction of a strong Th-1 type cell response due to a loss of microchimerism, which leads to CR. In this project, the PI proposes to study the mechanisms responsible for lymphocyte trafficking and cellular activation, the influence of persistent donor antigen presenting cells on the incidence and intensity of CR and whether maneuvers for augmentation of donor chimerism in human liver transplant patients lowers the severity of CR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENESIS ARTERIOSCLEROSIS

OF

TRANSPLANT

ASSOCIATED

Principal Investigator & Institution: Libby, Peter; Chief, Cardiovascular Medicine; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-SEP-1990; Project End 30-SEP-2003 Summary: Transplantation-associated arteriosclerosis (TxAA) is an intimal fibroproliferative lesion composed predominantly of vascular smooth muscle cells and associated matrix proteins, admixed with mononuclear inflammatory cells. TxAA causes progressive, insidious vascular occlusion and results in allograft ischemia; it represents the major long-term limitation to solid organ transplantation. Although TxAA is largely ascribed to an immune- mediated allogeneic response, it occurs even in the setting of immunosuppression adequate to block acute parenchymal rejection, and does not correlate strictly with episodes or severity of allograft rejection. Thus, cytokine-induced endothelial dysfunction, recruitment and activation of antigen-non-specific cells, or antibody-mediated processes may modulate the development of TxAA. We have proposed that TxAA is due to a chronic delayed-type hypersensitivity response of host T cells to donor vascular wall cells, distinct from the cytolytic response characteristic of acute rejection. This chronic response persists in part because of incomplete elimination of relevant foreign antigens. Moreover, the initial immune-specific response triggers the release of antigen non-specific effectors such as macrophages and cytokine networks less susceptible to immune modulation. We propose here to continue our long-term objectives of unraveling the mechanisms by which specific effector cell subsets and cytokines initiate and promote TxAA. Using a murine heterotopic cardiac transplant model, Specific Aims of this proposal are: 1) Test the hypothesis that acute rejection and TxAA are mediated via distinct T cell subsets and cytokines. Mice genetically-deficient in particular cytokines or their receptors ("knock-outs"), as well as adoptive transfer methodology, will be used to evaluate the contribution of specific cell subsets (e.g., Thelper 1-type cells, B cells) and cytokines in either promoting or ameliorating acute rejection and TxAA. 2) Identify the mechanisms underlying our seminal observations that acute parenchymal rejection and allograft failure are accelerated in inteferon (GKO) recipients, while TxAA is completely abrogated in long-term allografts in GKO recipients. The observations point to distinct mechanisms mediating acute vs. chronic allograft pathologies, and suggest that different therapeutic interventions will be uniquely applicable to each.

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

Project Title: P-GLYCOPROTEIN FUNCTION IN ALLOGRAFT REJECTION Principal Investigator & Institution: Frank, Markus H.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2005 Summary: (provided by applicant): The applicant is a nephrologist with an interest in transplant immunology, who is eligible for and fulfills all the necessary requirements to be considered for a Mentored Clinical Scientist Award. As part of his nephrology fellowship at the Brigham and Women's Hospital and The Children's Hospital in Boston, the applicant completed 3 years of laboratory-based research during which he gained practical experience in techniques of cellular and molecular immunology. The main thrust of his research has been the study of the role of P-glycoprotein, the multidrug resistance-associated ABC transporter, in alloimmunity, and the principle findings are now being published in the Journal of Immunology. The applicant is now completing his nephrology fellowship and will be appointed as a staff member at the Brigham and Women's Hospital and as an Instructor of Medicine at Harvard Medical School effective July 1, 2001. In this proposal, the applicant wishes to build on his findings that P-glycoprotein serves critical roles in vitro in T cell activation and APC function. He has found that specific P- glycoprotein blockade inhibits alloantigen- but not mitogen-dependent T cell activation by inhibiting IFN-gamma and IL-12 through a positive feedback loop, thus blocking a critical pathway in the initiation of primary alloimmune responses. These mechanisms may also be operative in vivo and Pglycoprotein may therefore play an important role in clinical allograft rejection. However, the in vivo role of P-glycoprotein in T cell activation and allorecognition has not been explored. In addition, the molecular signals and mechanisms that regulate Pglycoprotein expression by T lymphocytes in the course of alloimmune interactions are currently unknown. The goals of this proposal are to: 1) define the role of P-glycoprotein in the direct and indirect pathways of allorecognition and in allograft rejection in vivo in murine models of allotransplantation; 2) investigate the in vivo function of Pglycoprotein in antigen-specific T cell activation using a murine adoptive transfer system where a small population of peptide-specific CD4+ TCR transgenic T cells can be physically tracked and phenotypically examined; and 3) examine in vitro the role of Pglycoprotein in antigen presenting cell function and in the bi- directional activation of T cells and allogeneic endothelium which is critical for allograft rejection, based on the preliminary identification of a unique capacity of allogeneic endothelium to trigger T cellular P-glycoprotein expression. The applicant's training in molecular biology and cellular immunology has allowed him to discover a novel role of P-glycoprotein in alloimmunity. The applicant realizes that in order to further explore his recent findings he needs additional mentoring. The Mentored Clinical Scientist Development Award will provide the critical opportunity for the applicant to further expand his knowledge in immunology necessary for achieving independence. The Mentor's and the CoMentor's laboratories provide an ideal environment to accomplish the aims of this project because of their strong background in transplantation immunology, their collaborative momentum and their exemplary didactic and ethical curricula. After completing this project the applicant will be familiar with the critical in vitro and in vivo techniques of molecular and cellular immunology in order to examine independently and competitively the role of related or novel molecular targets in transplantation and allograft rejection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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•

Heart Transplant

Project Title: PHOSPHOLIPID METABOLISM AND TRAFFIC IN T. GONDII Principal Investigator & Institution: Joiner, Keith A.; Professor; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-AUG-1990; Project End 31-JUL-2007 Summary: (provided by applicant): Toxoplasma gondii is an important cause of focal central nervous system infections in patients with HIV, lethal infections in heart transplant patients, and devastating congenital infections of newborns. The organism is an obligate intracellular protozoan parasite, which is capable of invading and replicating in essentially all nucleated cells, and requires nutrients from the host cell to survive and replicate. The parasite resides in an unusual intracellular vacuole, which is extensively modified by secretion from parasite secretory organelles. The focus of our laboratory is to understand how these parasite-induced modifications of the vacuole contribute to the nutrient acquisition necessary for virulence. We have recently demonstrated that the parasite induces a unique process of microtubule-based invaginations from the host cell cytosol into the vacuolar space, for acquisition of nutrients internalized into the host cell via the host endocytic pathway. In particular, cholesterol internalized into the host cell via the LDL receptor is delivered to the parasite via this pathway. Cholesterol transport and metabolism by the parasite are targets for therapeutic intervention, since the organism cannot synthesize sterols de novo. In contrast, nothing is known about the biosynthetic capacity of the organism for phospholipids, nor about mechanisms for phospholipid acquisition from the host cell. These topics are readily amenable to study. For example, as one of many pieces of intriguing preliminary data, we show that extracellular parasites cannot synthesize phosphatidylcholine, the major T. gondii phospholipid, when provided with the head group precursor choline. Unlike cholesterol, this lipid should not be readily acquired from the host cell endocytic pathway, and must be accessed by another route. To elucidate a coherent scheme for phospholipid homeostasis in T. gondii, we will systematically determine 1.) Which phospholipids are synthesized by the parasite, 2.) which phospholipids are acquired from the host cell, 3.) the molecular mechanisms by which the parasite acquires needed phospholipids from the host cell. The long-term goal is to identify strategies to block T. gondii phospholipid acquisition from the host cell and thus to interfere with parasite growth. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: POST-TRANSPLANT INFLAMMATORY RESPONSE Principal Investigator & Institution: Fairchild, Robert L.; Staff; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 01-APR-1997; Project End 31-MAR-2007 Summary: (provided by applicant): Acute rejection of allografts remains a significant problem in clinical transplantation, undermining the function and survival of organs transplanted for the treatment of end-stage organ disease. Acute rejection is mediated by the coordinated infiltration and effector functions of T cells with specificity for alloantigens resulting in the destruction of the graft tissue. The factors directing T cells and other leukocytes into solid organ allografts remain poorly defined. In studies performed during the initial funding period of this grant we demonstrated the temporal induction of chemoattractant cytokines, chemokines, in skin allografts during the progression of acute rejection. Administration of antibodies to one of these chemokines, Mig, inhibited T cell infiltration into skin allografts and promoted long-term graft survival supporting the use of this strategy in transplantation. Our preliminary studies

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using a heart allograft model have indicated that an early program of inflammatory events regulates the production of T cell chemoattractants and T cell infiltration into the allografts. Antagonism of specific components of this early inflammation delays subsequent infiltration of alloantigen-pnmed T cells into these grafts and significantly extends allograft survival. In this competitive renewal application we will test the induction and inter-dependent relationships between specific components of the inflammatory response that leads to the production of the T cell chemoattractants such as Mig using a mouse model of vascularized heart allograft rejection. In Specific Aim 1 we will test the induction and role of TNFa and IL-1 on the induction of early chemokines anad later T cell chemoattractants in heart allografts. In Specific Aim 2 we will test the role of neutrophils and neutrophil and macrophage chemoattractants in the production of the T cell chemoattractants. Experiments in Specific Aim 3 will test the synergy between the adhesion molecule ICAM-1 and chemokines in directing leukocyte infiltration into heart allografts and the progression of inflammation during acute allograft rejection. The understanding of the role of each of these early inflammatory events in acute rejection should further elucidate important mechanisms of acute allograft rejection. Furthermore, the results should support the development of novel therapeutic reagents and strategies to inhibit these early inflammatory events and promote the survival of transplanted organs while decreasing the dependence on the generalized and debilitating immunosuppressive regimens currently in use. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PRESERVATION AND CARDIAC TRANSPLANT VASCULOPATHY Principal Investigator & Institution: Pinsky, David J.; Professor and Scientific Director; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-JUL-1999; Project End 31-MAY-2003 Summary: (adapted from the applicant's abstract): Mechanisms responsible for vascular failure of cardiac grafts, especially the development of transplant-associated coronary artery disease (TCAD), remain obscure. In a murine model of heart transplantation, preliminary data show a direct correlation between extent of initial ischemic injury and the degree of neointimal proliferation, more pronounced in allografts yet nevertheless present in isografts. To elucidate alloantigen-independent mechanisms of graft vascular injury caused by preservation, ischemic vessels were shown to exhibit a loss of vasoprotective nitric oxide (NO) and cyclic nucleotides, increased expression of leukocyte adhesion receptors and plasminogen activator inhibitor-1, inhibited expression of plasminogen activator genes, and increased reactive oxygen species. Novel electrochemical sensors show L-arginine or tetrahydrobiopterin deficiency subverts cNOS to make O2-, and that NO nearly vanishes after murine CTX due to rapid quenching by O2-; restoring deficient second messenger pathways (NO,cAMP, cGMP) with substrates, analogs, or type specific phosphodiesterase inhibitors improves acute graft vascular function and causes a striking reduction in TCAD; these benefits were reversed by inhibiting PKA. As adhesion receptor-null grafts (P-selectin, ICAM-1) or those puled with interleukin-1 receptor antagonist (IL-1ra) are protected from early vascular failure following prolonged preservation, the investigators hypothesize that early ischemic injury drives primary vascular failure and accelerates TCAD development, particularly in alloreactive vessels. The aims are (1) to elucidate mechanisms of preservation injury which contribute to primary graft failure or TCAD. Effects of preservation on electrochemical, functional, and histomorphometric endpoints will be studied in control, transgenic, or gene-deficient mice to assess the functional relevance of genes which modulate the cytokine, leukocyte adhesive, fibrinolytic, or

46

Heart Transplant

reactive oxidant milieu of the graft vasculature; and (2) to determine if attenuating early graft vascular injury can limit primary graft failure and TCAD development, examining the effects of early modulation of NO or cyclic nucleotide pathways, blockade of endothelial-leukocyte interactions, reduction of graft oxidant stress, or inhibition of intravascular thrombosis. An optimal cardiac preservation strategy will then be devised which protects early graft vascular function and reduces the occurrence or severity of TCAD. These experiments will provide new insights into mechanisms by which early ischemic injury leads to early graft failure and TCAD, and proffer new strategies for prevention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHIMERISM

PREVENTING

XENOGRAFT

REJECTION

BY

MOLECULAR

Principal Investigator & Institution: Iacomini, John J.; Associate Professor of Surgery; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): The acute shortage of human organs for transplantation has stimulated exploration into the possibility of using non-human donor organs for xenotransplantation. Pigs are now regarded as the most likely species to serve as donors for clinical xenotransplantation. The first major immunological barrier to overcome to allow successful xenotransplantation is rejection by natural antibodies (NAB) present in humans that are directed toward the carbohydrate epitope Gal(alpha1-3)Gal(beta1-4)GIcNAc-R (alphaGal) on porcine tissues. Like humans, knockout mice (GTo) carrying a null mutation in the gene encoding the glucosyltransferase UDP galactose:beta-D- galactosyl-1,4-N-acetyI-D-glucosaminide alpha(1-3)galactosyltransferase (E.C. 2.4.1.151, hereafter referred to as alphaGT) lack alphaGal epitopes on all tissues and develop in their serum NAB reactive against alphaGal. We have shown previously in GTo mice that genetic engineering of bone marrow (BM) using retroviral transduction to establish molecular chimerism can be used to induce long-term stable tolerance to alphaGal and prevent antibody mediated hyperacute rejection of cardiac transplants. These results demonstrate that B cells producing alphaGal reactive antibodies are functionally eliminated from the immunological repertoire of animals that express the retrovirally transduced alphaGT gene in BM derived cells. The goal of this proposal is to test the hypothesis that establishment of molecular chimerism can be similarly used to induce tolerance to the alphaGal epitope in non-human primates. The specific aims are to: 1) Determine the effect of molecular chimerism on production of alphaGal reactive NAB in primates; and 2) Determine whether the induction of molecular chimerism leads to tolerance to alphaGal in primates and determine the mechanism. These studies should provide practical mechanistic information important for the field of xenotransplantation and to the application of gene therapy to induce B cell tolerance, and may also advance our understanding of self-nonself discrimination in shaping the B cell repertoire. Furthermore, these studies may be generally applicable for re-establishing B cell tolerance in individuals with autoimmunity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREVENTION ANTIOXIDANTS

OF

GRAFT

REJECTION

BY

CATALYTIC

Principal Investigator & Institution: Tocco, Georges; Eukarion, Inc. 6-F Alfred Circle Bedford, Ma 01730

Studies

47

Timing: Fiscal Year 2003; Project Start 15-JUN-2003; Project End 31-MAY-2004 Summary: (provided by the applicant): Transplantation represents the only therapy for end-stage organ failure caused by a variety of incurable diseases. However, rejection by the host represents a major obstacle to long-term survival of transplants. While acute rejection is currently controlled by immunosuppressive drugs, continuous treatment with these non-selective agents impairs the entire immune system thereby increasing the risk for infections and cancer in patients. In addition, many of these drugs exhibit longterm toxic effects. Most importantly, a large proportion of solid organ transplants succumb to chronic rejection, a phenomenon associated with fibrosis, and vasculopathy. At present time, there is no treatment for chronic rejection. These observations underscore the need for novel therapies in transplantation. Eukarion Inc. has developed a class of low molecular weight molecules that are catalytic reactive oxygen species scavengers, acting as mimics for the endogenous antioxidant enzymes, superoxide dismutase and catalase. These compounds have demonstrated efficacy in 3 of the main events associated with tranplant rejection" i) tissue damage due to anoxia, ii) ischemia/reperfusion injury and iii) inflammation. Most importantly, we have shown that one of these compounds can delay the acute rejection of skin grafts in mice. Based on these observations we intend to develop a series a compounds with greater lipophilicity and in vivo half-life to be tested in the prevention of acute and/or chronic rejection of solid organ transplants for further development. To achieve this, we propose the following specific aims: 1) To synthesize and evaluate a series of analogs with greater potency or efficacy, i.e., a series with enhanced lipophilicity and improved in vivo half-life. 2) To test the effect of selected EUK compounds on anti-donor inflammatory immune response and on the rejection of heart allotransplants in mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREVENTION OF OSTEOPOROSIS AFTER TRANSPLANTATION Principal Investigator & Institution: Shane, Elizabeth J.; Professor of Clinical Medicine; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: Over the past decade, our studies of osteoporosis that develops after cardiac transplantation (TX) have resulted in new insights into the natural history, demographic and biochemical features of transplantation osteoporosis. The first year after TX is characterized by rapid bone loss (%5 to 12%) at the spine and hip and a very high fracture incidence (20% to 40%). Most studies show that done density stabilizes or improves during the second, and third post-transplant years. We therefore hypothesized that therapy to prevent bone loss could be limited to the first post-transplant years. We therefor hypothesized that therapy to prevent bone loss could be limited to the first post-transplant year. We have completed recruitment (n=146) to a one-year, doublemasked phase III clinical trial evaluating the safety and efficacy of two drugs in the prevention of bone loss during the first 12 months after cardiac transplantation: calcitirol [1,25 dihydroxvitamin D] and the bisphosphonate, alendrona te (ALN). Enrollment was completed in June of 2001 and 12 months of follow-up for all participants will be completed in June of 2002. In addition, we have prospectively monitored enrolled participants to assess the effect of study drug withdrawal on rates of bone loss, and fracture during the second and third post-transplant years. Approximately 50% of subjects begin to experience bone loss (ranging as high as 8% at the spine and 9% at the hip) after study drugs are withdrawn. This observation raises several important therapeutic questions. Most important is whether one year of therapy will suffice to prevent osteoporosis after cardiac TX. It is also important to determine whether ALN

48

Heart Transplant

and calcitirol differ with regard to maintenance of bone density after withdrawal and to elucidate the mechanisms and predictors of bone loss during the second and third posttransplant years. We hypothesize, given the long half-life of bisphosphonates in bone, that subjects who received ALN during the tr ial will be less likely to sustain bone loss after withdrawal of study drugs than those who received calcitirol. Funding for the trial ends in March, 2002. We are now applying for 3 years of support to complete 12 months of observation on those subjects enrolled after March, 2001 and to complete an additional 24 months of follow-up on enrolled participants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: QUALITY OF LIFE OUTCOMES >= 5 YRS POST HEART TRANSPLANT Principal Investigator & Institution: Grady, Kathleen L.; Nursing Director; Rush University Medical Center Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-DEC-2004 Summary: The purpose of this 5 years prospective, longitudinal study is to identify variables that are associated with and predict six outcomes of adult patients at 5 years to 10 years after heart transplantation (HT). The six outcomes are survival, functional ability, emotional status, work ability, satisfaction with HT, and perceived quality of life. Specific study aims are (1) to determine how variance in demographic, physical, and psychosocial factors over time is concurrently related to variance in the six outcomes over time (2) to identify demographic, physical, and psychosocial predictors of the six outcomes (3) to examine how physical and psychosocial factors that are related to the six outcomes change longitudinally (4) to examine the impact of age, gender, racial / ethnic background, and complications after HT on outcomes over time and (5) to examine the effect of using various statistical methods for handling missing data in order to improve the accuracy of prediction of outcomes. A prospective, longitudinal design will be used. Data will be collected every 6 months beginning at 5 years through 10 years after HT. Inclusion criteria are (1) >= 5 years post HT (2) age >= 21 years (3) able to read and write English, and (4) physically able to participate. Patients will complete a booklet of instruments, and chart data will be gathered. Variables to be measured include demographic variables (ex. age, gender, race, and marital status), physical variables (ex. medical history, medications, exercise testing, and complications), and psychosocial variables (ex. perceived health status, stress, coping, and social support), and the six outcome variables (within a stress, appraisal, and coping model). Statistical analyses will include longitudinal, multi-variable regression methods for repeated measures and parametric modeling of outcomes. Health-Related Implications. These data will provide information regarding (1) long-term benefits versus risks of HT, (2) patients at risk for poor outcomes, (3) and targets for interventions to improve outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RISK OF PORCINE PICORNAVIRUS IN XENOTRANSPLATATION Principal Investigator & Institution: Njenga, M Karuiki.; Veterinary Pathobiology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2004 Summary: (Adapted from applicant's abstract) This research career award is designed to provide the candidate with research experience in xenotransplantation biology and porcine animal model of infectious diseases, with the long-term objective of establishing a research program in xenozoonosis. The candidate has research experience in cellular

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and molecular virology and the mouse animal model and he has recently taken a faculty position at the University of Minnesota, which is renowned for research in the fields of transplantation and pig diseases. The research project will investigate the risk posed by persistent porcine viruses, which may escape detection by standard screening methods to become pathogenic in humans following xenotransplatation. The experiments will utilize porcine encephalomyocarditis virus (EMCV), which has been shown to causespecies infection, to evaluate the risk of human infection after transplantation of pig tissues by examining various pigs tissues/organs using sensitive molecular techniques to determine where the virus persists. Subsequently, the applicants will transplant chronically EMCV-infected porcine tissues into SCID (severe combined immunodeficient) mice reconstituted with human peripheral blood lymphocytes followed by immunosuppressive treatment (hu-PBL-ISCID), in order to determine the risk of such tissues transmitting disease. The hu-PBL-ISCID mice will serve as a model of suppressed immune system in transplant patients. This training program will also require the candidate to observe and assist in monkey-to-monkey (allo-) and pig-tomonkey (xeno-) transplantations in an established transplantation laboratory. The longterm goal is to transplant pig organs/tissues containing persistent porcine virus into primates in order to determine the risk of disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF AUTOIMMUNITY IN TRANSPLANT REJECTION Principal Investigator & Institution: Benichou, Gilles A.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-MAY-2008 Summary: (provided by applicant): The exact role of graft tissue specific antigens in transplant rejection is unknown. Recently, we have detected CD4+ T cell- and B cellmediated autoimmunity to cardiac myosin (CM) in murine, porcine, and human recipients of heart transplants. CM is known to initiate autoimmune myocarditis, an autoimmune disease causing cardiac tissue damage and heart failure. Most importantly, we have shown that: 1) pre-transplant sensitization of recipients to CM causes accelerated allograft rejection, 2) induced anti-CM responses are sufficient to trigger rejection of syngeneic heart grafts and 3) modulation of anti-CM responses in recipients results in long-term survival of transplanted hearts. Based on these results, we hypothesize that, in heart-transplanted individuals, the CD4 pathway of alloresponse contributes to acute and/or chronic heart graft rejection by triggering autoimmune responses to CM thereby causing cardiac tissue damages in a fashion similar to that observed in autoimmune myocarditis. To test this hypothesis, the specific aims of the present proposal are to: 1) identify CM determinants and characterize T cells mediating CM autoimmunity post-heart transplantation and, 2) investigate the mechanism(s) by which alloresponse causes autoimmunity to CM in heart-transplanted mice and, and 3) to elucidate the mechanisms by which modulation of anti-CM response can impact the rejection of heart allografts. We anticipate that this knowledge will provide new insights into the mechanisms governing the immune rejection of allotransplants and set the path for the development of new diagnostic tools and selective immune therapies to alleviate graft rejection in clinical transplantation. This award will enhance my career development by allowing me to devote my primary research effort to new transgenic and chimeric mice and a tissue-specific peptide approach for modulation in vivo of antigraft immunity. This will directly complement my previous training in heart transplantation and enhance my career interest in learning new ways of preventing anti-

50

Heart Transplant

donor immune reactivity and inducing tissue graft specific tolerance in human clinical organ transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF NEW T CELL PATHWAYS IN ALLOIMMUNITY Principal Investigator & Institution: Sayegh, Mohammed; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: The main goal of this project is to study the role of novel T cell costimulatory pathways in regulating alloimmune responses in vivo. We have a number of unique tools that will enable us to dissect the functions, mechanisms, and interactions of newly discovered T cell costimulatory pathways in regulating alloimmune responses in vivo. The proposal has two major specific aims. In aim 1, we plan to investigate the functions of novel T-cell costimulatory pathways in regulating alloimmune responses in vivo using models of solid organ and tissue (skin) transplants. Initially, we will focus on studying the functions of the PD1-PDLI/PDL2 pathway in regulating alloimmune responses in vivo. In future years we plan to study the functions of newer pathways as they are initially identified and appropriate reagents and animals are generated by the cores of the overall program project. Our hypothesis is that the PD1-PDLI/PDL2 pathway negatively regulates alloimmune responses in vivo. We will use gene targeting approaches and blocking monoclonal antibodies as tools to investigate the functions of this new pathway in alloimmune responses in vivo. We will define the role of this pathway in regulating CD4+ and CD8+ alloreactive T cells, Thl and Th2 alloimmune responses, and acute and chronic rejection using established skin and vascularized cardiac transplantation models in mice. We will also define the interactions between the PD1 pathway and other CD28 homologues (CD28, CTLA4, ICOS). Our corollary hypothesis is that signaling through PD1 promotes tolerance in alloreactive T cells. We will test novel therapeutic combinations using a PDL1Fc to promote donor specific tolerance. We will use unique in vitro and in vivo assays including specific TCR transgenic animals with defined allospecificity to class I (CD8) or class II MHC (CD4) alloantigens to better understand the mechanisms of targeting the PD1 costimulatory pathway in vivo. In aim 2 we will focus on developing non-toxic strategies to achieve donor bone marrow chimerism across fully allogeneic barriers without chemoradiotherapy conditioning. Our hypothesis is that targeting T cell costimulatory pathways promotes development of mixed allogeneic chimerism without chemoradiotherapy. We will target well defined and new T costimulatory pathways that are known to regulate initial CD4+ and CD8+ T cell expansion and/or subsequent survival. Successful strategies that induce donor T cell chimerism will be tested for specificity of tolerance using donor and third party skin graft rejection as a stringent transplant model. Furthermore, using novel models permitting tracking of host antidonor alloreactive CD4+ and CD8+ TCR transgenic T cells, we will examine the biology of graft resistance and determine how targeting new T cell costimulatory pathways affect alloreactivity in the context of mixed allogeneic chimerism. Overall, the studies in this project will dissect the functions and mechanisms of novel T cell costimulatory pathways in allograft rejection and tolerance. The results should yield useful information for future development of novel therapeutic strategies to induce transplantation tolerance to translate to primates and humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF REGULATORY T CELLS IN TRANSPLANT TOLERANCE Principal Investigator & Institution: Strom, Terry B.; Professor; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-AUG-1997; Project End 31-JUL-2007 Summary: (provided by applicant): We hypothesize that activation of T regulatory (T reg) cells constitutes an essential and common element of the pathway that creates peripheral allograft tolerance. We will test the hypothesis that: (i) the speed with which T reg cells expand after Ag activation and (ii) the pool size and potency of counteracting alloaggressive T cells are the variables that determine whether rejection or tolerance will occur. The overall aim of this proposal is to full define the role, phenotype, molecular mechanism of action, limitations of T reg cells in governing the allograft response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF THE GRANZYME B PATHWAY IN AGA Principal Investigator & Institution: Rosen, Antony; Professor; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: The long-term objectives of this project are to define the role of the granzyme B pathway in accelerated graft atherosclerosis, and its predominant mechanisms of pathogenesis in this setting. Recent data has underscored the fact that the granzyme B pathway plays a central role in transplant rejection, acting through induction of death and dysfunction of target cells through cleavage of highly specific intracellular and extracellular substrates. In preliminary studies, we have demonstrated that differentiated vascular smooth muscle cells (vSMCs) are preferentially and highly susceptible to granzyme B-induced proteolysis, and have observed that fibrillin-1 (a component of microfibrils in extracellular matrix which is prominent in blood vessels) is efficiently cleaved by granzyme B. We hypothesize that the granzyme B pathway plays a critical role in initiating and driving the specific vascular phenotype in AGA, through induction of ongoing damage of differentiated vSMCs, and cleavage of a critical extracellular matrix signal which leads to dysregulation of smooth muscle cell and endothelial cell function. We will address this hypothesis through the following specific aims: (1) Define the activity, targets and mechanisms of the granzyme B-induced dysfunction in vivo in human cardiac transplantation using unique probes of granzyme B-induced cleavage of intracellular and extracellular substrates; (2) Define the functional consequences of the granzyme B pathway on vessel structure and function, including intact vessels and isolated smooth muscle cells in vitro; (3) Address the role of granzyme B in development of AGA lesions in vivo by examining the effects of deficiency of GrB either in the whole animal or in distinct microenvironments, using granzyme B-deficient mice or mice expressing intracellular or secreted forms of a potent GrB inhibitor in vascular smooth muscle cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TGFB1 ALLOGRAFTS

GENE

TRANSFER

IN

VASCULARIZED

CARDIAC

Principal Investigator & Institution: Bishop, D. Keith.; Associate Professor; Surgery; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-JUL-1995; Project End 30-JUN-2004

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Summary: (adapted from applicants's abstract) Immunosuppressive gene therapy holds promise as an inductive therapy in transplantation. However, many fundamental aspects of this technology must be addressed before it may be applied to clinical transplantation. These include questions regarding the use of viral vs. non-viral vectors, underlying mechanisms of action, effects on systemic immunity, and the duration of transgene expression. The investigators have developed a model of TGFbeta1 gene transfer into mouse vascularized cardiac allografts to address these issues. Donor hearts are perfused with either DNA-liposome complexes or adenoviral vectors which encode the active form of TGFbeta1. Interestingly, CD4+ cells are readily suppressed by this modality, while CD8+ cells are not. This differential sensitivity is most pronounced when adenoviral vectors are used. The overall hypothesis to be tested is that transient depletion of CD8+ cells will enhance the efficacy of immunosuppressive gene therapy. Hence, the Specific Aims will: 1) Define mechanisms by which TGFbeta1 gene transfer mediates immunosuppressive activities. T cell functional assays will identify critical immune functions which are either turned off or turned on by TGFbeta1 gene transfer, and adoptive transfer studies will determine if regulatory cells are induced by TGFbeta1 gene transfer. 2) Elucidate mechanisms by which adenoviral mediated TGFbeta1 gene transfer stimulates CD8+ cells. The investigators will test the hypothesis that adenoviral vectors, but not DNA-liposome complexes, stimulate production of inflammatory cytokines which over-ride TGFbeta1 suppression of CD8+ cells. 3) Determine the impact of TGFbeta1 gene transfer on systemic immune surveillance. They will assess the effects of TGFbeta1 gene transfer on primary and memory responses to Listeria and on antibody responses to influenza immunization. 4) Determine if TGFbeta1 gene expression may be silenced following initial inductive immunosuppression. Tetracycline regulated promoters will be used to limit the duration of TGFbeta1 expression, and gene transfer of decorin, which binds and neutralizes TGFbeta1, will be employed to neutralize the transgene product. This study will provide insight for optimizing immunosuppressive gene therapy in clinical transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TGF-BETA TRANSPLANTATION

AND

IMMUNOSUPPRESSION

IN

ORGAN

Principal Investigator & Institution: Khanna, Ashwani K.; Medicine; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: (adapted from applicant's abstract): The investigators and others have previously demonstrated that CsA and more recently tacrolimus (Tac) induce transforming growth factor beta (TGF-B). A number of studies have demonstrated that TGF-B is both immunosuppressive and fibrogenic. Recently, they demonstrated that TGF-B mimics and anti-TGF-B abrogates both the anti-proliferative and fibrogenic effects of CsA in a non-transplant short-term in vivo mouse model. Cell-cycle arrest appears to be at least one main feature of the efficacy of immunosuppressive drugs, and TGF-B has been reported to induce the expression of one cell cycle inhibitor, p21. The investigators' that this phenomenon may be TGF-B- independent. If confirmed, these intriguing findings would suggest a potential dichotomy between at least some of the immunosuppressive properties of these agents and their fibrogenic effects, thus providing targets for pharmacologic modification to enhance or diminish specific properties. The current hypothesis based on these newer findings is that the efficacy of CsA and Tac is multifactorial and, in addition to the effects on TGF-B and IL-2, directly induces cell cycle inhibitors such as p21. The investigators also propose that the primary

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toxic effects of CsA and Tac are via the induction of TGF-B, which then induces fibrogenic genes including collagen and fibronectin. Accordingly, the specific aims of this proposal are 1) To determine whether the efficacy of CsA and Tac are dependent on TGF-B, p21 or both, using the complete MHC mismatch rat heart transplant model, which requires chronic immunosuppression to prevent rejection. The investigators will use antibodies to TGF-B and p21 alone or in combination to determine whether acute rejection is accelerated in CsA and Tac treated animals within the first 30 days posttransplant. 2) To further dissect the interaction between CsA and Tac, TGF-B and p21, using in vitro studies on A-549 cells that are either unmodified or are TGF-B- or p21deficient. The effect of CsA and Tac on the stimulation of promoter activity of p21 gene will be studied using TGF-B inducible and non-inducible promoter constructs made chimeric with luciferase reporter gene. 3) To determine whether the nephrotoxicity of CsA and Tac are secondary to TGF-B. In non-transplanted animals treated with CsA or Tac over 3-6 months, the investigators will use anti-TGF-B antibodies to attempt to abrogate the nephrotoxic effects. Also, to determine the time course of the induction of TGF-B1 and the ECM genes collagen and fibronectin, they will investigate the induction of these genes by CsA and Tac in glomerular mesangial cells and proximal tubular epithelial cells in vitro. These studies will directly determine the role (if any) of the TGFB and/or p21 pathways in the efficacy, and TGF-B in the toxicity, induced by CsA and tacrolimus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF FRACTALKINE IN ALLOGRAFT REJECTION Principal Investigator & Institution: Robinson, Lisa A.; Pediatrics; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2003 Summary: Fractalkine (FKN) is a novel chemokine/mucin hybrid molecule expressed on the surface of activated endothelium which has dual functions as a chemokine and an endothelial adhesion molecule. Our preliminary studies have identified a unique role for FKN in the pathogenesis of transplant rejection. The objective of this proposal is to develop a detailed understanding of the proinflammatory actions of FKN and its receptor CX3CR1 in immune responses such as allograft rejection. We hypothesize that these actions are determined by regulated expression of FYN on endothelial cell surfaces and that one contribution of FKN is to directly promote cellular immune functions. We will test these hypotheses through the following specific aims: Specific Aim #1: To characterize the actions of FKN and CX3CR1 to regulate immune cell functions. In preliminary studies, we have identified potent actions of FKN to promote certain cellular immune functions. We will systematically examine the role of FKN in regulating the activities of two inflammatory cell populations that are known to express CX3CR1: NK cells and macrophages. We will focus on effector functions that are relevant to allograft rejection. Specific Aim #2: To identify the mechanisms that regulate FKN expression on endothelium in an inflammatory response. Our preliminary experiments have demonstrated novel regulation of endothelial expression of FKN by the lipid mediator thromboxane A2. These studies will define the molecular mechanisms of this regulation and will examine the relevance of this pathway in an ongoing inflammatory response. We posit that this may be a critical component of platelet-endothelial interactions during inflammation. Specific Aim #3: To define the role of FKN and CX3CR1 in the pathogenesis of allograft rejection. In these experiments, we will examine the contribution of FKN and CX3CR1 to allograft rejection in a series of experimental models. Using a combination of neutralizing antibodies and genetically altered mice, we

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Heart Transplant

will define the role of the FKN- CX3CR1 pathway in acute and chronic allograft injury. These studies will test whether the in vitro actions of FKN defined in previous aims are relevant to in vivo immune responses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE USE OF PRIMATES FOR HUMAN XENOTRANSPLANTATION Principal Investigator & Institution: Zahorsky-Reeves, Joanne L.; Cardiothoracic Surgery; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 15-MAR-2001; Project End 28-FEB-2006 Summary: The long-term objective of this application is the prevention of the humoral rejection of porcine xenografts in patients. The objective of the current proposal is a detailed characterization of the xenoantibody response of an experimental model for human xenotransplantation, the cynomolgus monkey, and validation of this model as the basis for conducting clinically relevant experiments to prevent xenograft rejection in humans. In pursuit of this objective, our specific aims include determining the binding characteristics of IgM and IgG xenoantibodies in the cynomolgus monkey, and the sequences of the VH genes encoding them, both before and after transplantation of a vascularized porcine graft. Once this genetic information has been obtained, it will be used in the development and in vitro testing of an anti-idiotypic antibody against those xenoantibodies with the highest affinity to identified xenoantigens. This research should result in the full characterization of the xenoantibody response of an experimental model for human xenotransplantation and validation of this model as the basis for conducting clinically relevant experiments to prevent xenograft rejection in humans. Dr. Joanne Zahorsky-Reeves will be working under her mentor, Dr. Donald V. Cramer, in a laboratory with extensive background in the xenoantibody response in both rodent and human models. The applicant will become proficient in a variety of molecular biology techniques, including the development and screening of genetic libraries; the creation of single-chain antibodies; the production of anti-idiotypic antibodies using a mouse hybridoma system; and the evaluation of those anti-idiotypic Antibodies to specifically target and eliminate antibody- producing B cells. Mastering of these techniques will allow Dr. Zahorsky-Reeves to become an independent animal-based research not only in the field of xenotransplantation, but, broadly, in a variety of immunological settings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TISSUE ENGINEERING OF A CARDIAC PATCH Principal Investigator & Institution: Terracio, Louis; Associate Dean for Resarch; Basic Science and Craniofacial Biology; New York University 15 Washington Place New York, Ny 10003 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2005 Summary: (provided by applicant): Despite a dramatic decline over the past 15 years, cardiovascular disease remains the leading cause of death and disability in the Western world. The adult onset disease processes that compromise cardiac function include, infarction, ischemic heart disease, myocarditis, and a variety of idiopathic cardiomyopathies. The focal loss of muscular tissue, as a result of a congenital defect or a disease process, alters the unique architectural arrangement of the heart and impairs its function. An engineered segment of artificial myocardium (cardiac patch) potentially offers a nearly unlimited source of material for reconstructive surgery. In preliminary experiments from our lab we have successfully constructed small, multilayered cultures

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of fetal and neonatal cardiac myocytes that exhibit a tissue-like pattern of organization. These multilayered cultures are composed of myocytes that have an elongated, rod-like cell shape, but require further development before they would be suitable for transplantation. This proposal takes advantage of the Pl's experience in cardiac development, in vitro cultivation of cardiac myocytes on various ECM components, in vitro mechanical stimulation of cells in culture, morphological characterization of tissues, proof of concept studies, and established collaborations with bioengineering colleagues. The Specific Aims of this proposal are: 1) To use specially fabricated collagen substrates and a series of bioreactors to produce histotypic cultures of cardiac cells suitable for transplantation. 2) Characterize and compare the artificial myocardium to the intact heart by morphometric, biochemical and molecular techniques. 3) Transplant the artificial myocardium to in vivo locations that will allow vascularization of the tissue. The transplanted cultures will be compared by morphometric, biochemical, and molecular techniques to the structure and function of the intact heart. Data from these studies will identify the mechanical and chemical parameters necessary to produce the three-dimensional organization of the heart patches. These cultures will provide a potential source of biological material for repairing focal damage to the myocardium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TOLERANCE IN PRIMATES--THYMIC IMPLANTATION OF STEM CELL Principal Investigator & Institution: Allen, Margaret D.; The Hope Heart Institute 528 18Th Ave Seattle, Wa 98122 Timing: Fiscal Year 2002; Project Start 15-MAR-1995; Project End 30-SEP-2004 Summary: The aim of this proposal is to test in primates a new method for producing tolerance to solid organ grafts: implantation of purified donor CD34+ marrow cells into the recipient thymus. In pilot studies, the investigators have achieved: 1) hematopoietic microchimerism in 6/6 juvenile baboons with or without current triple drug immunosuppression; 2) specific prolongation of donor versus third party skin graft survival; and 3) absence of graft versus host disease at 16 months. These experiments test the feasibility of extending this approach to cardiac transplantation in a juvenile baboon model as a pre-clinical trial. The following questions are addressed: 1) Does intrathymic implantation of CD34+ marrow cells prolong survival of cardiac allografts? 2) What is the relationship between hematopoietic microchimerism and tolerance to a cardiac allograft? 3) Is intrathymic implantation of stem cells more effective than peripheral infusion? 4) What are the effects of current drug therapy on engraftment and tolerance? 5) What is the optimal timing of stem cell administration relative to cardiac transplantation? 6) What dose of cells is needed? 7) Are DR+ fractions necessary for engraftment? 8) Are measures of cellular immunity altered? Experiments are performed in juvenile baboons, implanting CD34+ cells in the thymus through a small thoracotomy and using a cervical heterotopic cardiac graft which facilitates biopsies. Immunosuppression consists of the tripe drug immunosuppressive regimen in current clinical practice, without myeloablation or host T cell depletion, or no immunosuppression. A dose of only 1x 10/6 cells has resulted in hematopoietic microchimerism in all recipients. Persistence of microchimerism. Histologic quantitation of infiltrating leukocyte subsets and coronary microvascular adhesion molecule expression will be compared to controls. The level of chimerism achieved, its persistence, the phenotype of stem cell progeny, effect on donor-directed CTLp, and the dependence on the thymus will be assessed. Implantation of CD34+ marrow cells in the thymus during a cardiac transplant procedure may provide a simple, safe method of

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producing tolerance to the graft and microchimerism. This methodology has obvious immediate clinical applications in solid organ transplantation. Depending on the level of chimerism achieved, the potential for introducing allogenic stem cells into an infant without immunosuppression might also have implications for the treatment of genetic deficiency diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM

TRANSPLANT

ARTERIOSCLEROSIS:

VIRAL

AND

HOST

Principal Investigator & Institution: Mocarski, Edward S.; Professor; Microbiology and Immunology; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 10-SEP-2001; Project End 30-JUN-2006 Summary: (provided by applicant): The fundamental objective of this Program in Immunopathogenesis of Chronic Graft Rejection is to address "TA: Viral and Host Mechanisms" by understanding pathogenic processes underlying this common manifestation of chronic rejection in heart transplant recipients. The Program Project focuses on the contribution of human cytomegalovirus (HCMV) in conjunction with immunopathogenic and inflammatory modulation that develops in patients who progress to TA. The study involves a large, organized multi-level evaluation of 160 heart transplant recipients. Peripheral blood and endomyocardial biopsy specimens will be collected eight times over the first year and three times in successive years to follow immune, virologic and inflammatory indicators that will be correlated with TA. The first project in this program will focus on the contribution of the HCMV-specific CD4 and CD8 T cell memory/effector function during the reactivation from latent or the initiation of primary infection and the progression to TA. This project will also investigate the activation state of cells. An inverse correlation is expected between the risk of progression to TA and the frequency of functional HCMV-specific T cells. The second project of this program will focus on levels of HCMV DNA and the induction of viral gene expression in patients at risk of TA. Sensitive solution and in situ DNA amplification and hybridization approaches will be used to follow viral DNA and mRNA levels in the follow-up period. This project will investigate the role of virus encoded or -induced chemokine (UL146/vCXC-l) and chemokine receptor (US28) expression in progression of TA. The proinflammatory capacity of viral strains and the highly variable UL146 chemokine gene, from patients progressing to TA will be investigated. An increase in virological indicators is expected during progression to TA. The third project will determine the impact of the Nitric Oxide Synthase(NOS) pathway by focusing on two major changes that can be measured in patients: (i) increases in vascular superoxide anion (O2-), and (ii) increases in ADMA. This project will investigate how HCMV infection augments these abnormalities via cytokine induced alterations in oxidative stress and ADMA accumulation. An impact of HCMV on endothelial and inflammatory NOS pathways is expected during progression to TA. Importantly, all three projects will work in parallel in peripheral blood cells/plasma/serum as well as directly in endomyocardial biopsies at all sampling times. Such an intense longitudinal study should provide the best possible setting to uncover associations and identify the contribution of HCMV to TA. The mechanisms, prognostic value and points of therapeutic intervention-directed at HCMV, the immune response to HCMV, immune activation and immunopathogenic events and the role of NOS pathways will all potentially emerge as a result of these collaborative efforts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TREATMENT OF EBV ASSOCIATED LYMPHOPROLIFERATIVE DISEASE Principal Investigator & Institution: Moss, Denis J.; Queensland Institute of Medical Research Herston Brisbane Qld, 4006 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2003 Summary: The treatment of Epstein-Barr virus (EBV)-associated lymphoproliferative disease in solid organ transplant patients poses a considerable challenge due to the underlying immunosuppression which inhibits the virus-specific cytotoxic T cell (CTL) response in vivo. Preliminary studies developed in our laboratory suggest that it may be possible to overcome this inherent problem using a novel protocol to activate autologous EBV-specific CTL lines from these patients and to show for the first time their potential use for immunotherapy against PTLD in solid organ transplant patients. To establish the clinical use of this protocol, we propose to conduct a phase I/II clinical trial in a cohort of solid organ transplant patients with PTLD. To achieve this, we have drawn together scientific expertise within the EBV Unit at QIMR and major transplant units in Australia. In the first instances, we propose to further refine the in vitro conditions for activating EBV-specific CTL from solid organ transplant patients who are on high levels of immunosuppression. Two absolute requirements have been set: (1) EBV specificity at the CTL peptide epitope level; and (2) complete lack of anti-donor alloreactivity which would threaten the integrity of the transplanted graft. Having defined these conditions, we propose to conduct a phase I/II trial by adoptively transferring autologous EBV-specific CTL into solid organ heart, lung, and heart/lung transplant patients with PTLD. As far as we are aware, this represents the first such trial to be conducted and seeks to (1) determine the safety of adoptively transferring EBVspecific CTL into solid organ transplant patients; (2) determine the longevity of these CTL in vivo using a genetic marker; and (3) determine the extent of clinical regression of PTLD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VASCULAR ALLOIMMUNITY

ENDOTHELIAL

GROWTH

FACTOR

IN

Principal Investigator & Institution: Flaxenburg, Jesse A.; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005 Summary: (provided by the applicant): Transplant patients are currently subjected to long term morbid therapy with immunosuppressive medications in order to prevent rejection of their grafts. For this reason, it is critical to devise therapies that are more specific and have improved side effect profiles. This will require a greater understanding into the mechanisms of allograft rejection. Vascular endothelial growth factor (VEGF) is the most potent angiogenic factor known. An underappreciated biologic function of VEGF is its role in initiating and perpetuating an inflammatory response through the induction of proinflammatory chemokines. Furthermore, this function of VEGF has major implications for alloimmune recognition. This proposal seeks to elucidate the mechanisms by VEGF can exert an inflammatory response in the setting of alloimmune stimulation. The understanding gained through these experiments is likely to uncover new, more specific targets for the treatment of allograft rejection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VENTRICULAR HEMORRHAGE

DYSFUNCTION

AFTER

SUBARACHNOID

Principal Investigator & Institution: Zaroff, Jonathan G.; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-MAY-2000; Project End 31-MAR-2005 Summary: The overall objective of this application is to support the principal investigator's development in a career focused on patient-oriented research. To accomplish this objective, the proposed program has both training and scientific components. The training component will include specific course work and instruction in biostatistics, clinical epidemiology, research methodology, and trial design. The scientific component of the proposed award will be in the field of neurocardiology, with a focus on cardiac dysfunction after subarachnoid hemorrhage (SAH). Many cardiac abnormalities have been reported after SAH. including electrocardiographic changes, arrhythmia, and left ventricular systolic dysfunction. Though many aspects of this syndrome remain unexplained, the most important issues are its undefined pathophysiology, reversibility, and therapy. The scientific program will test the following hypotheses: 2. Left (LV) and right (RV) ventricular systolic dysfunction occurring after SAH are reversible and independent of changes in myocardial perfusion and afterload. 3. Cause of donor brain death (SAH vs. others) and the presence of donor LV dysfunction are predictive of early recipient mortality after cardiac transplantation. A prospective cohort design will be used to determine the incidence and reversibility of RV and LV dysfunction after SAH, using serial echocardiographic measurements. In a substudy of patients with LV ejection fraction <40%, radionuclide imaging with technetium sestabmibi (MIBI) and meta[123]iodobenzylguanidine (MIBG) will be performed in order to determine the incidence of perfusion versus innervation abnormalities and their correlation with regional wall motion abnormalities of the left ventricle. In order to determine whether the observed contractile abnormalities are independent of changes in afterload, the LV end-systolic wall stress / end-systolic volume relationship will be determined in each substudy subject. A secondary analysis of the United Network for Organ Sharing (UNOS) and California Transplant Donor Network databases will be performed in order to determine the effects of donor cause of death and LV dysfunction on early recipient mortality rates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VIRAL CHEMOKINE RECEPTORS: TRANSPLANT VASCULAR SCLEROSIS Principal Investigator & Institution: Orloff, Susan L.; Surgery; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2004 Summary: The long term goal of this project is to identify mechanisms involved with human cytomegalovirus (HCMV) acceleration of transplant vascular sclerosis. The primary cause of graft loss of all vascularized organ transplants is due to a vascular lesion associated with chronic rejection. This form of vasculopathy referred to as TVS is characterized by concentric neointimal smooth muscle cell proliferation that results in vessel occlusion and ultimately graft failure. To date the only therapy available to treat severe TVS is retransplantation. Clinical studies in transplant recipients have demonstrated a direct link between HCMV and the acceleration of TVS. Based on these findings, we have developed a rat model of heart and small bowel transplantation in which CMV infection accelerates the time and severity of TVS. While the exact

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mechanism through which CMV mediates this process is unknown, recent work from our group suggests that CMV may contribute to TVS through induction of smooth muscle cell (SMC) migration towards sites of chemokine production through expression of a virally encoded chemokine receptor (US28). We have also observed that Rat and Murine CMV also induce SMC migration through their respective viral chemokine receptors R33 and M33, which are functional homologues of HCMV US28. We hypothesize that the mechanism of CMV-accelerated TVS involves the expression of virally encoded chemokine receptors leading to intimal SMC migration, which results in the characteristic vascular lesions of TVS. Therefore, we will utilize our in vitro and in vivo models to extend our observations and determine the role of virally encoded chemokine receptors in the development of TVS in three specific aims. First, using a rat cardiac transplant model of chronic rejection, we will determine the effects of virus on the kinetics of disease progression of TVS and the extent of viral expression in tissues as well as the cell types involved in the process. We will also determine the host factors such as chemokines and cytokines, and the contribution of R33 involved at various stages of the development of RCMV-induced TVS. Secondly, we will characterize the R33 domains involved in signaling which induce SMC migration and the ligands, which serve as agonists or antagonists to induced cellular movement. In the last specific, we will generate recombinant RCMV which contain mutations in domains involved in signaling to understand their contribution to TVS in the rat cardiac transplant model. Lastly, antagonists of R33 induced SMC migration in vitro will be tested for their ability to block TVS in the in vivo rat model. These studies will provide a valuable animal model to understand the role of CMV in the acceleration of TVS. In addition completion of these studies will form the basis for novel and rational design of therapeutic strategies to enhance long-term graft survival in HCMV infected transplant recipients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: XENOGENEIC STRUCTURE/FUNCTION

NATURAL

ANTIBODY

TARGETS-

Principal Investigator & Institution: Platt, Jeffrey L.; Director; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-SEP-1993; Project End 31-AUG-2006 Summary: (provided by applicant): The major problem in the field of transplantation is the lack of human organs and tissues for those who need them. This problem is so severe that by some estimates only 5-15 percent of the organ transplants needed is carried out. One approach to overcoming this problem is to use animal organs in lieu of human organs for transplantation, that is xenotransplantation. While xenotransplantation could in principle solve the problem of the shortage of organs, it is not presently feasible because the immune system of the recipient reacts severely with the graft. The first manifestation of this reaction is hyperacute rejection. Triggered by the binding of xenoreactive antibodies and the activation of complement, hyperacute rejection can now be overcome by various means including the use of pigs expressing human complement regulatory proteins as the source of xenografts. When hyperacute rejection is averted, a xenograft is subject to acute vascular rejection. Acute vascular rejection destroys organ xenografts over a period of days to weeks. It appears to be caused by antibodies in the recipient, which bind to blood vessels in the graft causing activation of endothelial cells and tissue injury that ensues. Fortunately, acute vascular rejection is not an invariable outcome of organ xenografts. Under some conditions, such as when xenoreactive antibodies are temporarily depleted, a graft may seemingly acquire resistance to injury by anti-donor antibodies, a condition referred to as

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Heart Transplant

accommodation. This application proposes studies that will elucidate the nature of the xenoreactive antibodies that cause acute vascular rejection of cardiac xenografts and determine how antibodies or other factors reacting with a graft may induce accommodation. Studies will be conducted in a model system in which porcine hearts are transplanted heterotopically into baboons. The antibodies produced by the baboons in response to the porcine organs will be studied at the time that acute vascular rejection or accommodation occurs. The specificity of those antibodies, number of antigens and frequency in pigs will be determined and the mechanisms by which those antibodies or other factors induce changes in endothelial cells will be ascertained. These experiments will provide information critical to the devising of new strategies for preventing acute vascular rejection or promoting the occurrence of accommodation of cardiac xenografts. 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 “heart transplant” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for heart transplant in the PubMed Central database: •

"Autoimmune rejection" of neonatal heart transplants in experimental Chagas disease is a parasite-specific response to infected host tissue. by Tarleton RL, Zhang L, Downs MO.; 1997 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20545

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A suggested technique for "orthotopic" heart transplantation in a patient with situs inversus. by Cooper DK, Ye Y, Chaffin JS, Zuhdi N.; 1993; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325111

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Cardiac transplantation for pediatric patients. With inoperable congenital heart disease. by Shaffer KM, Denfield SW, Schowengerdt KO, Towbin JA, Radovancevic B, Frazier OH, Price JK, Gajarski RJ.; 1998; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325503

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Concomitant Donor Heart Coronary Artery Bypass Grafting during Orthotopic Heart Transplantation. by Burnett CM, Radovancevic B, Birovljev S, Frazier OH, Duncan JM, Vega JD, Lonquist JL, Sweeney MS.; 1990; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=326469

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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Coronary intravascular ultrasound in 2 children after cardiac transplantation. by Latson LA, Tuzcu EM, Nissen S.; 1994; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325195

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Cutaneous T-Cell Lymphoma in a Cardiac Transplant Recipient. by McMullan DM, Radovancevic B, Jackow CM, Frazier OH, Duvic M.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101179

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Cytomegalovirus-Mediated Upregulation of Chemokine Expression Correlates with the Acceleration of Chronic Rejection in Rat Heart Transplants. by Streblow DN, Kreklywich C, Yin Q, De La Melena VT, Corless CL, Smith PA, Brakebill C, Cook JW, Vink C, Bruggeman CA, Nelson JA, Orloff SL.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140920

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Effect of IgM-positive crossmatches on survival in heart transplant recipients. by Scheinin SA, Radovancevic B, Kimball P, Duncan JM, Van Buren CT, Frazier OH, Kerman R.; 1995; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325212

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Effect of receiving a heart transplant: analysis of a national cohort entered on to a waiting list, stratified by heart failure severity. by Deng MC, De Meester JM, Smits JM, Heinecke J, Scheld HH.; 2000 Sep 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27468

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Endomyocardial biopsy in the evaluation of conditions leading to cardiac transplantation and in the evaluation of cardiac allograft rejection. by McAllister HA Jr.; 1995; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325211

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First reported case of Aspergillus granulosus infection in a cardiac transplant patient. by Fakih MG, Barden GE, Oakes CA, Berenson CS.; 1995 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=227968

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Genomic Stability of Legionella pneumophila Isolates Recovered from Two Cardiac Transplant Patients with Nosocomial Legionnaires' Disease. by Marrie TJ, Johnson WM, Tyler SD, Bezanson GS, Burbridge S.; 1994 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=264237

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Heart transplantation after emergency coronary artery bypass for failed angioplasty. by Hijazi A.; 1993; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325079

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Heart transplantation for acute occlusion of the left main coronary artery. by Fernandez-Gonzalez AL, Herreros JM, Alegria E.; 1993; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325100

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Heart transplantation in an 8-month-old girl. 10th anniversary report. by Frazier OH, Okereke OU, Radovancevic B, Towbin JA, Price JK, Denfield S, Chandler LB, Powers P, Bricker JT.; 1995; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325229

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Heart transplantation: approaching a new century. by Radovancevic B, Frazier OH.; 1999; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325599

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Increased expression of ICAM-1 in a case of accelerated coronary artery disease after heart transplantation. by Ballantyne CM, Masri BM, Clubb FJ Jr, Radovancevic B, Smith CW, Hawkins HK, Frazier OH, Willerson JT.; 1996; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325374

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Indirect enzyme-linked immunosorbent assay for immunoglobulin G and four immunoassays for immunoglobulin M to Toxoplasma gondii in a series of heart transplant recipients. by Sluiters JF, Balk AH, Essed CE, Mochtar B, Weimar W, Simoons ML, Ijzerman EP.; 1989 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=267352

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Kaposi's Sarcoma Associated with Previous Human Herpesvirus 8 Infection in Heart Transplant Recipients. by Emond JP, Marcelin AG, Dorent R, Milliancourt C, Dupin N, Frances C, Agut H, Gandjbakhch I, Calvez V.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=130767

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Legionella birminghamensis sp. nov. isolated from a cardiac transplant recipient. by Wilkinson HW, Thacker WL, Benson RF, Polt SS, Brookings E, Mayberry WR, Brenner DJ, Gilley RG, Kirklin JK.; 1987 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=269423

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Linked pacing after heterotopic heart transplantation with concurrent left ventricular reduction of the native heart. by Beyer E, Vatcharasiritham C, Sweeney M, Przybylowski P, Delgado R 3rd, Radovancevic B, Frazier OH.; 1998; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325576

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Molecular study of nosocomial nocardiosis outbreak involving heart transplant recipients. by Exmelin L, Malbruny B, Vergnaud M, Prosvost F, Boiron P, Morel C.; 1996 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=228943

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New immunosuppressive drugs in heart transplantation. by Costanzo MR.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59653

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Nocardia brasiliensis Cellulitis in a Heart Transplant Patient. by Sinnott JT IV, Holt DA, Alverez C, Greene J, Sweeney MS.; 1990; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=326471

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Nontransplant Cardiac Surgery as a Bridge to Heart Transplantation in Pediatric Dilated Cardiomyopathy. by Hsu RB, Chien CY, Wang SS, Chu SH.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124763

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Orthotopic heart transplantation with bicaval anastomosis. by Grande AM, Pozzoli M, Traversi E, Martinelli L, Minzioni G, D'Armini AM, Rinaldi M, Vigano M.; 1996; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325379

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Outcomes among pediatric heart transplant recipients. by Gajarski RJ, Rosenblatt HM, Denfield SW, Schowengerdt KO, Price JK, Towbin JA.; 1997; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325411

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Perfusionist-Transmitted Bacterial Mediastinitis in a Heart Transplant Recipient. by Hsu RB, Chen ML, Chang SC, Ko WJ, Chou NK, Wang SS, Chu SH.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101134

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Permanent pacing for asystole of the donor heart after heterotopic heart transplantation. by Kalife G, Radovancevic B, Fighali S.; 1997; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325399

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Postpericardiotomy syndrome in pediatric heart transplant recipients. Immunologic characteristics. by Cabalka AK, Rosenblatt HM, Towbin JA, Price JK, Windsor NT, Martin AB, Louis PT, Frazier OH, Bricker JT.; 1995; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325237

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Progressive visual deterioration leading to blindness after pediatric heart transplantation. by Schowengerdt KO Jr, Gajarski RJ, Denfield S.; 1993; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325116

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Prospective randomized trial of efficacy of ganciclovir versus that of anticytomegalovirus (CMV) immunoglobulin to prevent CMV disease in CMVseropositive heart transplant recipients treated with OKT3. by Aguado JM, GomezSanchez MA, Lumbreras C, Delgado J, Lizasoain M, Otero JR, Rufilanchas JJ, Noriega AR.; 1995 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=162800

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Selection of Patients for Heart Transplant. by Barnum BE.; 1987 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=324730

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The Clinical Coordinator's Role in Heart Transplantation. by Powers PL.; 1987 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=324731

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The history and development of cardiac transplantation. by DiBardino DJ.; 1999; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325641

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The Total Artificial Heart as a Bridge to Cardiac Transplantation Personal Recollections. by Cooley DA.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101178

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Update on pediatric heart transplantation. Long-term complications. by Gajarski RJ, Kearney DL, Price JK, Denfield SW.; 1997; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325467

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

A comparison of intravascular ultrasound with coronary angiography for evaluation of transplant coronary disease in pediatric heart transplant recipients. Author(s): Costello JM, Wax DF, Binns HJ, Backer CL, Mavroudis C, Pahl E. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 January; 22(1): 44-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12531412

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A limited sampling strategy for the estimation of 12-hour Neoral systemic drug exposure in heart transplant recipients. Author(s): Balram C, Sivathasan C, Cheung YB, Tan SB, Tan YS. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2002 September; 21(9): 1016-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12231373

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A prospective randomized controlled study on the efficacy and tolerance of two antilymphocytic globulins in the prevention of rejection in first-heart transplant recipients. Author(s): Schnetzler B, Leger P, Volp A, Dorent R, Pavie A, Gandjbakhch I. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 2002 June; 15(6): 317-25. Epub 2002 May 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12072903

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 strategy of hypothermic circulatory arrest for difficult heart transplant postventricular assist device. Author(s): Charbonneau E, Hendry PJ, Rubens FD, Collart F, Gariboldi V, Mesana TG. Source: The Annals of Thoracic Surgery. 2003 August; 76(2): 611-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12902118

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Aberrant T-cell activation via CD95 and apoptosis in peripheral T lymphocytes in stable heart transplant recipients. Author(s): Ankersmit HJ, Moser B, Hoffman M, Kocher AA, Schlechta B, BoltzNitulescu G, Wolner E. Source: Transplantation Proceedings. 2001 August; 33(5): 2860-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11498190

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Acute cardiovascular responses to leg-press resistance exercise in heart transplant recipients. Author(s): Oliver D, Pflugfelder PW, McCartney N, McKelvie RS, Suskin N, Kostuk WJ. Source: International Journal of Cardiology. 2001 November; 81(1): 61-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11690666

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Age-related heart rate response to exercise in heart transplant recipients. Functional significance. Author(s): Marconi C, Marzorati M, Fiocchi R, Mamprin F, Ferrazzi P, Ferretti G, Cerretelli P. Source: Pflugers Archiv : European Journal of Physiology. 2002 March; 443(5-6): 698-706. Epub 2001 December 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11889566

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Airbag trauma induced cutaneous fistulae in a heart transplant patient. Author(s): Alam M, Bickers DR. Source: Journal of the American Academy of Dermatology. 2002 August; 47(2 Suppl): S175-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12140454

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Ambulatory intraaortic balloon pump use as bridge to heart transplant. Author(s): Cochran RP, Starkey TD, Panos AL, Kunzelman KS. Source: The Annals of Thoracic Surgery. 2002 September; 74(3): 746-51; Discussion 751-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12238834

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Amplitude and timing of central aortic pressure wave reflections in heart transplant recipients. Author(s): Schofield RS, Schuler BT, Edwards DG, Aranda JM Jr, Hill JA, Nichols WW. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2002 September; 15(9): 809-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12219877

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An impaired cardiodynamic phase contributes to the abnormal VO(2) kinetics at exercise onset in both congestive heart failure and heart transplant patients but results from differing mechanisms. Author(s): M'Bouh S, Bellmont S, Lampert E, Epailly E, Zoll J, N'Guessan B, Ribera F, Geny B, Oyono S, Arnold P, Lonsdorfer J, Mettauer B. Source: Transplantation Proceedings. 2001 November-December; 33(7-8): 3543-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11750508

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An outbreak of mediastinitis among heart transplant recipients apparently related to a change in the united network for organ sharing guidelines. Author(s): Samuel R, Axelrod P, John KS, Fekete T, Alexander S, McCarthy J, Truant A, Todd B, Furukawa S, Eisen H, Spotnitz W. Source: Infection Control and Hospital Epidemiology : the Official Journal of the Society of Hospital Epidemiologists of America. 2002 July; 23(7): 377-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12138976

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Analysis of trends in hospital readmissions and postoperative complications in heart transplant recipients: single center study. Author(s): Donovan MP, Drusin RE, Edwards NM, Lietz K. Source: Transplantation Proceedings. 2002 August; 34(5): 1853-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176602

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Anesthetic considerations in the patient with a heart transplant. Author(s): Ashary N, Kaye AD, Hegazi AR, M Frost EA. Source: Heart Disease. 2002 May-June; 4(3): 191-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12028605

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Apoptosis and expression of heme oxygenase-1 in heart transplant recipients during acute rejection episode. Author(s): Chok R, Senechal M, Dorent R, Mallat Z, Leprince P, Pavie A, Ghossoub JJ, Gandjbakhch I. Source: Transplantation Proceedings. 2002 November; 34(7): 2815-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12431619

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Apoptosis and expression of heme oxygenase-1 in heart transplant recipients during acute rejection episodes. Author(s): Chok MK, Senechal M, Dorent R, Mallat Z, Leprince P, Bonnet N, Pavie A, Ghossoub JJ, Gandjbakhch I. Source: Transplantation Proceedings. 2002 December; 34(8): 3239-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12493432

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Are heart transplant recipients receiving cellular memories from their donated organ? A heuristic study. Author(s): Pearsall PK. Source: Hawaii Med J. 2001 November; 60(11): 282, 300. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11797489

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Assay of cytomegalovirus susceptibility to ganciclovir in renal and heart transplant recipients. Author(s): de Ona Navarro M, Melon S, Mendez S, Iglesias B, Palacio A, Bernardo MJ, Rodriguez-Lambert JL, Gomez E. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 2002 November; 15(11): 570-3. Epub 2002 September 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12461662

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Association between human herpesvirus type 6 and type 7, and cytomegalovirus disease in heart transplant recipients. Author(s): de Ona M, Melon S, Rodriguez JL, Sanmartin JC, Bernardo MJ. Source: Transplantation Proceedings. 2002 February; 34(1): 75-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11959192

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Avascular necrosis of the femoral head following heart transplant in a child. Author(s): Beals RK, Cobanoglu AM, Croy TJ. Source: Pediatric Transplantation. 2002 October; 6(5): 423-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12390431

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Baboon heart transplant in baby defended. Author(s): Mathews J. Source: Washington Post. 1984 October 29; : A1, A13. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11647782

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Benefits of photopheresis in the treatment of heart transplant patients with multiple/refractory rejection. Author(s): Dall'Amico R, Montini G, Murer L, Andreetta B, Tursi V, Feltrin G, Guzzi G, Angelini A, Zacchello G, Livi U. Source: Transplantation Proceedings. 1997 February-March; 29(1-2): 609-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9123152

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Bezafibrate and lovastatin decrease the oxidizability of low-density lipoproteins in heart transplant recipients with hyperlidemia. Author(s): Zambrana JL, Lopez-Miranda J, Blanco A, Arizon JM, Jansen S, Paniagua JA, Jimenez-Pereperez JA, Concha M, Perez-Jimenez F. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1998 December; 17(12): 1213-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9883763

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Bicaval anastomosis in a heart transplant recipient with left superior vena cava. Author(s): Rabago G, Martin-Trenor A, Lopez-Coronado JL, Macias A, Cosin-Sales J, Herreros JM. Source: The Annals of Thoracic Surgery. 2002 October; 74(4): 1242-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12400782

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Bilateral spontaneous lateral compartment syndrome in the legs of a patient who received a kidney and heart transplant. A case report. Author(s): Rosenfield AL, Bartal E. Source: The Journal of Bone and Joint Surgery. American Volume. 1992 June; 74(5): 7756. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1624494

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Bless the babies: one hundred fifteen late survivors of heart transplantation during the first year of life. The Loma Linda University Pediatric Heart Transplant Group. Author(s): Bailey LL, Gundry SR, Razzouk AJ, Wang N, Sciolaro CM, Chiavarelli M. Source: The Journal of Thoracic and Cardiovascular Surgery. 1993 May; 105(5): 805-14; Discussion 814-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8487560

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Blood gas dynamics at the onset of exercise in heart transplant recipients. Author(s): Braith RW, Limacher MC, Staples ED, Pollock ML. Source: Chest. 1993 June; 103(6): 1692-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8404086

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Blunted responses of doppler-derived aortic flow parameters during whole-body heavy isometric exercise in heart transplant recipients. Author(s): Auerbach I, Tenenbaum A, Motro M, Stroh CI, Har-Zahav Y, Fisman EZ. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2000 November; 19(11): 1063-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11077223

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Bone marrow changes in heart transplant recipients with peripheral cytopenia. Author(s): Castello A, Dal Bello B, Klersy C, Pistorio A, Vigano M, Ippoliti G, Arbustini E. Source: Transplantation. 1999 March 27; 67(6): 840-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10199732

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Breakdown of blood pressure and body fluid homeostasis in heart transplant recipients. Author(s): Braith RW, Mills RM Jr, Wilcox CS, Davis GL, Wood CE. Source: Journal of the American College of Cardiology. 1996 February; 27(2): 375-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8557909

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Breastfeeding an infant after heart transplant surgery. Author(s): Owens B. Source: Journal of Human Lactation : Official Journal of International Lactation Consultant Association. 2002 February; 18(1): 53-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11845738

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C(2) monitoring of cyclosporine in stable heart transplant patients after two daily and three daily doses. Author(s): Baraldo M, Francesconi A, Barbone F, Tursi V, Livi U, Furlanut M. Source: Transplantation Proceedings. 2002 December; 34(8): 3246-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12493435

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Cardiac output responses during exercise in volume-expanded heart transplant recipients. Author(s): Braith RW, Plunkett MB, Mills RM Jr. Source: The American Journal of Cardiology. 1998 May 1; 81(9): 1152-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9605058

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Cardiac rehabilitation following percutaneous revascularization, heart transplant, heart valve surgery, and for chronic heart failure. Author(s): Stewart KJ, Badenhop D, Brubaker PH, Keteyian SJ, King M. Source: Chest. 2003 June; 123(6): 2104-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796195

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Cardiac troponin T: a noninvasive marker for heart transplant rejection? Author(s): Alexis JD, Lao CD, Selter JG, Courtney MC, Correa DK, Lansman SL, Kushwaha SS, Gass AL. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1998 April; 17(4): 395-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9588584

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Cardiology patient pages. Heart transplant: what to expect. Author(s): Jurt U, Delgado D, Malhotra K, Bishop H, Ross H. Source: Circulation. 2002 October 1; 106(14): 1750-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12356623

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Care of the heart transplant patient. Author(s): Wrightson N, Blake A, English L. Source: Nurs Times. 2002 July 9-15; 98(28): 34-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12168377

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Catheter ablation of atrial flutter in a heart transplant recipient. Author(s): Krishnan SC, Falsone JM, Sanders WE, Chen H, Mill MR, Kushwaha SS. Source: Pacing and Clinical Electrophysiology : Pace. 2002 August; 25(8): 1262-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12358178

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Cavitary pneumonia due to Rhodococcus equi in a heart transplant recipient. Author(s): Kwak EJ, Strollo DC, Kulich SM, Kusne S. Source: Transplant Infectious Disease : an Official Journal of the Transplantation Society. 2003 March; 5(1): 43-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791074

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Centronuclear myopathy and cardiomyopathy requiring heart transplant. Author(s): Al-Ruwaishid A, Vajsar J, Tein I, Benson L, Jay V. Source: Brain & Development. 2003 January; 25(1): 62-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12536036

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Cerebral infection with Rhodococcus equi in a heart transplant recipient. Author(s): Kohl O, Tillmanns HH. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2002 October; 21(10): 1147-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12398884

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Cholelithiasis in infant and pediatric heart transplant patients. Author(s): Sakopoulos AG, Gundry S, Razzouk AJ, Andrews HG, Bailey LL. Source: Pediatric Transplantation. 2002 June; 6(3): 231-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12100508

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Circulating monocyte chemoattractant protein-1 in heart transplant recipients with cardiac allograft vasculopathy. Author(s): Beaudeux JL, Dorent R, Bernard M, Reagan M, Foglietti MJ, Gandjbakhch I, Cacoub P. Source: Clinical Biochemistry. 2002 February; 35(1): 77-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11937083

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Combined vitamin C and E supplementation retards early progression of arteriosclerosis in heart transplant patients. Author(s): Liu L, Meydani M. Source: Nutrition Reviews. 2002 November; 60(11): 368-71. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12462519

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Comparison of the efficacy and safety of Consupren solution and Sandimmun Neoral solution, 50 ml in stable heart transplant patients. Author(s): Toman J, Spinarova L, Krejci J, Hude P, Kopecna E, Kamarad V. Source: Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2002 December; 146(2): 87-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12572904

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Coronary artery disease in heart transplant recipients - diagnosis and treatment. Single centre experience based on results of elective coronary angiography. Author(s): Zakliczynski M, Lekston A, Swierad M, Wnek A, Buszman P, Przybylski R, Wojarski J, Przybylski J, Foremny J, Polonski L, Zembala M. Source: Kardiologia Polska. 2003 February; 58(2): 109-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14504636

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Correlation between serum creatinine, creatinine clearance, the calculated creatinine clearance and the glomerular filtration rate in heart transplant patients. Author(s): Cantarovich M, Giannetti N, Cecere R. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2002 July; 21(7): 815-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12100909

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Current experience with somatostatin analogues, especially angiopeptine, for the prevention of transplant vasculopathy in heart transplantation. Author(s): Wahlers T, Oppelt P, Pethig K, Heublein B. Source: Transplantation Proceedings. 1998 May; 30(3): 866-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9595129

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Current practices: immunosuppression induction, maintenance, and rejection regimens in contemporary post-heart transplant patient treatment. Author(s): Baran DA, Galin ID, Gass AL. Source: Current Opinion in Cardiology. 2002 March; 17(2): 165-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11981249

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Cutaneous infection caused by Ulocladium chartarum in a heart transplant recipient: case report and review. Author(s): Duran MT, Del Pozo J, Yebra MT, Crespo MG, Paniagua MJ, Cabezon MA, Guarro J. Source: Acta Dermato-Venereologica. 2003; 83(3): 218-21. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12816160

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Cytomegalovirus cholecystitis in a heart transplant recipient. Author(s): McMullan DM, Patel V, Radovancevic B, Hochman FL, Frazier OH. Source: Transplantation Proceedings. 2002 June; 34(4): 1271-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12072337

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De novo ampullary neuroendocrine tumor in an orthotopic heart transplant recipient. Author(s): Desai SS, Loh E, Kochman ML, Fraker D, DeNofrio D. Source: The American Journal of Gastroenterology. 1999 November; 94(11): 3382-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10566762

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Death after rejection with severe hemodynamic compromise in pediatric heart transplant recipients: a multi-institutional study. Author(s): Pahl E, Naftel DC, Canter CE, Frazier EA, Kirklin JK, Morrow WR; Pediatric Heart Transplant Study. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2001 March; 20(3): 279-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11257553

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Death-inducing receptors and apoptotic changes in lymphocytes of patients with heart transplant vasculopathy. Author(s): Ankersmit HJ, Moser B, Roedler S, Teufel I, Zuckermann A, Roth G, Lietz K, Back C, Gerlitz S, Wolner E, Boltz-Nitulescu G. Source: Clinical and Experimental Immunology. 2002 January; 127(1): 183-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11882051

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Dental management of a heart transplant patient. Author(s): Carlson-Mann LD. Source: Probe. 1996 March-April; 30(2): 77. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9611449

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Detection and prediction of acute heart transplant rejection with the myocardial T2 determination provided by a black-blood magnetic resonance imaging sequence. Author(s): Marie PY, Angioi M, Carteaux JP, Escanye JM, Mattei S, Tzvetanov K, Claudon O, Hassan N, Danchin N, Karcher G, Bertrand A, Walker PM, Villemot JP. Source: Journal of the American College of Cardiology. 2001 March 1; 37(3): 825-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11693758

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Detection of herpesvirus-like sequences in Kaposi's sarcoma from heart transplant recipients. Author(s): Briz M, Alonso-Pulpon L, Crespo-Leiro MG, Exposito C, Almagro M, Busto MJ, Fernandez MN. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1998 March; 17(3): 288-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9563605

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Detection of human herpesviruses 6 and 7 in heart transplant recipients by a multiplex polymerase chain reaction method. Author(s): Moschettini D, De Milito A, Catucci M, Marconi A, Rinina C, BianchiBandinelli ML, Valensin PE. Source: European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 1998 February; 17(2): 1179. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9629978

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Determinants and prognostic value of ischemic necrosis in early biopsies following heart transplant. Author(s): Esposito S, Maiello C, Renzulli A, Agozzino L, De Santo LS, Romano GP, Della Corte A, Amarelli C, Marra C, Giannolo B, Marmo J, Cotrufo M. Source: Heart and Vessels. 2000; 15(4): 167-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11471655

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Developing an outpatient ventricular assist device program to meet the needs of a “too successful” heart transplant program. Author(s): McGovern KJ. Source: J Cardiovasc Manag. 1998 September-October; 9(5): 19-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10185108

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Diagnosis and treatment of steroid resistant cellular rejection in heart transplant recipients--single center experience. Author(s): Zakliczynski M, Nozynski J, Zakliczynska H, Kozlowska K, Trzcinska I, Szewczyk M, Konecka-Mrowka D, Foremny J, Swierad M, Przybylski R, Pisarska H, Wojarski J, Durmala J, Zembala M. Source: Ann Transplant. 2003; 8(1): 25-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12848380

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Disseminated Cladophialophora bantiana infection in a heart transplant recipient. Author(s): Keyser A, Schmid FX, Linde HJ, Merk J, Birnbaum DE. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2002 April; 21(4): 503-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11927230

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Do heart transplant recipients need annual coronary angiography? Author(s): Sechtem U. Source: European Heart Journal. 2001 June; 22(11): 895-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11428812

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Dobutamine stress echocardiography: experience in pediatric heart transplant recipients. Author(s): Pahl E, Crawford SE, Swenson JM, Duffy CE, Fricker FJ, Backer CL, Mavroudis C, Chaudhry FA. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1999 July; 18(7): 725-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10452350

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Does use of intravascular ultrasound accelerate arteriopathy in heart transplant recipients? Author(s): Son R, Tobis JM, Yeatman LA, Johnson JA, Wener LS, Kobashigawa JA. Source: American Heart Journal. 1999 August; 138(2 Pt 1): 358-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10426852

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Donor and recipient characteristics that influence functional capacity of heart transplant recipients. Author(s): Richard R, Verdier JC, Pavie A, Rieu M. Source: Transplantation Proceedings. 2002 June; 34(4): 1262-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12072334

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Donor spontaneous intracerebral hemorrhage is associated with systemic activation of matrix metalloproteinase-2 and matrix metalloproteinase-9 and subsequent development of coronary vasculopathy in the heart transplant recipient. Author(s): Yamani MH, Starling RC, Cook DJ, Tuzcu EM, Abdo A, Paul P, Powell K, Ratliff NB, Yu Y, McCarthy PM, Young JB. Source: Circulation. 2003 October 7; 108(14): 1724-8. Epub 2003 September 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12975253

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Donor-derived soluble HLA plasma levels can not be used to monitor graft rejection in heart transplant recipients. Author(s): Koelman CA, Vaessen LM, Balk AH, Weimar W, Doxiadis II, Claas FH. Source: Transplant Immunology. 2000 March; 8(1): 57-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10834611

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Doppler tissue imaging for assessing left ventricular diastolic dysfunction in heart transplant rejection. Author(s): Stengel SM, Allemann Y, Zimmerli M, Lipp E, Kucher N, Mohacsi P, Seiler C. Source: Heart (British Cardiac Society). 2001 October; 86(4): 432-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11559685

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Double-helical CT as a new tool for tracking of allograft atherosclerosis in heart transplant recipients. Author(s): Shemesh J, Tenenbaum A, Stroh CI, Apter S, Har-Zahav Y, Fisman EZ, Itzchak Y, Motro M. Source: Investigative Radiology. 1999 July; 34(7): 485-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10399639

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Duration of graft cold ischemia does not affect outcomes in pediatric heart transplant recipients. Author(s): Scheule AM, Zimmerman GJ, Johnston JK, Razzouk AJ, Gundry SR, Bailey LL. Source: Circulation. 2002 September 24; 106(12 Suppl 1): I163-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12354727

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Early heart transplant in a child with advanced lymphoma. Author(s): Morgan E, Pahl E. Source: Pediatric Transplantation. 2002 December; 6(6): 509-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453205

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Echocardiographic backscatter signal analysis in heart transplant: is it useful in characterizing hypertrophy? Author(s): Maceira AM, Barba J, Cosin-Sales J, Rabago G. Source: Transplantation Proceedings. 2002 February; 34(1): 171-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11959235

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Effect of mycophenolate mofetil therapy on lymphocyte activation in heart transplant recipients. Author(s): Weigel G, Griesmacher A, Karimi A, Zuckermann AO, Grimm M, Mueller MM. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2002 October; 21(10): 1074-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12398872

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Effect of receiving a heart transplant. Peak exercise oxygen consumption is important predictor of outcome. Author(s): MacGowan GA, Murali S. Source: Bmj (Clinical Research Ed.). 2001 May 12; 322(7295): 1180; Author Reply 1180-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11379581

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Effect of receiving a heart transplant. Research target should be stratification procedures and mechanisms of death. Author(s): MacFadyen RJ. Source: Bmj (Clinical Research Ed.). 2001 May 12; 322(7295): 1180-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11379580

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Effect of receiving a heart transplant. Surely it is too late for a randomised controlled trial. Author(s): Satchithananda DK, Stoica SC, Parameshwar J, Wallwork J, Sharples LD. Source: Bmj (Clinical Research Ed.). 2001 May 12; 322(7295): 1179-80; Author Reply 11801. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11379579

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Effect of simvastatin on cyclosporine unbound fraction and apparent blood clearance in heart transplant recipients. Author(s): Akhlaghi F, McLachlan AJ, Keogh AM, Brown KF. Source: British Journal of Clinical Pharmacology. 1997 December; 44(6): 537-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9431828

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Effectiveness of metronidazole gel on cyclosporine-induced gingival overgrowth in heart transplant patients. Author(s): Montebugnoli L, Servidio D, Prati C. Source: Clinical Oral Investigations. 2002 March; 6(1): 24-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11996160

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Effects of an enhanced heart rate reserve on aerobic performance in patients with a heart transplant. Author(s): Ville NS, Varray A, Mercier B, Hayot M, Albat B, Chamari K, Prefaut C, Mercier J. Source: American Journal of Physical Medicine & Rehabilitation / Association of Academic Physiatrists. 2002 August; 81(8): 584-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12172067

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Effects of ursodeoxycholic acid (ursodiol) treatment on chronic viral hepatitis in heart transplant patients: results of a prospective, double-blind, placebo-randomized study. Author(s): Cadranel JF, Di Martino V, Dorent R, Bernard B, Hoang C, Myara A, Pauwels A, Ghoussoub JJ, Perrin M, Grippon P, Thabut D, Trivin F, Huraux JM, Gandjbakhch I, Opolon P, Lunel F. Source: Transplantation. 2003 April 15; 75(7): 977-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12698083

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Endomyocardial biopsy in the heterotopic heart transplant patient. Author(s): Arzouman DA, Arabia FA, Sethi GK, Copeland JG. Source: The Annals of Thoracic Surgery. 1998 March; 65(3): 857-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9527239

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End-stage left ventricular dysfunction associated with extreme clinical right ventricular failure: contraindication for heart transplant? Author(s): Ben-Gal T, Sahar G, Zafrir N, Berman M, Sagie A, Vidne B, Battler A, Aravot D. Source: Transplantation Proceedings. 2001 September; 33(6): 2900-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11543781

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Energy metabolism in diabetic and nondiabetic heart transplant recipients. Author(s): Benedini S, Fiocchi R, Battezzati A, Scifo P, Sereni LP, Gamba A, Mammana C, Del Maschio A, Perseghin G, Luzi L. Source: Diabetes Care. 2002 March; 25(3): 530-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11874942

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Epstein-Barr virus mediated graft rejection in heart transplant patients: implication of the cardiac cytoskeleton. Author(s): LeBlanc MH, Boudriau S, Doyle D, Gagnon A, Beaudoin D, Coulombe D, Gleeton O, Kingma JG Jr, Boutet M. Source: Transplantation Proceedings. 1998 May; 30(3): 918-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9595146

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Establishment and cidofovir sensitivity of a cell line from a heart transplant recipient with multiple cutaneous tumors. Author(s): Schacke M, Meerbach A, Thust R, Hyckel P, Wutzler P. Source: Neoplasma. 2003; 50(3): 165-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12937848

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Evaluation of a mentorship program for heart transplant patients. Author(s): Wright L, Pennington JJ, Abbey S, Young E, Haines J, Ross H. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2001 September; 20(9): 1030-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11557200

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Evaluation of pulmonary hypertension in heart transplant candidates. Author(s): Natale ME, Pina IL. Source: Current Opinion in Cardiology. 2003 March; 18(2): 136-40. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12652220

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Exercise does not induce oxidative stress in trained heart transplant recipients. Author(s): Jimenez L, Lefevre G, Richard R, Duvallet A, Rieu M. Source: Medicine and Science in Sports and Exercise. 2000 December; 32(12): 2018-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11128845

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Exercise tolerance in heart transplant patients with altered pulmonary diffusion capacity. Author(s): Ville N, Mercier J, Varray A, Albat B, Messner-Pellenc P, Prefaut C. Source: Medicine and Science in Sports and Exercise. 1998 March; 30(3): 339-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9526878

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Experience of patients with end-stage heart failure who underwent heart transplant at UCLA. Author(s): Hachida M, Nonoyama M, Miyagishima M, Hoshi H, Iwade K, Matsuda N, Saito S, Hosoda S, Koyanagi H, Laks H. Source: Heart and Vessels. 1997; Suppl 12: 34-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9476539

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Factors increasing the risk of allograft vascular disease in heart transplant recipients. Author(s): Arbustini E, Dal Bello B, Morbini P, Klersy C, Grasso M, Diegoli M, Gavazzi A, Campana C, Grossi P, Pellegrini C, Martinelli L, Ippoliti G, Specchia G, Vigano M. Source: G Ital Cardiol. 1997 October; 27(10): 985-99. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9359048

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Famciclovir treatment of chronic hepatitis B in heart transplant recipients: a prospective trial. Author(s): Wedemeyer H, Boker KH, Pethig K, Petzold DR, Flemming P, Tillmann HL, Vollmar J, Basturk M, Goldmann E, Griffin KE, Haverich A, Manns MP. Source: Transplantation. 1999 November 27; 68(10): 1503-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10589947

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Fatal hyperthyroidism after amiodarone treatment and total lymphoid irradiation in a heart transplant recipient. Author(s): Hauptman PJ, Fyfe B, Mechanick J, Lansman S, Gass A. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1993 May-June; 12(3): 513-6. Erratum In: J Heart Lung Transplant 1993 July-August; 12(4): 572. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8329429

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Fatal primary multidrug-resistant tuberculosis in a heart transplant recipient. Author(s): Di Perri G, Luzzati R, Forni A, Allegranzi B, Cazzadori A, Bonora S, Mazzucco A, Concia E. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 1998; 11(4): 305-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9704397

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Fatal visceral leishmaniasis in a heart transplant recipient. Author(s): Frapier JM, Abraham B, Dereure J, Albat B. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2001 August; 20(8): 912-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11502416

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Felodipine in hypertensive heart transplant recipients. Author(s): Ambrosi P, Bertucci B, Bertault-Peres P, Metras D. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1996 May; 15(5): 540-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8771512

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First experiences with the stable prostacyclin analog iloprost in the evaluation of heart transplant candidates with increased pulmonary vascular resistance. Author(s): Sablotzki A, Czeslick E, Gruenig E, Friedrich I, Schubert S, Borgermann J, Hentschel T. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 April; 125(4): 960-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12698166

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First-time status 1 heart transplant candidates: inevitably poor prognosis? Author(s): Sahar G, Berman M, Georghiou G, Ben Gal T, Kogan A, Stamler A, Aravot D, Vidne B. Source: Transplantation Proceedings. 2001 September; 33(6): 2951. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11543806

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Fish oil improves endothelium-dependent coronary vasodilation in heart transplant recipients. Author(s): Fleischhauer FJ, Yan WD, Fischell TA. Source: Journal of the American College of Cardiology. 1993 March 15; 21(4): 982-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8450169

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Five years' follow-up of renal glomerular and tubular functions in heart transplant recipients. Author(s): Hartmann A, Andereassen AK, Holdaas H, Simonsen S, Geiran O, Berg KJ. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1996 October; 15(10): 972-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8913913

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Five-year follow-up of hepatitis C-naive heart transplant recipients who received hepatitis C-positive donor hearts. Author(s): Gudmundsson GS, Malinowska K, Robinson JA, Pisani BA, Mendez JC, Foy BK, Mullen GM. Source: Transplantation Proceedings. 2003 June; 35(4): 1536-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12826214

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Follow-up after conversion to Neoral in stable heart transplant recipients. Author(s): Pethig K, Geiger M, Korn A, Grote M, Christians U, Wahlers T. Source: Transplantation Proceedings. 1996 August; 28(4): 2282-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8769226

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FPIA and EMIT methods compared for cyclosporine monitoring in heart transplant patients. Author(s): Fatio R, Sutsch G, Pei P, Follath F, Kiowski W. Source: Clinical Chemistry. 1998 March; 44(3): 693-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9510894

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French multicenter study of Neoral conversion in heart transplant patients. Author(s): Dorent R, Albat B, Baladier V, Billes MA, Dureau G, Epalily E, Guillemain R, Houyel L, Lelong B, Lentdecker P, Metras D, Monties JR, Petit T, Pol A, Soyer R, Villemot JP, Puget S, Gandjbakhch I. Source: Transplantation Proceedings. 1997 August; 29(5): 2326-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9270746

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Fulminant toxoplasmosis in a heart transplant recipient. Author(s): Hermanns B, Brunn A, Schwarz ER, Sachweh JS, Seipelt I, Schroder JM, Vogel U, Schoendube FA, Buettner R. Source: Pathology, Research and Practice. 2001; 197(3): 211-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11314787

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Functional and morphological findings in heart transplant recipients with a normal coronary angiogram: an analysis by dobutamine stress echocardiography, intracoronary Doppler and intravascular ultrasound. Author(s): Spes CH, Klauss V, Rieber J, Schnaack SD, Tammen AR, Uberfuhr P, Reichart B, Theisen K, Angermann CE, Mudra H. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1999 May; 18(5): 391-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10363681

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Functional restitution of cardiac control in heart transplant patients. Author(s): Toledo E, Pinhas I, Aravot D, Almog Y, Akselrod S. Source: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2002 March; 282(3): R900-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11832413

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Functional significance of cardiac reinnervation in heart transplant recipients. Author(s): Schwaiblmair M, von Scheidt W, Uberfuhr P, Ziegler S, Schwaiger M, Reichart B, Vogelmeier C. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1999 September; 18(9): 838-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10528745

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Functional status and quality of life of heart transplant recipients surviving beyond 5 years. Author(s): Aravot D, Berman M, Ben-Gal T, Sahar G, Vidne B. Source: Transplantation Proceedings. 2000 June; 32(4): 731-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10856562

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Fungal purulent constrictive pericarditis in a heart transplant patient. Author(s): Canver CC, Patel AK, Kosolcharoen P, Voytovich MC. Source: The Annals of Thoracic Surgery. 1998 June; 65(6): 1792-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9647112

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Gallstone disease in heart transplant recipients. Author(s): Richardson WS, Surowiec WJ, Carter KM, Howell TP, Mehra MR, Bowen JC. Source: Annals of Surgery. 2003 February; 237(2): 273-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12560786

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Ganciclovir resistance as a result of oral ganciclovir in a heart transplant recipient with multiple human cytomegalovirus strains in blood. Author(s): Baldanti F, Simoncini L, Sarasini A, Zavattoni M, Grossi P, Revello MG, Gerna G. Source: Transplantation. 1998 August 15; 66(3): 324-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9721800

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Ganciclovir resistance in a heart transplant recipient infected by cytomegalovirus. Author(s): Manso JV, Lambert JL, Ona M, de la Iglesia JL, Iglesias J. Source: International Journal of Cardiology. 1999 September 30; 71(1): 97-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10522573

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Ganciclovir treatment of active hepatitis B virus infection in a heart transplant patient. Author(s): Anand BS, Yoffe B, Young JB. Source: Journal of Clinical Gastroenterology. 1996 March; 22(2): 144-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8742657

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Gas exchange and cardiovascular kinetics with different exercise protocols in heart transplant recipients. Author(s): Grassi B, Marconi C, Meyer M, Rieu M, Cerretelli P. Source: Journal of Applied Physiology (Bethesda, Md. : 1985). 1997 June; 82(6): 1952-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9173964

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Gas exchange kinetics in heart transplant recipients. Author(s): Cerretelli P, Marconi C, Meyer M, Ferretti G, Grassi B. Source: Chest. 1992 May; 101(5 Suppl): 199S-205S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1576835

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Gastrointestinal complications and endoscopic findings in heart transplant patients. Author(s): Steck TB, Durkin MG, Costanzo-Nordin MR, Keshavarzian A. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1993 March-April; 12(2): 244-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8476897

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Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Author(s): Chowbay B, Cumaraswamy S, Cheung YB, Zhou Q, Lee EJ. Source: Pharmacogenetics. 2003 February; 13(2): 89-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12563178

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Global and regional left ventricular function in heart transplant patients: an angiographic follow-up study. Author(s): Boffa GM, Razzolini R, Livi U, Mantovan R, Faggian G, Stritoni P, Thiene G, Chioin R. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1992 September-October; 11(5): 878-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1420235

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Glucocorticoid-induced osteopenia in adolescent heart transplant recipients. Author(s): Braith RW, Howard C, Fricker FJ, Mitchell M, Edwards DG. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2000 September; 19(9): 840-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11008072

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Glucose metabolism in heart transplant recipients treated with FK506 or cyclosporine. Author(s): Sahar G, Berman M, Ben-Gal T, Sahar E, Kogan A, Michowitch R, Saute M, Kramer M, Sagie A, Shapira Y, Aravot D, Vidne BA. Source: Transplantation Proceedings. 2003 March; 35(2): 678. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12644092

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Gouty tophus simulating soft tissue tumor in a heart transplant recipient. Author(s): Chaoui A, Garcia J, Kurt AM. Source: Skeletal Radiology. 1997 October; 26(10): 626-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9361362

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Graft arteriosclerosis-induced myocardial pathology in heart transplant recipients: predictive value of endomyocardial biopsy. Author(s): Winters GL, Schoen FJ. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1997 October; 16(10): 985-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9361240

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Graft functional recovery and outcome after heart transplant: is troponin I a reliable marker? Author(s): Biagioli B, Simeone F, Marchetti L, Giomarelli P, Maccherini M, Scolletta S. Source: Transplantation Proceedings. 2003 June; 35(4): 1519-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12826210

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Graft vascular disease in heart transplant patients. Author(s): Mann J. Source: British Heart Journal. 1992 September; 68(3): 253-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1389752

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Graft vasculopathy among recipients of heart transplantation during the first 12 years of life. The Pediatric Heart Transplant Group. Author(s): Bailey LL, Zuppan CW, Chinnock RE, Johnston JK, Razzouk AJ, Gundry SR. Source: Transplantation Proceedings. 1995 June; 27(3): 1921-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7792838

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Guanosine-5'-triphosphate increases in red blood cells of heart transplant recipients treated with mycophenolate mofetil. Author(s): Griesmacher A, Weigel G, Seebacher G, Muller MM. Source: Advances in Experimental Medicine and Biology. 2000; 486: 139-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11783471

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HBV and HCV infections in heart transplant recipients. Author(s): Fagiuoli S, Minniti F, Pevere S, Farinati F, Burra P, Livi U, Naccarato R, Chiaramonte M. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2001 July; 20(7): 718-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11448796

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Heart transplant for anomalous origin of left coronary artery from pulmonary artery. Author(s): Nair KK, Zisman LS, Lader E, Dimova A, Canver CC. Source: The Annals of Thoracic Surgery. 2003 January; 75(1): 282-4; Discussion 284-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12537235

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Heart transplant patient teaching documentation. Author(s): Russell CL, Freiburghaus M. Source: Clinical Nurse Specialist Cns. 2003 September; 17(5): 249-57; Quiz 258-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14501306

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Heart transplant recipient climbs the Matterhorn. 42-year-old Kelly Perkins becomes the first person with a heart transplant to ascend the 4478-m peak. Author(s): Kapp C. Source: Lancet. 2003 September 13; 362(9387): 880-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13678995

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Heart transplant: a few non-medical aspects. Author(s): Francois J. Source: Acta Cardiol. 1982; 1982(Suppl. 28): 171-2. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11649507

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Heart transplantation and psychology--do we need psychology in transplant medicine? Author(s): Scheld HH, Schmid C, Drees G. Source: The Thoracic and Cardiovascular Surgeon. 2002 August; 50(4): 197-200. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12165867

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Hemodynamic effects of inhaled aerosolized iloprost and inhaled nitric oxide in heart transplant candidates with elevated pulmonary vascular resistance. Author(s): Sablotzki A, Hentschel T, Gruenig E, Schubert S, Friedrich I, Muhling J, Dehne MG, Czeslick E. Source: European Journal of Cardio-Thoracic Surgery : Official Journal of the European Association for Cardio-Thoracic Surgery. 2002 November; 22(5): 746-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12414041

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Hepatitis B infection in heart transplant patients. Author(s): Wedemeyer H, Pethig K, Manns MP, Boker KH. Source: Gastroenterology. 2001 April; 120(5): 1311-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11288750

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Hepatitis B virus infection in heart transplant recipients in a hepatitis B endemic area. Author(s): Ko WJ, Chou NK, Hsu RB, Chen YS, Wang SS, Chu SH, Lai MY. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2001 August; 20(8): 865-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11502409

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Hepatitis C status of heart transplant recipients. Author(s): Fagiuoli S, Cooper DK, Zuhdi N. Source: Clinical Transplantation. 1998 February; 12(1): 5-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9541416

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Hepatitis virus infections in heart transplant recipients: epidemiology, natural history, characteristics, and impact on survival. Author(s): Lunel F, Cadranel JF, Rosenheim M, Dorent R, Di-Martino V, Payan C, Fretz C, Ghoussoub JJ, Bernard B, Dumont B, Perrin M, Gandjbachkh I, Huraux JM, Stuyver L, Opolon P. Source: Gastroenterology. 2000 October; 119(4): 1064-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11040193

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High frequency of anti-endomysial reactivity in candidates to heart transplant. Author(s): Prati D, Bardella MT, Peracchi M, Porretti L, Cardillo M, Pagliari C, Tarantino C, Della TE, Scalamogna M, Bianchi PA, Sirchia G, Conte D; North Italy Transplant Programme Working Group (NITp). Source: Dig Liver Dis. 2002 January; 34(1): 39-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11926572

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High homocysteine, low folate, and low vitamin B6 concentrations: prevalent risk factors for vascular disease in heart transplant recipients. Author(s): Gupta A, Moustapha A, Jacobsen DW, Goormastic M, Tuzcu EM, Hobbs R, Young J, James K, McCarthy P, van Lente F, Green R, Robinson K. Source: Transplantation. 1998 February 27; 65(4): 544-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9500631

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Histopathological findings in heart transplant patients under tacrolimusmycophenolate mofetil versus cyclosporine microemulsion-azathioprine. Author(s): Sgrosso JL, Ferrer J, Araujo G, Romeo L, Parisi C, Vazquez MC. Source: Transplantation Proceedings. 2002 February; 34(1): 115-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11959214

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Hope, mood states and quality of life in female heart transplant recipients. Author(s): Evangelista LS, Doering LV, Dracup K, Vassilakis ME, Kobashigawa J. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 June; 22(6): 681-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12821165

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Hormonal, renal, hemodynamic responses to acute neutral endopeptidase inhibition in heart transplant patients. Author(s): Piquard F, Richard R, Charloux A, Doutreleau S, Hannedouche T, Brandenberger G, Geny B. Source: Journal of Applied Physiology (Bethesda, Md. : 1985). 2002 August; 93(2): 56975. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12133866

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Human papillomavirus 16 in a heart transplant recipient. Author(s): Auvinen E, Tarkkanen J, Mattila P, Mattila S. Source: Transplantation Proceedings. 2002 June; 34(4): 1281-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12072341

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Hypertension in heart transplant recipients: more than just cyclosporine. Author(s): Eisen HJ. Source: Journal of the American College of Cardiology. 2003 February 5; 41(3): 433-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12575971

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Hypertension in relation to nitric oxide, asymmetric dimethylarginine, and inflammation: different patterns in heart transplant recipients and individuals with essential hypertension. Author(s): Holm T, Aukrust P, Aagaard E, Ueland T, Haugstad TS, Kjekshus J, Simonsen S, Froland SS, Gullestad L, Andreassen AK. Source: Transplantation. 2002 November 27; 74(10): 1395-400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12451238

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Hypotension, acidosis, and vasodilatation syndrome post-heart transplant: prognostic variables and outcomes. Author(s): Chemmalakuzhy J, Costanzo MR, Meyer P, Piccione W, Kao W, Winkel E, Saltzberg M, Heroux A, Parrillo J. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2001 October; 20(10): 1075-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11595562

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Immunohistochemical model to predict risk for coronary artery disease and failure in heart transplant patients. Author(s): Labarre CA, Nelson DR, Pitts DE, Kirlin PC, Halbrook H. Source: American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2001 September; 1(3): 251-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12102259

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Impact of beta-blocker therapy on functional capacity criteria for heart transplant listing. Author(s): Pohwani AL, Murali S, Mathier MM, Tokarczyk T, Kormos RL, McNamara DM, MacGowan GA. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 January; 22(1): 78-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12531416

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Impact of cyclosporine 2-h level and mycophenolate mofetil dose on clinical outcomes in de novo heart transplant patients receiving anti-thymocyte globulin induction. Author(s): Cantarovich M, Giannetti N, Cecere R. Source: Clinical Transplantation. 2003 April; 17(2): 144-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12709082

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Implantable cardioverter defibrillator patch erosion in a heart transplant patient. Author(s): Chilukuri S, Herlihy JP, Massumkhani GA, Duncan JM Jr, Frazier OH. Source: The Annals of Thoracic Surgery. 2001 July; 72(1): 261-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11465194

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Implantation of biventricular assist devices for chronic heart transplant rejection. Author(s): Sezai A, Arusoglu L, Minami K, El-Banayosy A, Korfer R. Source: The Annals of Thoracic Surgery. 2002 August; 74(2): 609-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12173867

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Improvement of cardiovascular risk factors in heart transplant recipients after conversion from cyclosporine to tacrolimus: a role of the TGF-beta system. Author(s): van Riemsdijk IC, Baan CC, Balk AH, Vantrimpont PM, Maat LP, Weimar W. Source: Transplantation Proceedings. 2002 August; 34(5): 1864-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176606

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Increase in atrial size in long-term survivors of heart transplant. Author(s): Gudmundsson GS, Smull DL, Pisani BA, Bane CD, Mendez JC, Mullen GM, Jacobs WR. Source: Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. 2003 October; 16(10): 1043-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14566297

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Increased prevalence of autoimmune phenomena and greater risk for alloreactivity in female heart transplant recipients. Author(s): Lietz K, John R, Kocher A, Schuster M, Mancini DM, Edwards NM, Itescu S. Source: Circulation. 2001 September 18; 104(12 Suppl 1): I177-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11568052

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Independent association between plasma leptin levels and heart rate in heart transplant recipients. Author(s): Winnicki M, Phillips BG, Accurso V, van De Borne P, Shamsuzzaman A, Patil K, Narkiewicz K, Somers VK. Source: Circulation. 2001 July 24; 104(4): 384-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11468197

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Infection after pediatric heart transplantation: results of a multiinstitutional study. The Pediatric Heart Transplant Study Group. Author(s): Schowengerdt KO, Naftel DC, Seib PM, Pearce FB, Addonizio LJ, Kirklin JK, Morrow WR. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1997 December; 16(12): 1207-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9436132

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Infections in the heart transplant recipient. Author(s): Baas LS, Bell B, Giesting R, McGuire N, Wagoner LE. Source: Critical Care Nursing Clinics of North America. 2003 March; 15(1): 97-108. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12597045

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Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center. Author(s): Montoya JG, Giraldo LF, Efron B, Stinson EB, Gamberg P, Hunt S, Giannetti N, Miller J, Remington JS. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2001 September 1; 33(5): 629-40. Epub 2001 August 06. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11486285

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Inhibition of inosine monophosphate dehydrogenase activity by the plasma of heart transplant recipients receiving mycophenolate mofetil. Author(s): Griesmacher A, Weigel G, Seebacher G, Mallinger R, Laufer G, Muller MM. Source: Advances in Experimental Medicine and Biology. 1998; 431: 537-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9598124

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Inhomogeneity of myocardial perfusion in heart transplant recipients: evaluation with dobutamine thallium-201 SPECT. Author(s): Yen RF, Ho YL, Chou NK, Hsu RB, Huang PJ. Source: Nuclear Medicine Communications. 2001 September; 22(9): 1015-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11505211

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Internet teleconferencing method for telepathology consultations from lung and heart transplant patients. Author(s): Marchevsky AM, Lau SK, Khanafshar E, Lockhart C, Phan A, Michaels PJ, Fishbein MC. Source: Human Pathology. 2002 April; 33(4): 410-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12055675

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Interplay between methylenetetrahydrofolate reductase gene polymorphism 677C->T and serum folate levels in determining hyperhomocysteinemia in heart transplant recipients. Author(s): Potena L, Grigioni F, Viggiani M, Magnani G, Sorbello S, Falchetti E, Sassi S, Mantovani V, Bacchi-Reggiani L, Magelli C, Branzi A. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2001 December; 20(12): 1245-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11744407

90

Heart Transplant

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Invasive Scedosporium apiospermum infection in a heart transplant recipient presenting with multiple skin nodules and a pulmonary consolidation. Author(s): Kusne S, Ariyanayagam-Baksh S, Strollo DC, Abernethy J. Source: Transplant Infectious Disease : an Official Journal of the Transplantation Society. 2000 December; 2(4): 194-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11429031

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Is atropine infusion necessary to achieve the target heart rate in heart transplant patients during dobutamine stress echocardiography? Author(s): Flox A, Sanchez V, Delgado JF, Fernandez S, Tello R, Jimenez J, Garcia J, Gomez MA, Lombera F, Saenz de la Calzada C. Source: Transplantation Proceedings. 2002 December; 34(8): 3241-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12493433

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Itraconazole for the treatment of pulmonary aspergillosis in heart transplant recipients. Author(s): Nanas JN, Saroglou G, Anastasiou-Nana MI, Kostis EB, Petrochilou-Paschou VP, Kontoyannis DA, Stamatelopoulos SF, Moulopoulos SD. Source: Clinical Transplantation. 1998 February; 12(1): 30-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9541420

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Itraconazole-induced rhabdomyolysis and acute renal failure in a heart transplant recipient treated with simvastatin and cyclosporine. Author(s): Vlahakos DV, Manginas A, Chilidou D, Zamanika C, Alivizatos PA. Source: Transplantation. 2002 June 27; 73(12): 1962-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12131698

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Kaposi's sarcoma associated with previous human herpesvirus 8 infection in heart transplant recipients. Author(s): Emond JP, Marcelin AG, Dorent R, Milliancourt C, Dupin N, Frances C, Agut H, Gandjbakhch I, Calvez V. Source: Journal of Clinical Microbiology. 2002 June; 40(6): 2217-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12037090

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Kaposi's sarcoma in a heart transplant patient. Author(s): Gobitti C, De Vivo F, Franchin G, Minatel E, Innocente R, Trovo MG. Source: Acta Oncologica (Stockholm, Sweden). 1998; 37(7-8): 769-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10051001

Studies

91

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Kaposi's sarcoma occurring de novo in the surgical scar in a heart transplant recipient. Author(s): Micali G, Gasparri O, Nasca MR, Sapuppo A. Source: Journal of the American Academy of Dermatology. 1992 August; 27(2 Pt 1): 2734. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1430374

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Kidney function in cyclosporine-treated pediatric heart transplant recipients. Author(s): Laine J, Jalanko H, Leijala M, Sairanen H, Holmberg C. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1997 December; 16(12): 1217-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9436133

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Late acute rejection and subclinical noncompliance with cyclosporine therapy in heart transplant recipients. Author(s): De Geest S, Abraham I, Moons P, Vandeputte M, Van Cleemput J, Evers G, Daenen W, Vanhaecke J. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1998 September; 17(9): 854-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9773856

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Late reduction in cyclosporine dosage does not improve renal function in pediatric heart transplant recipients. Author(s): Rice JE, Shipp AT, Carlin JB, Vidmar SI, Weintraub RG. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2002 October; 21(10): 1109-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12398876

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Left circumflex coronary artery-to-left atrium fistulas detected by transesophageal echocardiography in heart transplant recipients. Author(s): Gascuena R, de Lombera F, Fernandez S, Santos M, Delgado J, Escribano P, Gomez MA. Source: Echocardiography (Mount Kisco, N.Y.). 2000 July; 17(5): 443-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10979018

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Left ventricular assist devices as alternative to heart transplant. When will they replace allogenic heart transplants? Author(s): Busund R. Source: Scandinavian Cardiovascular Journal : Scj. 2002 December; 36(6): 323-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12626196

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Heart Transplant

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Lethal systemic dissemination from a cutaneous infection due to Curvularia lunata in a heart transplant recipient. Author(s): Tessari G, Forni A, Ferretto R, Solbiati M, Faggian G, Mazzucco A, Barba A. Source: Journal of the European Academy of Dermatology and Venereology : Jeadv. 2003 July; 17(4): 440-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12834456

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Lifestyle assessment and heart transplant evaluation. Author(s): Mozdzierz GJ. Source: Transplantation Proceedings. 1999 June; 31(4A): 18S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10372036

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Lipid metabolism and immunosuppressive therapy in heart transplant recipients. Author(s): Berman M, Ben-Gal T, Stamler A, Kogan A, Shapira Y, Sagie A, Saute M, Kramer M, Aravot D, Vidne B, Sahar G. Source: Transplantation Proceedings. 2003 March; 35(2): 677. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12644091

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Lipoprotein abnormalities are highly prevalent in pediatric heart transplant recipients. Author(s): Chin C, Rosenthal D, Bernstein D. Source: Pediatric Transplantation. 2000 August; 4(3): 193-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10933319

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Long-term follow-up after total lymphoid irradiation in pediatric heart transplant recipients. Author(s): Chin C, Hunt S, Robbins R, Hoppe R, Reitz B, Bernstein D. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2002 June; 21(6): 667-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12057700

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Long-term follow-up of arrhythmias in pediatric orthotopic heart transplant recipients: incidence and correlation with rejection. Author(s): Kertesz NJ, Towbin JA, Clunie S, Fenrich AL, Friedman RA, Kearney DL, Dreyer WJ, Price JF, Radovancevic B, Denfield SW. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 August; 22(8): 889-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12909469

Studies

93

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Long-term outcome of chronic hepatitis B in heart transplant recipients. Author(s): Wedemeyer H, Pethig K, Wagner D, Flemming P, Oppelt P, Petzold DR, Haverich A, Manns MP, Boeker KH. Source: Transplantation. 1998 November 27; 66(10): 1347-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9846521

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Long-term outcome with the use of OKT3 induction therapy in heart transplant patients: a single-center experience. Author(s): Adamson R, Obispo E, Dychter S, Dembitsky W, Moreno-Cabral R, Jaski B, Gordon J, Hoagland P, Moore K, King J, Andrews J, Rich M, Daily PO. Source: Transplantation Proceedings. 1998 June; 30(4): 1107-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9636449

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Long-term results of cardiac transplantation from live donors: the domino heart transplant. Author(s): Anyanwu AC, Banner NR, Radley-Smith R, Khaghani A, Yacoub MH. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2002 September; 21(9): 971-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12231367

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Long-term results of CMV hyperimmune globulin prophylaxis in 377 heart transplant recipients. Author(s): Kocher AA, Bonaros N, Dunkler D, Ehrlich M, Schlechta B, Zweytick B, Grimm M, Zuckermann A, Wolner E, Laufer G. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 March; 22(3): 250-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12633691

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Long-term results of triple-drug-based immunosuppression in nonneonatal pediatric heart transplant recipients. Author(s): Gajarski RJ, Smith EO, Denfield SW, Rosenblatt HM, Kearney D, Frazier OH, Radovancevic B, Price JK, Kertesz NJ, Towbin JA. Source: Transplantation. 1998 June 15; 65(11): 1470-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9645805

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Low cyclosporin-A level due to Saint-John's-wort in heart transplant patients. Author(s): Ahmed SM, Banner NR, Dubrey SW. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2001 July; 20(7): 795. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11474706

94

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Low incidence and severity of transplant-associated coronary artery disease in heart transplants from live donors. Author(s): Anyanwu AC, Banner NR, Mitchell AG, Khaghani A, Yacoub MH. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 March; 22(3): 281-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12633695

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Lung cancer in heart transplant patients: a 16-year survey. Author(s): Dorent R, Mohammadi S, Tezenas S, Silvaggio G, Ghossoub JJ, Leger P, Vaissier E, Leprince P, Carnot F, Riquet M, Pavie A, Gandjbakhch I. Source: Transplantation Proceedings. 2000 December; 32(8): 2752-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11134787

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Lung nodular lesions in heart transplant recipients. Author(s): Munoz P, Palomo J, Guembe P, Rodriguez-Creixems M, Gijon P, Bouza E. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2000 July; 19(7): 660-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10930815

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Lymphoproliferative disorders in heart transplant recipients: role of hepatitis C virus (HCV) and Epstein-Barr virus (EBV) infection. Author(s): Buda A, Caforio A, Calabrese F, Fagiuoli S, Pevere S, Livi U, Naccarato R, Burra P. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 2000; 13 Suppl 1: S402-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11112042

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Malignant fibrous histiocytoma of the lung presenting as bronchial obstruction in a heart transplant recipient. Author(s): Alhadab T, Alvarez F, Phillips NJ, Hauptman PJ. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2002 October; 21(10): 1140-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12398882

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Management of hand and upper-extremity infections in heart transplant recipients. Author(s): Klein MB, Chang J. Source: Plastic and Reconstructive Surgery. 2000 September; 106(3): 598-601. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10987466

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Mechanical circulatory support of heart transplant patients. Author(s): Arafa O, Fiane AE, Svennevig JL, Geiran OR. Source: Transplantation Proceedings. 2001 February-March; 33(1-2): 1603-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11267436

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95

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Mid-term follow up results of Japanese heart transplant patients operated in UCLA Medical Center. Author(s): Hachida M, Nonoyama M, Hanayama N, Miyagishima M, Hoshi H, Saito S, Koyanagi H. Source: Jpn J Thorac Cardiovasc Surg. 2000 November; 48(11): 713-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11144091

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Mitral inflow and pulmonary venous Doppler measurements do not predict pulmonary capillary wedge pressure in heart transplant recipients. Author(s): Richards DR, Gilliland Y, Bernal JA, Smart FW, Stapleton DD, Ventura HO, Cheirif J. Source: American Heart Journal. 1998 April; 135(4): 641-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9539480

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Modeling the effects of functional performance and post-transplant comorbidities on health-related quality of life after heart transplantation. Author(s): Butler J, McCoin NS, Feurer ID, Speroff T, Davis SF, Chomsky DB, Wilson JR, Merrill WH, Drinkwater DC Jr, Pierson RN 3rd, Pinson CW. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 October; 22(10): 1149-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14550825

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Moderate acute rejection detected during annual catheterization in pediatric heart transplant recipients. Author(s): Kuhn MA, Deming DD, Cephus CE, Mulla NF, Chinnock RE, Razzouk AJ, Larsen RL. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 March; 22(3): 276-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12633694

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Monitoring of human cytomegalovirus infections in heart transplant recipients by pp65 antigenemia. Author(s): Senechal M, Dorent R, du Montcel ST, Fillet AM, Ghossoub JJ, Dubois M, Pavie A, Gandjbakhch I. Source: Clinical Transplantation. 2003 October; 17(5): 423-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14703924

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Morbidity, mortality beyond the 10th year following heart transplant: data from a population of 163 patients. Author(s): Sebbag L, Boissonnat P, Obadia JF, Gare JP, Perinetti M, Loire R, Dureau G. Source: Transplantation Proceedings. 2001 November-December; 33(7-8): 3551-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11750511

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Morphological and functional assessment of the septal course of a left coronary artery originating from the right sinus of valsalva in a heart transplant patient. Author(s): Schiele TM, Weber C, Klauss V. Source: J Invasive Cardiol. 2003 April; 15(4): 224-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12668853

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Mucosal leishmaniasis in a heart transplant recipient. Author(s): Iborra C, Caumes E, Carriere J, Cavelier-Balloy B, Danis M, Bricaire F. Source: The British Journal of Dermatology. 1998 January; 138(1): 190-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9536248

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Multicenter US study of hospital resource utilization associated with cytomegalovirus-related readmission of renal and heart transplant patients. Author(s): Henderson R, Carlin D, Kohlhase K, Leader S. Source: Transplant Infectious Disease : an Official Journal of the Transplantation Society. 2001; 3 Suppl 2: 57-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11926752

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Multidrug-resistant Corynebacterium striatum pneumonia in a heart transplant recipient. Author(s): Tarr PE, Stock F, Cooke RH, Fedorko DP, Lucey DR. Source: Transplant Infectious Disease : an Official Journal of the Transplantation Society. 2003 March; 5(1): 53-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791076

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Mycobacterium haemophilum infections in heart transplant recipients: case report and review of the literature. Author(s): Fairhurst RM, Kubak BM, Pegues DA, Moriguchi JD, Han KF, Haley JC, Kobashigawa JA. Source: American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2002 May; 2(5): 476-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12123216

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Mycophenolate mofetil in pediatric heart transplant recipients: a single-center experience. Author(s): Dipchand AI, Benson L, McCrindle BW, Coles J, West L. Source: Pediatric Transplantation. 2001 April; 5(2): 112-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11328549

Studies

97

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Mycophenolate mofetil reduces anti-HLA antibody production and cellular rejection in heart transplant recipients. Author(s): Lietz K, John R, Schuster M, Ankersmit J, Burke E, Suciu-Foca N, Edwards N, Mancini D, Itescu S. Source: Transplantation Proceedings. 2002 August; 34(5): 1828-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176593

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Mycophenolic acid concentrations in long-term heart transplant patients: relationship with calcineurin antagonists and acute rejection. Author(s): Cantin B, Giannetti N, Parekh H, Panchal SN, Kwok BW, Najem R, Woodman K, Hunt SA, Valantine HA. Source: Clinical Transplantation. 2002 June; 16(3): 196-201. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12010143

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Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil. Author(s): Dipchand AI, Pietra B, McCrindle BW, Rosebrook-Bicknell HL, Boucek MM. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2001 October; 20(10): 1035-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11595558

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Myocardial gene expression of inflammatory cytokines after heart transplantation in relation to the development of transplant coronary artery disease. Author(s): Ueland T, Sikkeland LI, Yndestad A, Eiken HG, Holm T, Guevara C, Haug T, Endresen K, Froland SS, Gullestad L, Andreassen AK, Geiran O, Simonsen S, Aukrust P. Source: The American Journal of Cardiology. 2003 September 15; 92(6): 715-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12972116

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Myocardial infarction after endomyocardial biopsy in a heart transplant patient. Author(s): Drobinski G, Dorent R, Ghossoub JJ, Collet JP, Choussat R, Montalescot G, Thomas D, Gandjbackch I. Source: Journal of Interventional Cardiology. 2002 October; 15(5): 403-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12440185

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Native cardiectomy in a heterotopic heart transplant recipient. Author(s): Pham SM, Kormos RL, Griffith BP. Source: The Journal of Thoracic and Cardiovascular Surgery. 1996 October; 112(4): 110911. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8873740

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Natural leukocyte interferon alfa for the treatment of chronic viral hepatitis in heart transplant recipients. Author(s): Fagiuoli S, Pevere S, Minniti F, Livi U, Caforio AL, Naccarato R, Chiaramonte M. Source: Transplantation. 2003 April 15; 75(7): 982-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12698084

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Neoral dose monitoring with cyclosporine 2-hour postdose levels in heart transplant patients receiving anti-thymocyte globulin induction. Author(s): Cantarovich M, Quantz M, Elstein E, Ergina P, Magnan C, de Varennes B. Source: Transplantation Proceedings. 2000 March; 32(2): 446-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10715475

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Neostigmine produces bradycardia in a heart transplant patient. Author(s): Backman SB, Ralley FE, Fox GS. Source: Anesthesiology. 1993 April; 78(4): 777-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8466076

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Neuropsychological functioning among heart transplant candidates: a case control study. Author(s): Putzke JD, Williams MA, Daniel JF, Foley BA, Kirklin JK, Boll TJ. Source: J Clin Exp Neuropsychol. 2000 February; 22(1): 95-103. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10649548

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Neuropsychological performance as a function of cardiac status among heart transplant candidates: a replication. Author(s): Temple RO, Putzke JD, Boll TJ. Source: Percept Mot Skills. 2000 December; 91(3 Pt 1): 821-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11153855

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Nonadherence is associated with late rejection in pediatric heart transplant recipients. Author(s): Ringewald JM, Gidding SS, Crawford SE, Backer CL, Mavroudis C, Pahl E. Source: The Journal of Pediatrics. 2001 July; 139(1): 75-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11445797

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Noninvasive detection of allograft rejection in heart transplant recipients by use of Doppler tissue imaging. Author(s): Puleo JA, Aranda JM, Weston MW, Cintron G, French M, Clark L, Fontanet HL. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1998 February; 17(2): 176-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9513856

Studies

99

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Noninvasive markers for acute heart transplant rejection in children with the use of automatic border detection. Author(s): Kimball TR, Semler DC, Witt SA, Khoury PR, Daniels SR. Source: Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. 1997 November-December; 10(9): 964-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9440074

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Noninvasive rejection monitoring after heart transplant. Author(s): Iberer F, Grasser B, Schreier G, Prenner G, Schaffellner S, Allmayer T, Wasler A, Petutschnigg B, Muller H, Hutten H, Schaldach M, Tscheliessnigg KH. Source: Transplantation Proceedings. 1997 November; 29(7): 3126. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9365694

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Normal short-term renal response to acute volume expansion in heart transplant recipients: a role for atrial natriuretic peptide? Author(s): Geny B, Charloux A, Schaefer A, Brandt C, Charpentier A, Kretz JG, Eisenmann B, Haberey P, Piquard F. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1998 November; 17(11): 1081-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9855447

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Omega-3 fatty acids enhance tumor necrosis factor-alpha levels in heart transplant recipients. Author(s): Holm T, Berge RK, Andreassen AK, Ueland T, Kjekshus J, Simonsen S, Froland S, Gullestad L, Aukrust P. Source: Transplantation. 2001 August 27; 72(4): 706-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11544435

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Omega-3 fatty acids improve blood pressure control and preserve renal function in hypertensive heart transplant recipients. Author(s): Holm T, Andreassen AK, Aukrust P, Andersen K, Geiran OR, Kjekshus J, Simonsen S, Gullestad L. Source: European Heart Journal. 2001 March; 22(5): 428-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11207085

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Optimal timing for surveillance endomyocardial biopsies in heart transplant patients receiving antithymocyte globulin induction. Author(s): Cantarovich M, de Gruchy S, Forbes C, Marpole D, Elstein E, Magnan C, de Varennes B. Source: Transplantation Proceedings. 1999 February-March; 31(1-2): 79. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10083015

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Optimum maintenance trough levels of cyclosporine in heart transplant recipients given corticosteroid-free regimen. Author(s): Nohria A, Ehtisham J, Ramahi TM. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1998 September; 17(9): 849-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9773855

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Osteonecrosis of the calcaneum in a heart transplant recipient. Author(s): Huwez FU, Belcher PR, Pathi VL, Naik SK, Wheatley DJ. Source: The Thoracic and Cardiovascular Surgeon. 1997 August; 45(4): 204-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9323824

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Outcome of de novo hepatitis C virus infection in heart transplant recipients. Author(s): Ong JP, Barnes DS, Younossi ZM, Gramlich T, Yen-Lieberman B, Goormastic M, Sheffield C, Hoercher K, Starling R, Young J, Smedira N, McCarthy P. Source: Hepatology (Baltimore, Md.). 1999 November; 30(5): 1293-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10534352

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Outcomes among pediatric heart transplant recipients. Author(s): Gajarski RJ, Rosenblatt HM, Denfield SW, Schowengerdt KO, Price JK, Towbin JA. Source: Texas Heart Institute Journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital. 1997; 24(2): 97-104. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9205982

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Outcomes of hepatitis C positive (HCV+) heart transplant recipients. Author(s): Lake KD, Smith CI, Milfred-La Forest SK, Pritzker MR, Emery RW. Source: Transplantation Proceedings. 1997 February-March; 29(1-2): 581-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9123138

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Outpatient inotropic therapy in heart transplant candidates: should its use influence waiting list priority status? Author(s): Winkel E, Kao W, Fisher SG, Heroux AL, Johnson MR, Costanzo MR. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1998 August; 17(8): 809-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9730431

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Out-patient versus in-hospital ambulatory 24-h blood pressure monitoring in heart transplant recipients. Author(s): Vanhaecke J, Van Cleemput J, Droogne W, Fagard R, Staessen J. Source: Journal of Human Hypertension. 1999 March; 13(3): 199-202. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10204817

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Pathogenesis of bone loss in heart transplant candidates and recipients. Author(s): Kerschan-Schindl K, Strametz-Juranek J, Heinze G, Grampp S, Bieglmayer C, Pacher R, Maurer G, Fialka-Moser V, Pietschmann P. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 August; 22(8): 843-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12909462

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Pharmacokinetics of mycophenolate mofetil in heart transplant recipients. Author(s): Seebacher G, Mallinger R, Laufer G, Grimm M, Griesmacher A, Weigel G, Wolner E, Muller MM. Source: Advances in Experimental Medicine and Biology. 1998; 431: 801-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9598174

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Plasma C-reactive protein as a marker of cardiac allograft vasculopathy in heart transplant recipients. Author(s): Hognestad A, Endresen K, Wergeland R, Stokke O, Geiran O, Holm T, Simonsen S, Kjekshus JK, Andreassen AK. Source: Journal of the American College of Cardiology. 2003 August 6; 42(3): 477-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12906976

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Points to note from indications for heart transplantation to post-heart transplant care: from the care of patients with refractory heart failure and overseas heart transplantation. Author(s): Nunoda S, Kurosawa R, Kogashi K, Yamagishi S, Mitsui F, Funabashi W. Source: Heart and Vessels. 1997; Suppl 12: 37-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9476540

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Predictors of early mortality after heart transplantation: the Canadian transplant experience from 1981 to 1992. The CASCADE Investigators. Canadian Study of Cardiac Transplant Atherosclerosis Determinants. Author(s): Carrier M, Rivard M, Latter D, Kostuk W. Source: The Canadian Journal of Cardiology. 1998 May; 14(5): 703-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9627527

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Predictors of exercise capacity and the impact of angiographic coronary artery disease in heart transplant recipients. Author(s): Gullestad L, Myers J, Edvardsen T, Kjekshus J, Geiran O, Simonsen S. Source: American Heart Journal. 2004 January; 147(1): 49-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14691418

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Preemptive treatment for the prevention of cytomegalovirus disease: in lung and heart transplant recipients. Author(s): Egan JJ, Lomax J, Barber L, Lok SS, Martyszczuk R, Yonan N, Fox A, Deiraniya AK, Turner AJ, Woodcock AA. Source: Transplantation. 1998 March 15; 65(5): 747-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9521215

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Pregnancy after heart transplant: update and case report. Author(s): Morini A, Spina V, Aleandri V, Cantonetti G, Lambiasi A, Papalia U. Source: Human Reproduction (Oxford, England). 1998 March; 13(3): 749-57. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9572447

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Preserved response of mitochondrial function to short-term endurance training in skeletal muscle of heart transplant recipients. Author(s): Zoll J, N'Guessan B, Ribera F, Lampert E, Fortin D, Veksler V, Bigard X, Geny B, Lonsdorfer J, Ventura-Clapier R, Mettauer B. Source: Journal of the American College of Cardiology. 2003 July 2; 42(1): 126-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12849672

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Prevention and treatment of cytomegalovirus infection and disease in heart transplant recipients. Author(s): Avery RK. Source: Current Opinion in Cardiology. 1998 March; 13(2): 122-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9593552

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Quality of life in renal, hepatic, and heart transplant patients. Author(s): Insense B, Vilardell J, Aranzabal J, Lago AM. Source: Transplantation Proceedings. 1999 September; 31(6): 2647-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10500757

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Quality of life outcomes after heart transplantation in individuals bridged to transplant with ventricular assist devices. Author(s): Dew MA, Kormos RL, Winowich S, Harris RC, Stanford EA, Carozza L, Griffith BP. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2001 November; 20(11): 1199-212. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11704480

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Reactive hemophagocytic syndrome associated with disseminated histoplasmosis in a heart transplant recipient. Author(s): Masri K, Mahon N, Rosario A, Mirza I, Keys TF, Ratliff NB, Starling RC. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 April; 22(4): 487-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12681429

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Reduced myocardial perfusion reserve and transmural perfusion gradient in heart transplant arteriopathy assessed by magnetic resonance imaging. Author(s): Muehling OM, Wilke NM, Panse P, Jerosch-Herold M, Wilson BV, Wilson RF, Miller LW. Source: Journal of the American College of Cardiology. 2003 September 17; 42(6): 105460. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13678930

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Reduction of tricuspid annular doppler tissue velocities in pediatric heart transplant patients. Author(s): Fyfe DA, Mahle WT, Kanter KR, Wu G, Vincent RN, Ketchum DL. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 May; 22(5): 553-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12742418

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Regulatory CD8+CD28- T cells in heart transplant recipients. Author(s): Colovai AI, Mirza M, Vlad G, Wang S, Ho E, Cortesini R, Suciu-Foca N. Source: Human Immunology. 2003 January; 64(1): 31-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12507812

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Renal function and safety of heart transplant recipients switched to mycophenolate mofetil and low-dose cyclosporine. Author(s): Baryalei M, Zenker D, Pieske B, Tondo K, Dalichau H, Aleksic I. Source: Transplantation Proceedings. 2003 June; 35(4): 1539-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12826215

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Resistance exercise prevents glucocorticoid-induced myopathy in heart transplant recipients. Author(s): Braith RW, Welsch MA, Mills RM Jr, Keller JW, Pollock ML. Source: Medicine and Science in Sports and Exercise. 1998 April; 30(4): 483-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9565927

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Resistance exercise training and alendronate reverse glucocorticoid-induced osteoporosis in heart transplant recipients. Author(s): Braith RW, Magyari PM, Fulton MN, Aranda J, Walker T, Hill JA. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 October; 22(10): 1082-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14550817

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Review of literature on heart transplant recipients' return to work: predictors and outcomes. Author(s): Paris W, Woodbury A, Thompson S, Hutkin-Slade L, Levick M, Nothegger S, Arbuckle P, Cooper DK. Source: Social Work in Health Care. 1997; 26(2): 87-9; Author Reply 91-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9433742

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Rhodococcus equi pneumonia in a heart transplant recipient in Korea, with emphasis on microbial diagnosis. Author(s): Yoo SJ, Sung H, Chae JD, Kim MN, Pai CH, Park J, Kim JJ. Source: Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2003 March; 9(3): 230-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12667256

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Role of dobutamine stress echocardiography in heart transplant patients. Author(s): Akosah KO, Mohanty PK. Source: Chest. 1998 March; 113(3): 809-15. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9515861

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Scedosporium apiospermum (Pseudallescheria boydii) infection in a heart transplant recipient: a case of mistaken identity. Author(s): Lopez FA, Crowley RS, Wastila L, Valantine HA, Remington JS. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1998 March; 17(3): 321-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9563611

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Scedosporium apiospermum pneumonia and sternal wound infection in a heart transplant recipient. Author(s): Talbot TR, Hatcher J, Davis SF, Pierson RN 3rd, Barton R, Dummer S. Source: Transplantation. 2002 December 15; 74(11): 1645-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12490804

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Should physical activity and/or competitive sports be curtailed in pediatric heart transplant recipients? Author(s): Ficker FJ. Source: Pediatric Transplantation. 2002 August; 6(4): 267-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12234265

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Sinus node dysfunction in a heart transplant patient secondary to severe sinus node artery obstruction--a case report. Author(s): Hasdemir C, Chandrasekaran K, Lazzara R, Reynolds DW. Source: Angiology. 2003 November-December; 54(6): 725-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14666963

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Soluble inflammatory markers in coronary sinus and peripheral blood of heart transplant recipients. Author(s): Hsu RB, Tsay YG, Lee CM, Chen RJ, Wang SS, Chu SH. Source: Clinical Transplantation. 2003 August; 17(4): 331-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12868989

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Spectrum of left ventricular dysfunction in potential pediatric heart transplant donors. Author(s): Paul JJ, Tani LY, Shaddy RE, Minich LL. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 May; 22(5): 548-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12742417

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Spontaneous recovery from severe parvovirus B19 pure red cell aplasia, in a heart transplant recipient, as demonstrated by marrow culture. Author(s): Amiot L, Langanay T, Drenou B, Lelong B, Le Prise PY, Logeais Y, Colimon R, Fauchet R. Source: Hematology and Cell Therapy. 1998 April; 40(2): 71-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9615250

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Subcutaneous exophiala jeanselmei infection in a heart transplant patient. Author(s): Calista D, Leardini M, Arcangeli F. Source: European Journal of Dermatology : Ejd. 2003 September-October; 13(5): 489. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14756122

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Successful management of disseminated Nocardia transvalensis infection in a heart transplant recipient after development of sulfonamide resistance: case report and review. Author(s): Lopez FA, Johnson F, Novosad DM, Beaman BL, Holodniy M. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 April; 22(4): 492-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12681430

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Sustained use of nesiritide to aid in bridging to heart transplant. Author(s): Hill JA, Hsu K, Pauly DF, Schofield R, Aranda JM Jr. Source: Clin Cardiol. 2003 May; 26(5): 211-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12769247

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T gamma/delta hepatosplenic lymphoma in a heart transplant patient after an Epstein-Barr virus positive lymphoproliferative disorder: a case report. Author(s): Kraus MD, Crawford DF, Kaleem Z, Shenoy S, MacArthur CA, Longtine JA. Source: Cancer. 1998 March 1; 82(5): 983-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9486591

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Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. Author(s): Zheng H, Webber S, Zeevi A, Schuetz E, Zhang J, Bowman P, Boyle G, Law Y, Miller S, Lamba J, Burckart GJ. Source: American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2003 April; 3(4): 477-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12694072

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Temporal profiles of physical health in family members of heart transplant recipients: predictors of health change during caregiving. Author(s): Dew MA, Goycoolea JM, Stukas AA, Switzer GE, Simmons RG, Roth LH, DiMartini A. Source: Health Psychology : Official Journal of the Division of Health Psychology, American Psychological Association. 1998 March; 17(2): 138-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9548705

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The application of human monoclonal antibodies for monitoring donor derived soluble HLA class I molecules in the serum of heart transplant recipients. Author(s): Koelman CA, Mulder A, Jutte NH, Vaessen LM, Balk AH, Weimar W, Doxiadis II, Claas FH. Source: Human Immunology. 1998 February; 59(2): 106-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9536433

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The clinical value of ultrasonic tissue characterization in the management of heart transplant patients. Author(s): Lieback E, Nawrocki M, Meyer R, Bellach J, Warnecke H, Cohnert T. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 1992; 5 Suppl 1: S231-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14621787

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The effect of successful heart transplant treatment of heart failure on central sleep apnea. Author(s): Mansfield DR, Solin P, Roebuck T, Bergin P, Kaye DM, Naughton MT. Source: Chest. 2003 November; 124(5): 1675-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14605034

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The isolation of Aspergillus fumigatus from respiratory tract specimens in heart transplant recipients is highly predictive of invasive aspergillosis. Author(s): Munoz P, Alcala L, Sanchez Conde M, Palomo J, Yanez J, Pelaez T, Bouza E. Source: Transplantation. 2003 February 15; 75(3): 326-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12589152

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The registry of the International Society for Heart and Lung Transplantation: twentieth official adult heart transplant report--2003. Author(s): Taylor DO, Edwards LB, Mohacsi PJ, Boucek MM, Trulock EP, Keck BM, Hertz MI. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 June; 22(6): 616-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12821159

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Transmission of hepatitis B virus among heart transplant recipients during endomyocardial biopsy procedures. Author(s): Osterhaus AD, Vos MC, Balk AH, de Man RA, Mouton JW, Rothbarth PH, Schalm SW, Tomaello AM, Niesters HG, Verbrugh HA. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1998 February; 17(2): 158-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9513854

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Trimethoprim-sulfamethoxazole as toxoplasmosis prophylaxis for heart transplant recipients. Author(s): Munoz P, Arencibia J, Rodriguez C, Rivera M, Palomo J, Yanez J, Bouza E. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003 April 1; 36(7): 932-3; Author Reply 933. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12652396

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U.S. refuses to finance prison heart transplant. Author(s): Kolata G. Source: Ny Times (Print). 1994 February 5; : 6. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11647968

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Unique considerations for the pediatric heart transplant recipient: the role of the school nurse. Author(s): Duitsman DM, Suddaby EC, Masterson G. Source: J Sch Nurs. 1999 August; 15(3): 10-3. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10745796

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Uricosuric effect of the angiotensin II receptor antagonist losartan in heart transplant recipients. Author(s): Minghelli G, Seydoux C, Goy JJ, Burnier M. Source: Transplantation. 1998 July 27; 66(2): 268-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9701277

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Urinary retinol binding protein is a good marker of progressive cyclosporine nephrotoxicity after heart transplant. Author(s): Camara NO, Matos AC, Rodrigues DA, Pereira AB, Pacheco-Silva A. Source: Transplantation Proceedings. 2001 May; 33(3): 2129-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11377474

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Urologic experience in 48 heart transplant recipients. Author(s): Donaldson DS, Fuselier HA. Source: Southern Medical Journal. 1997 November; 90(11): 1084-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9386047

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Use of behavioral contingency contracting with heart transplant candidates. Author(s): Cupples SA, Steslow B. Source: Progress in Transplantation (Aliso Viejo, Calif.). 2001 June; 11(2): 137-44. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11871049

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Use of cyclosporine MEPC (Neoral) in heart transplant recipients. Author(s): Fukushima N, Ohtake S, Sawa Y, Nishimura M, Kobayashi Y, Shirakura R, Nakata S, Matsuda H. Source: Transplantation Proceedings. 1998 November; 30(7): 3337-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9838473

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Usefulness of B-type natriuretic peptide as a noninvasive screening tool for cardiac allograft pathology in pediatric heart transplant recipients. Author(s): Claudius I, Lan YT, Chang RK, Wetzel GT, Alejos J. Source: The American Journal of Cardiology. 2003 December 1; 92(11): 1368-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14636927

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Usefulness of chronotropic incompetence to dipyridamole in predicting myocardial perfusion defects in heart transplant recipients. Author(s): De Chiara B, Bigi R, Devoto E, Cavenaghi G, Turazza F, Sara R, Colombo T, Frigerio M, Parodi O. Source: The American Journal of Cardiology. 2003 October 15; 92(8): 1001-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14556885

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Usefulness of plasma vitamin B(6), B(12), folate, homocysteine, and creatinine in predicting outcomes in heart transplant recipients. Author(s): Nahlawi M, Seshadri N, Boparai N, Naso A, Jacobsen DW, McCarthy P, Young J, Robinson K. Source: The American Journal of Cardiology. 2002 April 1; 89(7): 834-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11909569

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Vaccination against tick-borne encephalitis under therapeutic immunosuppression. Reduced efficacy in heart transplant recipients. Author(s): Dengler TJ, Zimmermann R, Meyer J, Sack FU, Girgsdies O, Kubler WE. Source: Vaccine. 1999 February 26; 17(7-8): 867-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10067693

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Varicella in a pediatric heart transplant population on nonsteroid maintenance immunosuppression. Author(s): Dodd DA, Burger J, Edwards KM, Dummer JS. Source: Pediatrics. 2001 November; 108(5): E80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11694664

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Vascular antithrombin and clinical outcome in heart transplant patients. Author(s): Labarrere CA, Torry RJ, Nelson DR, Miller SJ, Pitts DE, Kirlin PC, Halbrook HG. Source: The American Journal of Cardiology. 2001 February 15; 87(4): 425-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11179526

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Vasovagal syncope in heart transplant patients during dental surgery. Author(s): Montebugnoli L, Montanari G. Source: Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 1999 June; 87(6): 666-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10397654

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VDD pacing with single lead in a heart transplant recipient: case report. Author(s): Sanmartin Fernandez M, Pulpon LA, Oteo JF, Exposito Pineda C, Espana Barrio E, Fernandez Lozano I, Silva Melchor L, Serrano Fiz S, de Artaza Andrade M. Source: Pacing and Clinical Electrophysiology : Pace. 1996 October; 19(10): 1522-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8904548

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Ventricular fibrillation in a heterotopic heart transplant recipient. Author(s): McMullan DM, Wilansky S, Frazier OH. Source: The Annals of Thoracic Surgery. 2003 February; 75(2): 598. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12607690

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Ventriculoarterial coupling and left ventricular efficiency in heart transplant recipients. Author(s): Arnoult F, Loiseau A, Aptecar E, Loisance D, Nitenberg A. Source: Transplantation. 1997 August 27; 64(4): 617-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9293876

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Very high frequency oscillations in the heart rate and blood pressure of heart transplant patients. Author(s): Toledo E, Pinhas I, Aravot D, Akselrod S. Source: Medical & Biological Engineering & Computing. 2003 July; 41(4): 432-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12892366

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Viremia and excretion of TT virus in immunosuppressed heart transplant recipients and in immunocompetent individuals. Author(s): Wolff C, Diekmann A, Boomgaarden M, Korner MM, Kleesiek K. Source: Transplantation. 2000 February 15; 69(3): 351-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10706041

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VO(2) kinetics reveal a central limitation at the onset of subthreshold exercise in heart transplant recipients. Author(s): Mettauer B, Zhao QM, Epailly E, Charloux A, Lampert E, Heitz-Naegelen B, Piquard F, di Prampero PE, Lonsdorfer J. Source: Journal of Applied Physiology (Bethesda, Md. : 1985). 2000 April; 88(4): 1228-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10749812

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What health educators should know about pediatric heart transplant recipients. Author(s): Duitsman D. Source: The Journal of School Health. 1996 October; 66(8): 305-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8899589

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Wheeze in a heart transplant patient with lymphoma. Author(s): Sridhar M, Jeffers M, Brankin E, Soukop M, Banham S. Source: Postgraduate Medical Journal. 1995 June; 71(836): 375-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7644405

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When and why do heart transplant recipients die? A 7 year experience of 1068 cardiac transplants. Author(s): Gallo P, Baroldi G, Thiene G, Agozzino L, Arbustini E, Bartoloni G, Bonacina E, Bosman C, Catani G, Cocco P, et al. Source: Virchows Arch a Pathol Anat Histopathol. 1993; 422(6): 453-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8333149

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When to transplant: Recipient selection for heart transplantation. Author(s): Grady KL. Source: The Journal of Cardiovascular Nursing. 1996 January; 10(2): 58-70. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8656238

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Which test for detecting accelerated coronary artery disease in the heart transplant patient? Author(s): Delahaye F, Gare JP. Source: European Heart Journal. 1997 April; 18(4): 537-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9129874

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CHAPTER 2. NUTRITION AND HEART TRANSPLANT Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and heart transplant.

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

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

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

Acceptance of a pump-driven infusion therapy with prostaglandin E1 as a bridge to heart transplantation. Author(s): Department of Cardiology, University of Vienna. Source: Daneschvar, H Pacher, R Rodler, S Stanek, B Hulsmann, M Grimm, M Laufer, G Wolner, E Bunzel, B Wien-Klin-Wochenschr. 1996; 108(16): 510-4 0043-5325

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Acitretin for prophylaxis of cutaneous malignancies after cardiac transplantation. Author(s): Heart Transplant Unit, The Prince Charles Hospital, Brisbane, Australia. Source: McNamara, I R Muir, J Galbraith, A J J-Heart-Lung-Transplant. 2002 November; 21(11): 1201-5 1053-2498

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Caring for the cardiac transplant patient. Source: Hutchings, S M Monett, Z J Crit-Care-Nurs-Clin-North-Am. 1989 June; 1(2): 24561 0899-5885

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Characteristics and clinical relevance of chronic anemia in adult heart transplant recipients. Author(s): Division of Transplantation Surgery, Department of Surgery, School of Medicine, Karl-Franzens-University Graz, Austria. [email protected] Source: Muller, H M Horina, J H Kniepeiss, D Tripolt, M B Stadelbauer, V Schweiger, M Tscheliessnigg, K H Clin-Transplant. 2001 October; 15(5): 343-8 0902-0063

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Clinical microbiological case: poor radiologic evolution of pulmonary tuberculosis in a heart transplant patient. Author(s): Reina Sofia University Hospital, Cordoba, Spain. Source: Gavilan, F Torre Cisneros, J Vizcaino, M A Arizon, J M Lama, R Lopez Rubio, F Sanchez Guijo, P Clin-Microbiol-Infect. 2001 July; 7(7): 367-8, 399-401 1198-743X

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Coronary reactivity to ergonovine--possible relationship to accelerated coronary arterial disease in cardiac transplant recipients. Author(s): Department of Cardiology and Cardiac Surgical Unit, Harefield Hospital, Middlesex. Source: Kushwaha, S Lythall, D Maseri, A Mitchell, A Yacoub, M Eur-Heart-J. 1991 April; 12(4): 520-5 0195-668X

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Cyclosporine does not enhance the development of accelerated coronary artery disease: experimental study in a rat cardiac transplant model. Author(s): Department of Cardiac Surgery, Heart Center, University of Leipzig, Leipzig, Germany. [email protected] Source: Richter, Markus Skupin, Manfred Schramm, David Weinert, Marc Richter, Heike Mohr, Friedrich Wilhelm Olbrich, Hans Georg J-Heart-Lung-Transplant. 2002 April; 21(4): 425-34 1053-2498

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Delisting of infants and children from the heart transplantation waiting list after carvedilol treatment. Author(s): Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, [email protected] Source: Azeka, E Franchini Ramires, J A Valler, C Alcides Bocchi, E J-Am-Coll-Cardiol. 2002 December 4; 40(11): 2034-8 0735-1097

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Electrophysiology of heterotopic heart transplant: experimental study in dogs. Author(s): Service of Experimental Surgery, Hospital Puerta de Hierro, Universidad Autonoma Madrid, Spain.

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Source: Alvarez, L Escudero, C Alzueta, J Silva, L Marquez Montes, J Castillo Olivares, J L Eur-Heart-J. 1990 June; 11(6): 517-24 0195-668X •

Elevated free fractions of valproic acid in a heart transplant patient with hypoalbuminemia. Author(s): Transplant Research Fellow, University of Michigan Medical Center, Ann Arbor, MI, USA. Source: Haroldson, J A Kramer, L E Wolff, D L Lake, K D Ann-Pharmacother. 2000 February; 34(2): 183-7 1060-0280

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Ethnic disparity in clinical outcome after heart transplantation is abrogated using tacrolimus and mycophenolate mofetil-based immunosuppression. Author(s): The Ochsner Cardiomyopathy and Heart Transplantation Center, Ochsner Clinic Foundation, New Orleans, LA, USA. [email protected]. Source: Mehra, M R Uber, P A Scott, R L Park, M H Transplantation. 2002 December 15; 74(11): 1568-73 0041-1337

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Fluvastatin decreases soluble thrombomodulin in cardiac transplant recipients. Author(s): Department of Cardiology, Hopital de la Timone, Marseille, France. Source: Ambrosi, P Aillaud, M F Habib, G Kreitmann, B Metras, D Luccioni, R Bouvenot, G Juhan Vague, I Thromb-Haemost. 2000 January; 83(1): 46-8 0340-6245

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Folate supplementation after heart transplantation: effects on homocysteine plasma levels and allograft vascular disease. Author(s): Institute of Cardiology, University of Bologna, Italy. Source: Potena, L Grigioni, F Magnai, G Sorbello, S Sassi, S Poci, M G Carigi, S Bacchi Reggiani, L Leone, O Magelli, C Branzi, A Clin-Nutr. 2002 June; 21(3): 245-8 0261-5614

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Hodgkin's disease after cardiac transplant: a report of two cases. Author(s): Department of Haematology, Addenbrookes NHS Trust, Cambridge, UK. Source: Hood, I M Mahendra, P McNeil, K Marcus, R E Clin-Lab-Haematol. 1996 June; 18(2): 115-6 0141-9854

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Homocysteine--a treatable risk factor for allograft vascular disease after heart transplantation? Author(s): Department of Thoracic and Cardiovascular Surgery, Division of Surgery, Hannover Medical School, Hannover, Germany. [email protected] Source: Kutschka, I Pethig, K Struber, M Dieterich, C Harringer, W Haverich, A J-HeartLung-Transplant. 2001 July; 20(7): 743-6 1053-2498

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Hyperhomocyst(e)inemia induces accelerated transplant vascular sclerosis in syngeneic and allogeneic rat cardiac transplants. Author(s): Department of Surgery, Oregon Health and Science University, Portland 97201, USA. Source: Cook, J W Yin, Q Malinow, M R Orloff, S L Am-J-Transplant. 2002 March; 2(3): 244-51 1600-6135

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Hyperhomocysteinaemia in heart transplant recipients. Author(s): Department of Cardiology, Hopital de la Timone, Marseille, France. Source: Ambrosi, P Barlatier, A Habib, G Garcon, D Kreitman, B Roland, P H Saingra, S Metras, D Luccioni, R Eur-Heart-J. 1994 September; 15(9): 1191-5 0195-668X

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Hypertension, creatinine, and plasma renin activity in heart transplant recipients. Author(s): Department of Medicine, School of Medicine, University of Pittsburgh, Pennsylvania 15261. Source: Rutan, G H Shapiro, A P Thompson, M E Nigalye, R L McDonald, R H Johnsen, A M Trento, A Kormos, R L J-Hum-Hypertens. 1990 December; 4(6): 659-64 0950-9240

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Immunological rejection of heart transplant: how lytic granules from cytotoxic T lymphocytes damage guinea pig ventricular myocytes. Author(s): Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York. Source: Binah, O Marom, S Rubinstein, I Robinson, R B Berke, G Hoffman, B F PflugersArch. 1992 February; 420(2): 172-9 0031-6768

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Increasing plasma homocysteine during follow-up in heart transplant recipients: effects of folate and renal function. Author(s): Institute of Cardiovascular Diseases, University of Bologna, Italy. Source: Potena, L Grigioni, F Magnani, G Sorbello, S Sassi, S Marinucci, L Conti, R Carinci, V Leone, O Arpesella, G Coccheri, S Magelli, C Branzi, A Ital-Heart-J. 2000 May; 1(5): 344-8 1129-471X

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Lifestyle and health status in long-term cardiac transplant recipients. Author(s): Department of Adult Health Nursing, Virginia Commonwealth University, Richmond, 23298, USA. Source: Salyer, J Sneed, G Corley, M C Heart-Lung. 2001 Nov-December; 30(6): 445-57 0147-9563

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Long-term prostacyclin infusion to reduce pulmonary hypertension in a pediatric cardiac transplant candidate prior to transplantation. Author(s): Division of Cardiology, Department of Pediatrics, St. Louis, Missouri 63110, USA. Source: Kao, B Balzer, D T Huddleston, C B Canter, C E J-Heart-Lung-Transplant. 2001 July; 20(7): 785-8 1053-2498

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Myocyte function and [Ca 2+ ]i homeostasis during early allogenic heart transplant rejection. Author(s): Division of Cardiology, University of Utah Health Sciences Center, 50 North Medical Drive, Salt Lake City, UT 84132, USA. Source: Ritter, M Su, Z Yao, A Zubair, I Xu, S Shelby, J Barry, W H Transplantation. 2001 November 27; 72(10): 1603-7 0041-1337

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N-acetylcysteine neither lowers plasma homocysteine concentrations nor improves brachial artery endothelial function in cardiac transplant recipients. Author(s): University Health Network, The Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada. Source: Miner, S E S Cole, D E C Evrovski, J Forrest, Q Hutchison, S J Holmes, K Ross, H J Can-J-Cardiol. 2002 May; 18(5): 503-7 0828-282X

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Pharmacodynamic monitoring of mycophenolic acid in rabbit heterotopic heart transplant model. Author(s): Departments of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada. Source: Langman, L J Nakakura, H Thliveris, J A LeGatt, D F Yatscoff, R W Ther-DrugMonit. 1997 April; 19(2): 146-52 0163-4356

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Predictability and other aspects of post-transplant diabetes mellitus in heart transplant recipients. Author(s): Department of Internal Medicine, Utrecht, The Netherlands. [email protected] Source: Nieuwenhuis, M G Kirkels, J H J-Heart-Lung-Transplant. 2001 July; 20(7): 703-8 1053-2498

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Predictors of pericardial effusion after orthotopic heart transplantation. Author(s): Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center at Dallas, Tex 75390, USA. Source: Quin, J A Tauriainen, M P Huber, L M McIntire, D D Kaiser, P A Ring, W S Jessen, M E J-Thorac-Cardiovasc-Surg. 2002 November; 124(5): 979-83 0022-5223

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Pretransplant rinse of hearts preserved with colloid-free UW solution and more effective heart preservation: studies in a rat abdominal heart transplant model. Author(s): Monash University, Department of Medicine, Monash Medical School, Alfred Hospital, Commercial Road, Prahran, Victoria, 3181 Australia. Source: Baxter, Kirsty Howden, Brian O Jablonski, Paula Transplantation. 2002 January 15; 73(1): 23-31 0041-1337

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Prevention of osteoporosis in cardiac transplant recipients. Author(s): Division of Cardiology, Heart Transplant/Heart Failure Program, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA. [email protected] Source: Pisani, Barbara Mullen, G Martin Curr-Opin-Cardiol. 2002 Mar; 17(2): 160-4 0268-4705

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Primary immunosuppression with tacrolimus and mycophenolate mofetil versus cyclosporine and azathioprine in heart transplant recipients. Author(s): Division of Thoracic and Cardiovascular Surgery, Hannover Medical School, Hannover, Germany. [email protected] Source: Teebken, O E Struber, M Harringer, W Pichlmaier, M A Haverich, A TransplantProc. 2002 June; 34(4): 1265-8 0041-1345

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Pyridoxine improves endothelial function in cardiac transplant recipients. Author(s): Department of Medicine, University of Toronto, Toronto, Ontario, Canada. Source: Miner, S E Cole, D E Evrovski, J Forrest, Q Hutchison, S Holmes, K Ross, H J JHeart-Lung-Transplant. 2001 September; 20(9): 964-9 1053-2498

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Regulation of matrix metalloproteinases and effect of MMP-inhibition in heart transplant related reperfusion injury. Author(s): Department of Cardiothoracic Surgery, Falk Cardiovascular Research Building, Stanford University School of Medicine, Stanford, CA, USA. [email protected] Source: Falk, V Soccal, P M Grunenfelder, J Hoyt, G Walther, T Robbins, R C Eur-JCardiothorac-Surg. 2002 July; 22(1): 53-8 1010-7940

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Reversal of chronic cyclosporine nephrotoxicity after heart transplantation-potential role of mycophenolate mofetil. Author(s): Heart and Lung Transplant Unit, St. Vincent's Hospital, Sydney, Australia. Source: Tedoriya, T Keogh, A M Kusano, K Savdie, E Hayward, C Spratt, P M Wilson, M Macdonald, P S J-Heart-Lung-Transplant. 2002 September; 21(9): 976-82 1053-2498

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Safety and efficacy of atorvastatin in heart transplant recipients. Author(s): Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA. Source: Patel, Devang N Pagani, Francis D Koelling, Todd M Dyke, David B Baliga, Ragavendra R Cody, Robert J Lake, Kathleen D Aaronson, Keith D J-Heart-LungTransplant. 2002 February; 21(2): 204-10 1053-2498

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Simvastatin initiated early after heart transplantation: 8-year prospective experience. Author(s): Division of Cardiac Surgery, Munich-Bogenhausen, Germany. [email protected]

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Source: Wenke, K Meiser, B Thiery, J Nagel, D von Scheidt, W Krobot, K Steinbeck, G Seidel, D Reichart, B Circulation. 2003 January 7; 107(1): 93-7 1524-4539 •

Suggested guidelines for the use of tacrolimus in cardiac transplant recipients. Author(s): Department of Medicine, Division of Cardiology, University of Utah, Salt Lake City, Utah 84132, USA. Source: Taylor, D O Barr, M L Meiser, B M Pham, S M Mentzer, R M Gass, A L J-HeartLung-Transplant. 2001 July; 20(7): 734-8 1053-2498

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Surgical experience with retroperitoneal heterotopic heart transplantation in the large white domestic swine. Author(s): Department of Surgery, Montreal Heart Institute, Montreal, Quebec, Canada. [email protected] Source: Perrault, L P Malo, O Desjardins, N Bidouard, J P Villeneuve, N Vilaine, J P Vanhoutte, P M J-Invest-Surg. 2002 Jan-February; 15(1): 45-55 0894-1939

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Systemic arterial pressure and brachial arterial flow-mediated dilatation in young cardiac transplant recipients. Author(s): Department of Pediatrics, Division of Pediatric Cardiology, University of Michigan, Ann Arbor, Michigan 48198-0204, USA. [email protected] Source: Lim, D S Gomez, C A Goldberg, C S Crowley, D C Rocchini, A P Charpie, J R Am-J-Cardiol. 2002 November 1; 90(9): 1035-7 0002-9149

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T-cell lymphoma in the parotid region after cardiac transplant: case report. Author(s): Salivary Gland Center, Columbia University School of Dental and Oral Surgery, New York-Presbyterian Hospital (Columbia Campus), New York, NY, USA. Source: Mandel, L Surattanont, F Dourmas, M J-Oral-Maxillofac-Surg. 2001 June; 59(6): 673-7 0278-2391

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The antineoplastic drug Paclitaxel has immunosuppressive properties that can effectively promote allograft survival in a rat heart transplant model. Author(s): University of Regensburg, Department of Surgery, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. Source: Tange, Stefan Scherer, Marcus N Graeb, Christian Weiss, Thomas Justl, Martin Frank, Erika Andrassy, Joachim Jauch, Karl Walter Geissler, Edward K Transplantation. 2002 January 27; 73(2): 216-23 0041-1337

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The evolving management of acute right-sided heart failure in cardiac transplant recipients. Author(s): Division of Cardiothoracic Surgery, Ohio State University, Columbus, Ohio 43201-1214, USA. Source: Stobierska Dzierzek, B Awad, H Michler, R E J-Am-Coll-Cardiol. 2001 October; 38(4): 923-31 0735-1097

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Valacyclovir prevention of cytomegalovirus reactivation after heart transplantation: a randomized trial. Author(s): North West Lung Centre, Wythenshawe Hospital, Manchester, United Kingdom. [email protected] Source: Egan, Jim J Carroll, Kevin B Yonan, Nizar Woodcock, Ashley Crisp, Adam JHeart-Lung-Transplant. 2002 April; 21(4): 460-6 1053-2498

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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The following is a specific Web list relating to heart transplant; 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: •

Food and Diet Omega-3 Fatty Acids Source: Integrative Medicine Communications; www.drkoop.com

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CHAPTER 3. DISSERTATIONS ON HEART TRANSPLANT Overview In this chapter, we will give you a bibliography on recent dissertations relating to heart transplant. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “heart transplant” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on heart transplant, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Heart Transplant ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to heart transplant. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

The Historical Development of Cardiac Transplantation by Kesling, Gary L., PhD from Texas Woman's University, 1987, 216 pages http://wwwlib.umi.com/dissertations/fullcit/8816803

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The Relationship of Psychosocial Factors to Recuperation and Quality of Life in Heart Transplant Recipients by Duitsman, Dalen Mark, HSD from Indiana University, 1991, 183 pages http://wwwlib.umi.com/dissertations/fullcit/9131260

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

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CHAPTER 4. CLINICAL TRIALS AND HEART TRANSPLANT Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning heart transplant.

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

Development of a Hospital-Based Home Program for the Use of Inhaled Nitric Oxide in the Chronic Management of Severe Cardiopulmonary Diseases Condition(s): Pulmonary Hypertension; Lung Disease; Sickle Cell Disease; Cardiac transplant; Lung transplant Study Status: This study is currently recruiting patients. Sponsor(s): INO Therapeutics Purpose - Excerpt: The purpose of this program is to evaluate the logistic issues and patient requirements for chronic pulsed INOmax delivery in ambulatory, home-care patients. To understand patient needs, patients with a variety of underlying diseases will be included. Safety of chronic therapy will be monitored by serial measurements of methemoglobin, platelet function assay and reported adverse events. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00041574

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Study of Heart Transplant Rejection Condition(s): Heart Transplantation; MedlinePlus consumer health information Study Status: This study is currently recruiting patients.

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These are listed at www.ClinicalTrials.gov.

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Sponsor(s): Warren G Magnuson Clinical Center (CC) Purpose - Excerpt: This study will investigate the causes of acute and chronic rejection of transplanted hearts. To find better ways to detect, treat and possibly prevent heart transplant rejection, more information about the cause is needed. Acute and chronic heart transplant rejection may be caused by certain substances the body produces in response to the new heart. This study will try to find a blood or urine test that detects genes and proteins that can serve as markers of rejection. Such a test may lead to earlier detection and improved treatment. Patients between 18 and 65 years of age who are on a wait list for heart transplant at a UNOS-approved heart transplant center, whose institutional review board has approved this protocol, may be eligible for this study. Healthy volunteers will also be included in the study to establish a database of normal values for comparison with patients undergoing heart transplant. In addition, patients who have had a heart transplant within the past 1 to 5 years will be enrolled in a pilot study. Normal volunteers will be screened for participation with an electrocardiogram (EKG) and echocardiogram, non-invasive tests to evaluate heart function. Participants will undergo the following procedures: - Review of medical records - Patients who have had a heart transplant and those on a wait list to receive a heart will have their medical records reviewed to collect information on their condition. - Blood samples - 60 cc (about 3 tablespoons) of blood will be collected from all participants by needle stick in a vein. The sample will be analyzed for genes and proteins that might predict heart rejection. In addition, many genes in blood cells and cells lining blood vessels that are unrelated to heart transplant rejection and whose functions or significance are unknown will also be examined for ideas for future research. Patients enrolled while on a wait list will, after transplantation, have an additional 44 cc (about 2 tablespoons) of blood collected at each heart biopsy and rejection episode during the first year of transplant, and 60 cc collected with each yearly biopsy for the next 9 years. - Urine samples - Between 100 and 300 cc (3 to 10 ounces) of urine may be collected from all participants to confirm blood test results Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00042614 •

Efficacy study of Zenapax in combination with CellCept, Cyclosporine and Corticosteroids in heart transplant Condition(s): Transplants Study Status: This study is no longer recruiting patients. Sponsor(s): Hoffmann-La Roche Purpose - Excerpt: The purpose of this study is to determine whether the combination of Zenapax, CellCept, Cyclosporine and Corticosteroids are effective in patients recieving heart transplants. Phase(s): Phase III; MedlinePlus consumer health information Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00048165

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Osteoporosis Prevention After Heart Transplant Condition(s): Osteoporosis; Cardiac transplantation

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Study Status: This study is completed. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); Merck Research Laboratories Purpose - Excerpt: During the first year after a heart transplant, people often rapidly lose bone from their spine and hips. About 35 percent of people who receive heart transplants will suffer broken bones during the first year after transplantation. This study will compare the safety and effectiveness of the drug alendronate (Fosamax) and the active form of vitamin D (calcitriol) in preventing bone loss at the spine and hip after a heart transplant. In this study, people who have had a successful heart transplant will receive either active alendronate and a "dummy pill" instead of calcitriol, or active calcitriol and a dummy pill instead of alendronate for the first year after their transplant, starting within 1 month after transplant surgery. We will measure bone density in the hip and spine at the start of the study and after 6 and 12 months, and will also check for broken bones in the spine. This research should lead to ways of preventing this crippling form of osteoporosis. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000412

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “heart transplant” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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CHAPTER 5. PATENTS ON HEART TRANSPLANT Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “heart transplant” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on heart transplant, we have not necessarily excluded nonmedical patents in this bibliography.

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

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

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

Adaptive device for supporting cardiac function during diastolic dysfunction and method therefor Inventor(s): Chekanov; Valeri S. (Franklin, WI) Assignee(s): Heart Care Associates, Llc (milwaukee, Wi) Patent Number: 6,540,666 Date filed: January 8, 2002 Abstract: An adaptive heart binding device and method for the treatment of heart failure. The device has a non-distendible jacket to prevent the heart from expanding beyond a preselect volume. A first chamber corresponding the right ventricle and a second chamber corresponding to the left ventricle are located between the heart and the jacket. The first and second chamber can be inflated to exert additional pressure on the heart over time without additional surgery. The gradual pressure increase hemodynamically remodels the heart so that is performs more like a non-diseased heart. The binding device can be used as a bridge to or in place of heart transplant. Excerpt(s): The present invention pertains to a method and apparatus for treating congestive heart disease and related valvular dysfunction. More particularly, the present invention is directed to an adaptive cardiac constraint having an outer non-extentible device and a pair of inner inflatable members for preventing over-extension of the heart during diastole. Congestive heart disease is a progressive and debilitating illness. The disease is characterized by a progressive enlargement of the heart. As the heart enlarges, the heart is performing an increasing amount of work in order to pump blood each heart beat. In time, the heart becomes so enlarged the heart cannot adequately supply blood. An afflicted patient is fatigued, unable to perform even simple exerting tasks and experiences pain and discomfort. Further, as the heart enlarges, the internal heart valves may not adequately close. This impairs the function of the valves and further reduces the heart's ability to supply blood. Causes of congestive heart failure (CHF) are not fully known. In certain instances, CHF may result from viral infections. In such cases, the heart may enlarge to such an extent that the adverse consequences of heart enlargement continue after the viral infection has passed and the disease continues its progressively debilitating course. Web site: http://www.delphion.com/details?pn=US06540666__

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Coxsackie virus vectors for delivery of nucleic acids encoding antigenic or therapeutic products Inventor(s): Chapman; Nora M. (Omaha, NE), Kolbeck; Peter (Carmichael, CA), Malone, III; James M. (Redwood, CA), Tracy; Steven M. (Omaha, NE) Assignee(s): Board of Regents of the University of Nebraska (lincoln, Ne) Patent Number: 6,323,024 Date filed: March 27, 2000 Abstract: The present invention is drawn to the use of attenuated Coxsackievirus cardiotropic virus vectors as efficient gene transfer vectors to deliver immunomodulatory or other biologically active proteins and/or antigenic epitopes in

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transient infections to aid in preventing, ameliorating, and/or ablating infectious viral heart disease and reducing, or ablating entirely, heart transplant rejection. Additionally, other organs or tissues may be targeted with specific picornaviruses. In particular, an attenuated CVB3 viral vector able to express a cytokine is provided. This cytokineexpressing viral vector is able to deliver the cytokine to a target tissue and reduce disease symptoms. Excerpt(s): The present invention relates generally to the fields of molecular biology and virology. More specifically, the present invention relates to a biologically engineered, attenuated Coxsackievirus and its use as a delivery vehicle for nucleic acids encoding antigenic or biologically active proteins. The coxsackieviruses, members of the family Picornaviridae, are divided into two groups, based essentially on their pathogenicity and replication in newborn mice. The Group B coxsackieviruses (CVB) are composed of six serotypes (1-6). Similar to other members of the Picornaviridae, the CVB genome is a single-stranded, messenger sense, polyadenylated RNA molecule (for review see Romero, J. R. et al., Current Topics in Microbiology and Immunology 223: 97-152, 1997). Genome analysis of the CVB shows that they are organized into a 5' nontranslating region, a protein coding region containing a single open reading frame, a 3' nontranslated region and a terminal poly-A tail, similar to other Picornaviruses. The CVB protein coding region can be further divided into three regions, P1, P2 and P3. P1 encodes the four capsid proteins VP4 (1A), VP2 (1B), VP3 (1C) and VP 1 (1D); P2 and P3 encode the non-structural proteins required for the CVB lifecycle: 2A (protease), 2B, 2C, 3A 3B (Vpg), 3C (protease) and 3D (polymerase) (See Romero et al., 1997, supra). The genomes of CVB that have been fully sequenced are very similar to one another in length, ranging from 7389 nucleotides (CVB1) to 7402 nucleotides (CVB5) (Romero et al., 1997 supra). Variations in length are due to differences within the coding region of VP1 and VP2 (capsid proteins) and in the 5' and 3' non-translated regions. The 5' nontranslated regions also show remarkable similarity in length. For a detailed review of the similarities among the CVB genomes, refer to Romero et al, supra, 1997. Web site: http://www.delphion.com/details?pn=US06323024__ •

Method and apparatus for heart transplant monitoring and analog telemetry calibration Inventor(s): Mulier; Peter M. J. (St. Paul, MN), Thompson; David L. (Fridley, MN), Wahlstrand; John D. (Shoreview, MN) Assignee(s): Medtronic, Inc. (minneapolis, Mn) Patent Number: 5,402,794 Date filed: July 1, 1992 Abstract: A cardiac pacemaker with an analog telemetry system. A calibration circuit within the pacemaker is adapted to provide a reference signal of known character to the pacemaker's telemetry system. The reference signal is transmitted across the telemetry link as if it were an actual cardiac signal, and received by an external programmer. Since the reference signal has known, predetermined qualities, the programmer can automatically calibrate and scale the telemetry signal from the pacemaker, thereby increasing the accuracy of the telemetry channel. The increased accuracy is particular useful in assessing rejection of a transplanted heart, which is known to be associated with a 15% decline in the peak R-wave amplitude of the cardiac signal.

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Excerpt(s): This invention relates to the field of cardiac pacemakers, and more particularly to a pacemaker having an automatic calibration signal for an analog telemetry channel. As of Jan. 1, 1991, over 16,000 heart transplants have taken place worldwide, more than 87% of these since 1984 (according to Kreitt et al., "The Registry of the International Society for Heart and Lung Transplantation: Eight Annual Report", The Journal of Heart and Lung Transplantation, Number 4, Jul.-Aug. 1991, pp. 491-498). Rejection of the transplanted heart within two years is the cause of death in 40% or more of all cases. Currently, the preferred method for monitoring rejection is by serial transvenous endomyocardial biopsy. Such a procedure is invasive and relatively traumatic, and must usually be performed at specialized facilities. Typically, two such tests are performed during the first six post-implant months; thereafter, the tests are given less frequently, but throughout the patient's lifetime. Up to a day may be required to obtain results from such a test. One known shortcoming of the serial transvenous endomyocardial biopsy in evaluating heart rejection is that existing scar tissue in the heart, which can occur for various reasons other than heart rejection, can be erroneously interpreted as indicating rejection. It has also been found, however, that certain features of the electrical cardiac signal in transplant patients may also be utilized as an indicator of heart rejection. See, e.g., Warnecke et al., "Noninvasive Monitoring of Cardiac Allograft Rejection by Intramyocardial Electrogram Recordings", Circulation 74 (suppl. III), III-72-III-76, 1986. In particular, it has been found that the onset of heart rejection is accompanied by a reduction of up to 15% in the magnitude of intracardiac R-wave and T-wave peaks. See, e.g., Rosenbloom et al., "Noninvasive Detection of Cardiac Allograft Rejection by Analysis of the Unipolar Peak-to-Peak Amplitude of Intramyocardial Electrograms", Ann. Thorac. Surg., 1989; 47:407-411; see also, e.g., Grace et al., "Diagnosis of Early Cardiac Transplant Rejection by Fall in Evoked T Wave Amplitude Measured Using an Externalized QT Driven Rate Responsive Pacemaker", PACE, vol. 14, Jun. 1991. The ability to monitor and detect this phenomenon would therefore facilitate the early detection and treatment of rejection. To this end, an implantable pacemaker with an accurate analog telemetry channel for transmitting intracardiac signals would greatly enhance the ability of a monitoring physician to assess the cardiac condition. Web site: http://www.delphion.com/details?pn=US05402794__ •

Method for treatment of angina and myocardial infarctions with omental lipids Inventor(s): Catsimpoolas; Nicholas (Newton Centre, MA), Gavras; Haralambos (Wayland, MA), Haudenschild; Christian C. (Newtonville, MA), Klibaner; Michael I. (Brookline, MA) Assignee(s): Angio-medical Corporation (new York, Ny), Trustees of Boston University (boston, Ma) Patent Number: 4,778,787 Date filed: December 20, 1985 Abstract: Angiogenesis healing factors residing in omentum-derived lipid fractions with or without gangliosides or their synthetic equivalents can be used to treat myocardial ischemic conditions including but not limited to myocardial infarction, angina, as well as in heart transplant, vascular grafts, and re-opened vessels leading to improved vascularization, perfusion, collagenization and organization of said lesions; the involved and adjacent tissues.

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Excerpt(s): Angiogenesis healing factor(s) residing in an omentum-derived lipid fraction are used to treat myocardial ischemic conditions including but not limited to myocardial infarction (MI), angina, heart transplants and hearts with vascular grafts or recanalized coronary arteries with the purpose of improving vascularization, perfusion and organization of the involved and adjacent tissues. Heart attacks are a major cause of death and the overall mortality rate during the first months after MI average 30%. Most of the deaths occur in the first 12 hours. Myocardial infarction is ischemic necrosis due to occlusion or substantial narrowing of a coronary artery by thrombus, or by atherosclerosis, or by hemorrhage into an atherosclerotic plaque, or by spastic constriction, or by a combination of these mechanisms. Web site: http://www.delphion.com/details?pn=US04778787__ •

Method of inotropic treatment of heart disease using hypothermia Inventor(s): Dae; Michael W. (Belmont, CA), Stull; Paul M. (San Mateo, CA) Assignee(s): Radiant Medical, Inc. (redwood City, Ca) Patent Number: 6,607,517 Date filed: August 24, 2001 Abstract: A method for treating cardiac failure such as congestive heart failure by application of hypothermia. Hypothermia may be applied by endovascular cooling using a heat exchange catheter circulating heat exchange fluid between an external heat exchanger controlled using temperature feedback from a temperature probe on or in the patient to cool the heart to a sufficiently low temperature for a sufficient length of time to increase cardiac output and improve the vascular condition of the patient. The patient may be maintained in the hypothermic condition for a period of time and is then rewarmed slowly and controllably. The endovascular temperature management may be controlled automatically in response to a temperature probe on the patient, and shivering while the patient is cool may be combated using surface warming and antishivering drugs. The method is applicable to treat congestive heart failure and may be used repeatedly on the same patient to restore that patient to adequate heart function when the vascular condition of that patient has become unacceptable. The method may be used to maintain a patient until a heart transplant becomes available. The method may be used to stabilize a patient's condition to allow needed surgery or intervention. The method may be used in conjunction with other treatments including drugs, balloon pumps, pacing devices and ventricular assist devices. Excerpt(s): This invention relates generally to methods for medical treatment and more particularly to the application of hypothermia by various means including by endovascular heat exchange to treat chronic heart disease. These methods find particular usefulness in treating congestive heart failure. The condition of heart failure is complex and may be diagnosed by any one or a number of different criteria: the cardiac output may be low, generally consideredbelow 2.5 liters per minute; the stroke volume of the heart may be low, for example below 25 cc; the ejection fraction of the sick heart may be below 40%; there may be echocardiographic findings of enlarged or improperly pumping hear; physical examinations including x-rays and stress testing may indicate cardiac failure; there may be cardiomegally; there may be increased left ventricular wall thickness and chamber dilation indicative of cardiac failure; there may be pulmonary edema, which with other sympotoms and findings may indicate cardiac failure; there may be angiographic findings indicative of heart failure; and a diagnostic test of blood components, such as electrolytes or proteins may indicate heart failure. This lis is not

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exhaustive of the symptoms and findings that may help diagnose heart failure, but is offered to show the extent to which heart failure impacts the entire patient and may radically deteriorate the patient's life quality. One common condition is congestive heart failure (CHF). CHF is one of the most serious health problems in the world. An estimated 4.8 million Americans alone have CHF. It is often the end stage of serious heart disease; half of those diagnosed with CHF will be dead within 5 years. An estimated 400,000 new case are diagnosed each year. It is the most common diagnosis in hospital patients age 65 years and older, with the disease affecting 10% of all those over the age of 70. The financial cost of treatment of CHF patients is over $17 billion a year. The human cost is beyond measure. Web site: http://www.delphion.com/details?pn=US06607517__ •

Noninvasive detection of rejection in heart transplant patients Inventor(s): Bianco; Richard W. (Minneapolis, MN), Bolman, III; R. M. (Minneapolis, MN), Slovut; David P. (Golden Valley, MN), Wenstrom; John C. (Salida, CO) Assignee(s): Regents of the Univeristy of Minnesota (minneapolis, Mn) Patent Number: 5,285,793 Date filed: May 21, 1992 Abstract: A method and apparatus for diagnosing heart rejection is disclosed. Heart rejection is diagnosed based on the pattern of interbeat intervals. The interbeat intervals of the heart are measured shortly after transplant to establish a baseline pattern. The patterns of interbeat intervals from subsequent measurements are compared to the baseline to detect changes from the baseline indicating rejection. The apparatus of the invention measures the interbeat intervals using a Schmidt trigger that detects the upstroke of the QRS and produces a corresponding pulse. The intervals between pulses are timed to produce a series of interbeat interval measurements that are stored and analyzed. Software provides for automated pattern analysis. Excerpt(s): The present invention pertains generally to the field of transplant medicine, and more particularly to a device and method for the non-invasive detection of graft rejection in heart transplant recipients. Tissue rejection is the principal cause of heart transplant failures, occurring when a recipient's immune system attacks the transplanted heart. Suppressing this immune system response is critical to the success of heart transplants. Pharmaceutical agents such as Cyclosporine A (CSA), steroids and Azathioprine are used to control and suppress a recipient's immune system response to grafted tissue. However, suppressing a recipient's immune system renders him more vulnerable to infection. Adjusting immune system suppression to the minimum required is thus a major objective. To do this, the transplanted heart tissue must be monitored continuously and carefully for signs of rejection. Recognizing the onset and severity of rejection is a major problem. Tissue rejection in heart transplant recipients is generally silent until the heart is damaged irreversibly. It is crucial to decide whether or not a patient is rejecting his or her transplanted heart, so that potentially life saving therapy can be started immediately. Thus, early and reliable detection of graft rejection is vital to the success of heart transplants. Web site: http://www.delphion.com/details?pn=US05285793__

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Noninvasive diagnosis for allograft rejection Inventor(s): Ansari; Aftab A. (Stone Mountain, GA), Sell; Kenneth W. (Atlanta, GA), Villinger; Francois (Decatur, GA) Assignee(s): Emory University (atlanta, Ga) Patent Number: 5,635,365 Date filed: August 7, 1995 Abstract: The present invention provides a noninvasive method for diagnosing and/or predicting a rejection episode in a transplant patient, for example, in a heart transplant patient, by determining a rise in the frequency of thioguanine-resistant mutant peripheral blood mononuclear cells. Those resistant mutant cells have a deficiency in the purine salvage enzyme hypoxanthine guanine phosphoribosyltransferase. The relative frequency of the mutant cells in the population from a sample can be determined by direct plating in the presence of a selection medium and by determining of the mutation by polymerase chain reaction technology. Excerpt(s): The field of this invention is the area of allograft rejection and the diagnosis and/or prediction of allograft rejection. Specifically, the present invention provides a method for the diagnosis and/or prediction of immune rejection of transplanted organs or tissue, for example, a cardiac transplant; the rejection episode is diagnosed or predicted via determination of an increase in the frequency of peripheral blood mononuclear cells lacking hypoxanthine-guanine phosphoribosyltransferase activity. Nearly 2000 heart transplants are performed in the United States each year, and many other organs, such as lung, kidney, liver and pancreas, are transplanted into patients as well. There is a relatively stable population of about 16,000 to 20,000 heart transplant patients. Unfortunately, the average heart transplant patient survives only 8 to 10 years after receiving a transplant. New recipients, as well as the existing cohort of transplant recipients, need to be monitored for evidence of allograft rejection so that treatment can be administered as soon as possible. If transplant rejection is diagnosed relatively late, there is often significant tissue damage in the transplanted organ and hospitalization is almost inevitable. If the damage to the organ is extensive, a retransplant may also be required. The current method for the monitoring and diagnosis of rejection after human cardiac transplant is invasive, and it entails the use of the transvenous myocardial bioptome to procure cardiac biopsy samples, which are then examined for histological evidence of rejection. A graded score of 0 to 4 is used; a score of 0 is assigned where there is no evidence of rejection and 4 is the maximum score of tissue damage and rejection. This pathology-graded score, together with clinical criteria, are used to institute immunosuppressive therapies for heart transplant patients with a diagnosis of rejection. By contrast, liver, kidney and lung transplants can be monitored by noninvasive enzymatic assays of urine and/or blood. However, in those cases, damage to the transplanted organ has occurred by the time diminished function is reflected in the tests, and the present invention provides an earlier method for diagnosis and/or prediction of rejection episodes. Web site: http://www.delphion.com/details?pn=US05635365__

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System and method for monitoring heart transplant rejection Inventor(s): Gebhardt; Ursala (Huissen, NL) Assignee(s): Vitatron Medical, B.v. (dieren, Nl) Patent Number: 5,197,480 Date filed: June 8, 1990 Abstract: A pacemaker system and method for predicting cardiac allograft rejection noninvasively through the analysis of the T-wave amplitudes of evoked heartbeats. A pacemaker suitable for detecting the T-wave portions of heartbeat signals, such as the Rhythmyx pacemaker, is utilized for providing T-wave information, preferably the amplitude of the T-wave, which information is analyzed for determining a trend indicative of rejection. A decrease, or diminution of evoked T-wave amplitude indicates rejection, and can be used for appropriate follow-up treatment. Excerpt(s): This invention relates to medical systems and methods for noninvasively monitoring a transplanted heart to diagnose cardiac allograft rejection. It is well known that following human heart transplantation there is danger of rejection of the new heart by the host patient. Such rejection, referred to as cardiac allograft rejection, has been widely studied and discussed in the medical literature. While techniques dealing with, i.e. treating such rejection, have advanced greatly, there still remains a need for accurate, noninvasive, safe and relatively simple diagnosis of such rejection. One technique for determining the condition of the transplanted heart is to perform a biopsy. However, such an invasive technique is clearly not desirable, and there is a substantial need for an accurate and reliable noninvasive means of diagnosis. Web site: http://www.delphion.com/details?pn=US05197480__

Patent Applications on Heart Transplant As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to heart transplant: •

Bag for at least partially enveloping a heart Inventor(s): Haindl, Hans; (Wennigsen, DE) Correspondence: Attention OF Melissa Jean Pytel; Merchant & Gould P.C.; P.O. Box 2903; Minneapolis; MN; 55402-0903; US Patent Application Number: 20020133055 Date filed: May 7, 2002 Abstract: A pouch to at least partly enclose a heart (1), the wall of the pouch (2) being elastic. The purpose of the pouch is to enclose at least part of a heart (1) and to oppose excessive dilation of the heart (1) that might be due to infectious disease of the heart muscle, for instance a viral infection or an autoimmune process. In many cases the use of such a pouch (2) may circumvent the need for a heart transplant.

10

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

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Excerpt(s): This application is a continuation of application no. PCT/EP98/03619, filed Jun. 16, 1998, which application claims the priority of German application no. 197 26 389.5, filed Jun. 21, 1997, and each of which is incorporated herein by reference. The invention relates to a bag, hereafter called pouch, with which to at least partly enclose a heart. Infectious disease of the heart muscle both by viral infection and by autoimmune processes may lead to enlarged heart volume. If such an enlargement exceeds a critical value, the result will be progressive heart dilation which can be explained by Laplace's law. As the volume subtended by the left heart chamber increases, the stresses in the walls of this cavity will increase. Consequently the muscle fibrils are overloaded and their ideal range of elongation is exceeded. When this excessive elongation takes place, there is, as a rule, a residual volume in the heart. Then the muscle fibrils must operate against a primarily high wall strain, and are further extended thereby. A vicious cycle arises, leading to increasing distension of the heart and consequent heart insufficiency. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Chest cavity classifier apparatus and method for an artificial heart transplant Inventor(s): McNair, Douglas S.; (Gloucester, MA), Mitsa, Theophano; (Beverly, MA) Correspondence: Nutter Mcclennen & Fish Llp; World Trade Center West; 155 Seaport Boulevard; Boston; MA; 02210-2604; US Patent Application Number: 20020188228 Date filed: April 27, 2001 Abstract: An automated classifier receives input data indicative of a prospective surgical patient's mediastinal volume, body surface area and gender, and provides a classifier output signal indicative of quality of fit of a totally implantable artificial heart in the chest cavity of the patient. The present invention assists the surgical team in making their preoperative decision regarding whether or not the totally implantable artificial heart will fit in the chest cavity of the candidate patient. The classifier may also receive as input parameters: the distance between the patient's spine at the sternum at the level of the pulmonary bifurcation; the distance between the spine and the sternum in a caudal heart slice; the maximum left to right distance dimension of the heart; the distance from the rightmost end of the heart to the left chest wall; and the maximum left to right dimension of the chest cavity. Each of the input signals to the classifier is multiplied by an associated regression coefficient, and the resultant products are summed to provide a dependent variable whose value is indicative of quality of fit. To ensure that the classifier provides an accurate measure of quality of fit, the classifier coefficients are developed using a training process, and preferably verified in a testing process. Excerpt(s): The present invention relates generally to cardiac assist devices and, in particular to an automated classifier for assessing preoperatively whether a cardiac assist device will fit within a patient's chest cavity. A totally implantable artificial heart offers the potential for an excellent quality of life for the recipient. Recent progress in modern technology, improvements in surgical techniques and increased understanding of circulatory physiology of cardiac assist device recipients indicate that a permanent mechanical replacement heart is now becoming a viable therapy for the treatment of patients having end-stage heart failure. Realization of this potential requires minimization of the size and weight of the implantable elements including the blood pump assembly. Current design activities have focused on the most effective, anatomically compatible configuration of the blood pump, including the inflow and

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outflow ports. However, because the size, shape and topography of the anatomical structures of the chest cavity vary among patients, a particular blood pump will not fit into the chest cavity of all candidate patients. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Coxsackievirus vectors and their use in prevention and treatment of disease Inventor(s): Chapman, Nora M.; (Omaha, NE), Tracy, Steven M.; (Omaha, NE) Correspondence: Janet E. Reed, ESQ.; Woodcock Washburn Llp; 46th Floor; One Liberty Place; Philadelphia; PA; 19103; US Patent Application Number: 20030190329 Date filed: March 26, 2001 Abstract: The present invention is drawn to the use of attenuated coxsackievirus cardiotropic virus vectors as efficient gene transfer vectors to deliver immunomodulatory or other biologically active proteins and/or antigenic epitopes in transient infections to aid in preventing, ameliorating, and/or ablating infectious viral heart disease and reducing, or ablating entirely, heart transplant rejection. Specifically disclosed are univalent and multivalent vaccines for certain viruses, including adenovirus and coxsackieviruses. Also disclosed are compositions and methods for suppressing onset of type 1 diabetes, using vectors of the invention that express immunomodulatory proteins, specifically IL-4. Excerpt(s): This application is a continuation-in-part of U.S. application Ser. No. 09/403,672, having a filing date of Mar. 27, 2000 and claiming priority under 35 U.S.C.sctn.371 to International Application No. PCT/US98/04291, which itself claims priority under 35 U.S.C.sctn.120 to U.S. application Ser. No. 08/812,121, filed Mar. 5, 1997, now U.S. Pat. No. 6,071,742, issued Jun. 6, 2000. The entireties of each of the abovelisted applications are incorporated by reference herein. The present invention relates generally to the fields of molecular biology and virology. More specifically, the present invention relates to an attenuated Coxsackievirus, its use as a delivery vehicle for nucleic acids encoding antigenic or biologically active proteins, and treatment or prevention of viral infection or type 1 diabetes. Various scientific articles, scholarly publications and patent documents are referred to herein to describe the state of the art to which the invention pertains. Each of these documents is incorporated by reference herein in its entirety. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Non-peptide CCR1 receptor antagonists in combination with cyclosporin A for the treatment of heart transplant rejection Inventor(s): Horuk, Richard; (Lafayette, CA) Correspondence: Wendy L. Washtien; Berlex Biosciences, Legal Department; 15049 San Pablo Avenue; P.O. Box 4099; Richmond; CA; 94804-0099; US Patent Application Number: 20020039997 Date filed: July 25, 2001 Abstract: This invention is directed to pharmaceutical compositions useful in treating heart transplant rejection in mammals comprising a pharmaceutically acceptable

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excipient, a therapeutically effective amount of a non-peptide CCR1 receptor antagonist and a sub-nephrotoxic amount of cyclosporin A. Excerpt(s): This is a non-provisional application claiming priority under 35 U.S.C.sctn. 119 provisional application Nos. 601222,053, filed Jul. 31, 2000, and 60/231,282, filed Sep. 8, 2000. The present invention relates to pharmaceutical compositions useful in the treatment of heart transplant rejection in mammals which comprise a pharmaceutically acceptable excipient, a therapeutically effective amount of a non-peptide CCR1 receptor antagonist and a sub-nephrotoxic amount of cyclosporin A. The present invention also relates to a method of using such pharmaceutical compositions in treating heart transplant rejection in mammals. An important component of the inflammatory process involves the migration and activation of select populations of leukocytes from the circulation and their accumulation in the affected tissue. While the idea of leukocyte trafficking is not new, it has enjoyed a renaissance recently following the discovery and characterization of the selectin and integrin families of adhesion molecules and the large family of selective chemotatic cytokines known as chemokines. Chemokine receptors are expressed on leukocytes and process the signals following the binding of the chemokine whereby such signals are eventually transduced into migration or activation of the leukocytes towards the source of the chemokine. Therefore, by regulating the migration and activation of leukocytes from the peripheral blood to extravascular sites in organs, skin, articulations or connective, tissue, chemokines play a critical role in the maintenance of host defense as well as in the development of the immune response. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of an angiotensin II receptor antagonist for the preparation of drugs to increase the survival rate of renal transplant patients Inventor(s): Remuzzi, Giuseppe; (Bergamo, IT) Correspondence: Browdy And Neimark, P.L.L.C.; Sutie 300; 624 Ninth Street, N.W.; Washington; DC; 20001-5303; US Patent Application Number: 20020115702 Date filed: February 19, 2002 Abstract: The present invention relates to the use, for the preparation of drugs to increase the survival rate of transplant patients, including renal and heart transplant patients, of a therapeutically effective amount of an angiotension II receptor antagonist compound, such as the class of substituted imidazoles represented by formula (I) and in particular by losartan potassium, 2-butyl-4-chloro-[(2'-tetrazol-5-yl)biphenyl-4-il]methyl]-5-(hydroxymethyl)imidazole potassium salt. Excerpt(s): This invention relates to the use of an angiotensin II receptor antagonist, such as substituted imidazole compounds, for the treatment of Post-transplant hypertension. The invention also relates to use of an angiotensin II receptor antagonist, such as substituted imidazole compounds, for the preparation of drugs to increase the survival rate of transplant patients, including renal transplant patients. The invention also relates to a method of using an angiotensin II receptor antagonist, such as substituted for increasing the survival rate of transplant patients, including renal transplant patients. Substituted imidazoles of formula I are known to inhibit the action of the octapeptide hormone angiotensin II (AII) and are useful therefore in alleviating angiotensin induced hypertension. The enzyme renin acts on a blood plasma.alpha.2-globulin, angiotensinogen, to produce angiotensin I, which is then converted by angiotensin

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converting-enzyme to AII. The latter substance is a powerful vasopressor agent which has been implicated as a causitive agent, for producing high blood pressure in various mammalian species, such as the rat, dog, and man. The compounds disclosed in this application inhibit the action of AII at its receptors on target cells and thus prevent the increase in blood pressure produced by this hormone-receptor interaction. The present application discloses a method for the improvement of insulin sensitivity by administering an angiotensin II receptor antagonist, such as a substituted imidazole of formula I, to a species of mammal with hypertension due to angiotensin II. Administration of an angiotensin II receptor antagonist, such as a substituted imidazole of formula I, with a diuretic, such as furosemide or hydrochlorothiazide; either as a stepwise combined therapy (diuretic first) or as a physical mixture, enhances the antihypertensive effect of the compound, while also improving the insulin sensitivity of the patient. wherein R1 is hydrogen, nitro or amino; R2 is phenyl, furyl or thienyl optionally substituted by halogen, lower alkyl, lower alkoxy or di-lower alkylamino; R3 is hydrogen or lower alkyl and X is halogen; and their physiologically acceptable salts. These compounds have diuretic and hypotensive actions. 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 heart transplant, 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 “heart transplant” (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 heart transplant. You can also use this procedure to view pending patent applications concerning heart transplant. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 6. BOOKS ON HEART TRANSPLANT Overview This chapter provides bibliographic book references relating to heart transplant. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on heart transplant include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print®). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “heart transplant” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “heart transplant” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “heart transplant” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

A Change of Heart: Journal of a Heart Transplant by Bill Long; ISBN: 1874597219; http://www.amazon.com/exec/obidos/ASIN/1874597219/icongroupinterna

•

A Heart Full of Life: The Powerful but Wonderfully Warm and Whimsical Journey of a Heart Transplant Recipient by Bea Gene, Gene Bea; ISBN: 1410758745; http://www.amazon.com/exec/obidos/ASIN/1410758745/icongroupinterna

•

A Matter of Heart: One Woman's Triumph over Breast Cancer and a Heart Transplant by Nancy Shank Pedder; ISBN: 1892803240; http://www.amazon.com/exec/obidos/ASIN/1892803240/icongroupinterna

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A Personal Letter to Allen: The Personal Journal of a Wife's Thoughts and Feelings As Her Husband Struggles to Survive, Before and After a Heart Transplant by Judy Barnes; ISBN: 1591291097; http://www.amazon.com/exec/obidos/ASIN/1591291097/icongroupinterna

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Christiaan Barnard and the Story of the First Successful Heart Transplant (Unlocking the Secrets of Science) by John Bankston; ISBN: 158415120X; http://www.amazon.com/exec/obidos/ASIN/158415120X/icongroupinterna

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Dinosaur Heart Transplants: Renewing Mainline Congregations by R. Robert Cueni; ISBN: 0687084660; http://www.amazon.com/exec/obidos/ASIN/0687084660/icongroupinterna

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Early Heart Transplant Surgery in the UK: Early Heart Transplant Surgery in the UK (Wellcome Witnesses to Twentieth Century Medicine) by E.M. Tansey (Editor), L.A. Reynolds (Editor); ISBN: 1841290076; http://www.amazon.com/exec/obidos/ASIN/1841290076/icongroupinterna

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Heart Transplants by Nancy Hoffman; ISBN: 1560069295; http://www.amazon.com/exec/obidos/ASIN/1560069295/icongroupinterna

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Heart Transplants & Other Misappropriations by David Lunde; ISBN: 0773400087; http://www.amazon.com/exec/obidos/ASIN/0773400087/icongroupinterna

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Heart transplants : concerns about cost, access, and availability of donor organs : report to the chairman, Subcommittee on Health, Committee on Ways and Means, House of Representatives (SuDoc GA 1.13:HRD-89-61) by U.S. General Accounting Office; ISBN: B000102U2K; http://www.amazon.com/exec/obidos/ASIN/B000102U2K/icongroupinterna

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Laura's New Heart: A Healer's Spiritual Journey Through a Heart Transplant by Laura L. Fine; ISBN: 1414064330; http://www.amazon.com/exec/obidos/ASIN/1414064330/icongroupinterna

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Life In Limbo : Waiting for a Heart Transplant by Lisa Stiles Nance (Author); ISBN: 0595297722; http://www.amazon.com/exec/obidos/ASIN/0595297722/icongroupinterna

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Stories of the Heart: Reflections on the Heart Transplant Journey: Stories of Hope and Inspiration by Nancy Siemers (Editor), et al; ISBN: 1886513147; http://www.amazon.com/exec/obidos/ASIN/1886513147/icongroupinterna

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The Alarming History of Medicine : Amusing Anecdotes from Hippocrates to Heart Transplants by Richard Gordon (Author); ISBN: 0312167636; http://www.amazon.com/exec/obidos/ASIN/0312167636/icongroupinterna

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The Reluctant Warrior : A Journey Through My Baby's Heart Transplant by Mary Chan; ISBN: 1893162184; http://www.amazon.com/exec/obidos/ASIN/1893162184/icongroupinterna

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Through the Fire: The True Story of the Death to Life Experiences of a Preacher Who Recieved a Heart Transplant by John W. Watts; ISBN: 1414053339; http://www.amazon.com/exec/obidos/ASIN/1414053339/icongroupinterna

•

Transplant Coronary Artery Disease : The Nemesis of Heart Transplantation (Acta Biomedica Lovaniensia, No. 219) by Johan Van Cleemput, Johan Van Cleemput; ISBN: 9058670449; http://www.amazon.com/exec/obidos/ASIN/9058670449/icongroupinterna

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Chapters on Heart Transplant In order to find chapters that specifically relate to heart transplant, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and heart transplant 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 “heart transplant” (or synonyms) into the “For these words:” box.

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CHAPTER 7. MULTIMEDIA ON HEART TRANSPLANT Overview In this chapter, we show you how to keep current on multimedia sources of information on heart transplant. 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 heart transplant is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “heart transplant” 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 “heart transplant” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on heart transplant: •

Organ Transplants Source: Medstar Productions. Contact: Available from Films for the Humanities. P.O. Box 2053, Princeton, NJ 08540. (609) 452-1128 or (800) 257-5126. PRICE: $149 (VHS); $249 (UMatic). Order No. FM1461. Rental: $75. Summary: The process of transplanting organs is featured in this program. A patient on dialysis waits for a kidney, recieves surgery, and reacts to the operation. The program also shows two patients after their operations: one whose body rejected the kidney and one whose body accepted it. Also shown is a full heart transplant.

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CHAPTER 8. PERIODICALS AND NEWS ON HEART TRANSPLANT Overview In this chapter, we suggest a number of news sources and present various periodicals that cover heart transplant.

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

New policy curbs exaggeration of heart transplant urgency Source: Reuters Medical News Date: March 12, 2004

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•

Donor serum markers point to heart transplant graft failure Source: Reuters Medical News Date: January 21, 2004

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Support devices help kids awaiting heart transplants Source: Reuters Health eLine Date: December 12, 2003

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Mechanical support cuts waiting list deaths for pediatric heart transplantation Source: Reuters Industry Breifing Date: December 11, 2003

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Sleep apnea may persist in heart failure patients after cardiac transplantation Source: Reuters Medical News Date: December 05, 2003

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Viagra cuts blood pressure in heart transplantees Source: Reuters Health eLine Date: October 24, 2003

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Stem cells may eliminate need for heart transplant Source: Reuters Health eLine Date: September 01, 2003

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Improvement maintained for 2 years after cardiac transplant in AIDS patient Source: Reuters Medical News Date: June 04, 2003

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Heart transplant in HIV+ man raises ethics issues Source: Reuters Health eLine Date: June 04, 2003

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Milrinone costly aid in heart transplant candidates Source: Reuters Industry Breifing Date: March 07, 2003

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Cardiac transplant function rapidly assessed by BNP assay Source: Reuters Medical News Date: January 20, 2003

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Carvedilol can obviate pediatric cardiac transplant in some cases Source: Reuters Medical News Date: December 30, 2002

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Heart rate response to exercise after heart transplantation improves in some Source: Reuters Medical News Date: December 20, 2002

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Simvastatin significantly improves survival after heart transplantation Source: Reuters Industry Breifing Date: December 09, 2002

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Older people do just as well after heart transplant Source: Reuters Health eLine Date: October 29, 2002

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Traveling after a heart transplant is safe Source: Reuters Medical News Date: September 02, 2002

Periodicals and News

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Factors influencing reinnervation after heart transplantation defined Source: Reuters Medical News Date: July 10, 2002

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Reevaluation of heart transplantation criteria needed based on beta-blocker use Source: Reuters Industry Breifing Date: June 06, 2002

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Jarvik 2000 successful in patients awaiting heart transplantation Source: Reuters Industry Breifing Date: May 28, 2002

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Device helps patients awaiting heart transplant Source: Reuters Health eLine Date: May 28, 2002

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Regular exercise improves endothelial function after heart transplant Source: Reuters Medical News Date: May 17, 2002

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LVAD bridge to heart transplantation improves posttransplant survival Source: Reuters Industry Breifing Date: April 18, 2002

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Vitamins C, E may aid heart transplant patients Source: Reuters Health eLine Date: March 29, 2002

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Antioxidant vitamins slow arteriosclerosis in heart transplant recipients Source: Reuters Medical News Date: March 28, 2002

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Leg-press resistance exercise can be safe for heart transplant recipients Source: Reuters Medical News Date: December 19, 2001

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Heart transplant patients benefit when switched from cyclosporin A to tacrolimus Source: Reuters Industry Breifing Date: September 03, 2001

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Allergy drug prevents complication of heart transplantation in mice Source: Reuters Medical News Date: July 19, 2001

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The NIH Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine.

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Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “heart transplant” (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 “heart transplant” (or synonyms). If you know the name of a company that is relevant to heart transplant, 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 “heart transplant” (or synonyms).

Academic Periodicals covering Heart Transplant Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to heart transplant. In addition to these sources, you can search for articles covering heart transplant that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical

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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 9. 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 heart transplant. 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).

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Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.

Mosby’s Drug Consult™ Mosby’s Drug Consult™ database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/.

PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.

Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to heart transplant by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/. Scroll down the page, and on the left toolbar, click on “Orphan Drug Designation Database.” On this page (http://www.rarediseases.org/search/noddsearch.html), type “heart transplant” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for

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marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for heart transplant: •

Imciromab pentetate (trade name: Myoscint) http://www.rarediseases.org/nord/search/nodd_full?code=780

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

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APPENDICES

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

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute11: •

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

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

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

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

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

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

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

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

11

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

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

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

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

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

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

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

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

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

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

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

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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

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

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

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

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

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

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

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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:13 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

•

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

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

•

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

•

Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

•

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

•

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

•

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

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

12

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 13 See http://www.nlm.nih.gov/databases/databases.html.

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•

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

•

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

The NLM Gateway14 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “heart transplant” (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 20918 187 795 46 43 21989

HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.18 Simply search by “heart transplant” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

14

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

15

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 16 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 17 18

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

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

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Coffee Break: Tutorials for Biologists19 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.20 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.21 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

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

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

•

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

19 Adapted 20

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

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 21 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.

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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 heart transplant 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 heart transplant. 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 heart transplant. 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 “heart transplant”:

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Guides on heart transplant Heart Transplantation http://www.nlm.nih.gov/medlineplus/hearttransplantation.html

•

Other guides Congenital Heart Disease http://www.nlm.nih.gov/medlineplus/congenitalheartdisease.html Kidney Transplantation http://www.nlm.nih.gov/medlineplus/kidneytransplantation.html Liver Transplantation http://www.nlm.nih.gov/medlineplus/livertransplantation.html Lung Transplantation http://www.nlm.nih.gov/medlineplus/lungtransplantation.html Organ Transplantation http://www.nlm.nih.gov/medlineplus/organtransplantation.html Pancreas Transplantation http://www.nlm.nih.gov/medlineplus/pancreastransplantation.html

Within the health topic page dedicated to heart transplant, the following was listed: •

General/Overviews Heart Transplant: What to Expect http://circ.ahajournals.org/cgi/reprint/106/14/1750.pdf Transplant Primer - Heart Transplant Source: Scientific Registry of Transplant Recipients http://www.ustransplant.org/primer/heart.html

•

Specific Conditions/Aspects Organ Donation Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=4697 Organ Facts: Heart / Lung Source: United Network for Organ Sharing http://www.transplantliving.org/OrganFacts/heartlung.aspx

•

Children Heart Transplants in Infants and Children Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=4589

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Latest News FDA Approves Heart Assist Device for Children Source: 02/26/2004, Food and Drug Administration http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01280.html

•

Organizations American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=1200000 Division of Transplantation Source: Health Resources and Services Administration http://www.hrsa.gov/osp/dot/dotmain.htm National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/ Scientific Registry of Transplant Recipients http://www.ustransplant.org/index.html United Network for Organ Sharing http://www.transplantliving.org/

•

Research Cholesterol-Lowering Drug Improves Survival after Heart Transplant Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3007095 Post-Transplant Nerve Regrowth Better with Young Hearts, Quick Surgery Source: American Heart Association http://www.americanheart.org/presenter.jhtml%3Bjsessionid=OPXXMBWSX34PX WFZOAHCCZQ?identifier=3003617 While-You-Wait Implantable Heart Assist Device Appears Effective Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3002820

•

Statistics About Transplants: Fast Facts Source: Scientific Registry of Transplant Recipients http://www.ustransplant.org/facts.html Heart Center Data Profile Source: Organ Procurement and Transplantation Network http://www.optn.org/organDatasource/stateData.asp?type=state&mqsd=1&displ ay=Heart Heart Transplants and Statistics Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=4588 Heart/Lung Data Center Profile Source: Organ Procurement and Transplantation Network http://www.optn.org/organDatasource/stateData.asp?type=state&mqsd=1&displ

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ay=HeartLung Organ Facts Source: United Network for Organ Sharing http://www.transplantliving.org/OrganFacts/default.aspx 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 heart transplant. 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: •

Gift: Two Families' Stories About Organ and Tissue Donation Source: South Deerfield, MA: Channing L. Bete Company, Inc. 1996. 15 p. Contact: Available from Channing L. Bete Company, Inc. 200 State Road, South Deerfield, MA 01373-0200. (800) 628-7733. Fax (800) 499-6464. PRICE: $1.25 each for 1-24 copies; discounts available for larger orders. Summary: This booklet is designed to help readers understand the process of organ donation. The booklet tells the stories of two African American families; one in which the father lies dying in need of a heart transplant, and the other in which a young man was killed and his wife must decide about donating his organs. Topics include the need for donor organs; informed consent and required paperwork; how the organs are removed from the donor; religious and ethical concerns; and psychosocial considerations. The booklet is illustrated with line drawings of the families, hospital setting, and physicians. The back page of the booklet provides telephone numbers for more information, as well as a blank Uniform Donor Card for readers to sign and discuss with their families. The National Guideline Clearinghouse™

The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site located at http://www.guideline.gov/ by using the keyword “heart transplant” (or synonyms). The following was recently posted:

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ACC/AHA 2002 guideline update for exercise testing. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing) Source: American College of Cardiology Foundation - Medical Specialty Society; 1997 July (revised 2002 Sep); 59 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3427&nbr=2653&a mp;string=heart+AND+transplant

•

ACC/AHA guideline update on perioperative cardiovascular evaluation for noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperati Source: American College of Cardiology Foundation - Medical Specialty Society; 1996 March 15 (revised 2002); 58 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3149&nbr=2375&a mp;string=heart+AND+transplant

•

ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines). A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1993 Guidelines for Perc Source: American College of Cardiology Foundation - Medical Specialty Society; 2001 June; 66 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2840&nbr=2066&a mp;string=cardiac+AND+transplant

•

ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evalua Source: American College of Cardiology Foundation - Medical Specialty Society; 1995 November 1 (revised 2001 Dec); 56 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3114&nbr=2340&a mp;string=heart+AND+transplant

•

ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Source: American College of Cardiology Foundation - Medical Specialty Society; 1998 April (revised 2002 Sep); 48 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3439&nbr=2665&a mp;string=heart+AND+transplant

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Appropriate patient preparation for renal replacement therapy Source: Renal Physicians Association - Medical Specialty Society; 2002 October; 78 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3591&nbr=2817&a mp;string=cardiac+AND+transplant

•

ASHP therapeutic guidelines on antimicrobial prophylaxis in surgery Source: American Society of Health-System Pharmacists - Professional Association; 1999 September 15; 50 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2182&nbr=1408&a mp;string=heart+AND+transplant

•

Cardiac rehabilitation Source: Agency for Healthcare Research and Quality - Federal Government Agency [U.S.]; 1995 October (reviewed 2000); 202 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1049&nbr=93& ;string=heart+AND+transplant

•

Cardiac rehabilitation. A national clinical guideline Source: Scottish Intercollegiate Guidelines Network - National Government Agency [Non-U.S.]; 2002 January; 32 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3185&nbr=2411&a mp;string=heart+AND+transplant

•

Chemotherapy and biotherapy: guidelines and recommendations for practice Source: Oncology Nursing Society - Professional Association; 2001; 226 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3209&nbr=2435&a mp;string=heart+AND+transplant

•

Guideline for the management of intravascular catheter-related infections Source: American College of Critical Care Medicine - Professional Association; 2001 May; 24 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2790&nbr=2016&a mp;string=heart+AND+transplant

•

Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients Source: American Society for Blood and Marrow Transplantation - Professional Association; 2000 October 20; 126 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2573&nbr=1799&a mp;string=cardiac+AND+transplant

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Guidelines for the diagnosis and treatment of chronic heart failure Source: European Society of Cardiology - Medical Specialty Society; 2001 September; 34 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2976&nbr=2202&a mp;string=heart+AND+transplant

•

Guidelines for the prevention of intravascular catheter-related infections Source: American Academy of Pediatrics - Medical Specialty Society; 1996 (revised 2002 August 9); 36 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3387&nbr=2613&a mp;string=heart+AND+transplant

•

K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification Source: National Kidney Foundation - Disease Specific Society; 2002 February; 246 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3192&nbr=2418&a mp;string=heart+AND+transplant

•

Management of chronic kidney disease and pre-ESRD in the primary care setting Source: Department of Defense - Federal Government Agency [U.S.]; 2000 November; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3099&nbr=2325&a mp;string=heart+AND+transplant

•

Management of type 2 diabetes mellitus Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1996 March (revised 2002 Sep); 77 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3499&nbr=2725&a mp;string=heart+AND+transplant

•

Management of unerupted and impacted third molar teeth. A national clinical guideline Source: Scottish Intercollegiate Guidelines Network - National Government Agency [Non-U.S.]; 2000 March; 24 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2305&nbr=1531&a mp;string=cardiac+AND+transplant

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Massachusetts guidelines for adult diabetes care Source: Massachusetts Department of Public Health, Bureau of Family and Community Health, Diabetes Control Program - State/Local Government Agency [U.S.]; 1999 June (revised 2001 Jun); Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=3429&nbr=2655&a mp;string=heart+AND+transplants

•

National High Blood Pressure Education Program: Working Group report on high blood pressure in pregnancy Source: National Heart, Lung, and Blood Institute (U.S.) - Federal Government Agency [U.S.]; 1990 (revised 2000 Jul); 39 pages http://www.guideline.gov/summary/summary.aspx?doc_id=1478&nbr=704&am p;string=heart+AND+transplant

•

NKF-K/DOQI clinical practice guidelines for peritoneal dialysis adequacy: update 2000 Source: National Kidney Foundation - Disease Specific Society; 1997 (updated 2000); 72 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2782&nbr=2008&a mp;string=heart+AND+transplant

•

NKF-K/DOQI clinical practice guidelines for vascular access: update 2000 Source: National Kidney Foundation - Disease Specific Society; 1997 (updated 2000); 45 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2783&nbr=2009&a mp;string=heart+AND+transplant

•

Policy statement: recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (Prevnar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis Source: American Academy of Pediatrics - Medical Specialty Society; 2000 August; 5 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2773&nbr=1999&a mp;string=heart+AND+transplants

•

Practice guidelines for the treatment of candidiasis Source: Infectious Diseases Society of America - Medical Specialty Society; 2000 April; 17 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2670&nbr=1896&a mp;string=cardiac+AND+transplant

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Preventing pneumococcal disease among infants and young children. Recommendations of the Advisory Committee on Immunization Practices (ACIP) Source: Centers for Disease Control and Prevention - Federal Government Agency [U.S.]; 2000 October. 6; 37 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2568&nbr=1794&a mp;string=cardiac+AND+transplant

•

Pulmonary rehabilitation Source: American Association for Respiratory Care - Professional Association; 2002; 9 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3211&nbr=2437&a mp;string=heart+AND+transplant 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 heart transplant. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

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

•

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

•

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

•

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

•

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

•

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

•

WebMD®Health: http://my.webmd.com/health_topics

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to heart transplant. By consulting all of associations

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listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with heart transplant. 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 heart transplant. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “heart transplant” (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 “heart transplant”. 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 “heart transplant” (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 “heart transplant” (or a synonym) into the search box, and click “Submit Query.”

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175

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.22

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

22

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)23: •

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

•

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

•

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

•

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

•

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

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

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

•

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

23

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

Finding Medical Libraries 177 •

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

•

Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

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

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

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

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

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

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

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

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

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

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

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Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

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

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

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

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National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

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

Finding Medical Libraries 179 •

Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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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

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

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

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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 heart transplant: •

Basic Guidelines for Heart Transplant Heart transplant Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003003.htm

•

Signs & Symptoms for Heart Transplant Fever Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003090.htm Problems breathing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003075.htm

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Diagnostics and Tests for Heart Transplant Dialysis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003421.htm

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Surgery and Procedures for Heart Transplant Kidney transplant Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003005.htm

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Background Topics for Heart Transplant Bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000045.htm Heart disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000147.htm Immune response Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000821.htm Physical activities Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001941.htm

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

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

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

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

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

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HEART TRANSPLANT DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Ablation: The removal of an organ by surgery. [NIH] Abscess: A localized, circumscribed collection of pus. [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] Accommodation: Adjustment, especially that of the eye for various distances. [EU] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylcysteine: The N-acetyl derivative of cysteine. It is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates. [NIH] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Actin: Essential component of the cell skeleton. [NIH] Actinin: A protein factor that regulates the length of R-actin. It is chemically similar, but immunochemically distinguishable from actin. [NIH] Acute leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [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] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adhesions: Pathological processes consisting of the union of the opposing surfaces of a wound. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH]

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Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adoptive Transfer: Form of passive immunization where previously sensitized immunologic agents (cells or serum) are transferred to non-immune recipients. When transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy (immunotherapy, adoptive). [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] 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] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [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] Afterload: The tension produced by the heart muscle after contraction. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Alendronate: A nonhormonal medication for the treatment of postmenopausal osteoporosis in women. This drug builds healthy bone, restoring some of the bone loss as a result of osteoporosis. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on

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homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allo: A female hormone. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [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] Amebiasis: Infection with any of various amebae. It is an asymptomatic carrier state in most individuals, but diseases ranging from chronic, mild diarrhea to fulminant dysentery may occur. [NIH] Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] 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 Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [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] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU]

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Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anastomosis: A procedure to connect healthy sections of tubular structures in the body after the diseased portion has been surgically removed. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In 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] Anergy: Absence of immune response to particular substances. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angiogram: An x-ray of blood vessels; the person receives an injection of dye to outline the vessels on the x-ray. [NIH] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [NIH] Angiotensin I: The decapeptide precursor of angiotensin II, generated by the action of renin on angiotensinogen. It has limited pharmacologic activity. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Anomalies: Birth defects; abnormalities. [NIH] Anoxia: Clinical manifestation of respiratory distress consisting of a relatively complete absence of oxygen. [NIH]

Dictionary 187

Antecedent: Existing or occurring before in time or order often with consequential effects. [EU]

Antiallergic: Counteracting allergy or allergic conditions. [EU] Antianginal: Counteracting angina or anginal conditions. [EU] Antiarrhythmic: An agent that prevents or alleviates cardiac arrhythmia. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibiotic Prophylaxis: Use of antibiotics before, during, or after a diagnostic, therapeutic, or surgical procedure to prevent infectious complications. [NIH] Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] 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] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] 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] Antiserum: The blood serum obtained from an animal after it has been immunized with a particular antigen. It will contain antibodies which are specific for that antigen as well as antibodies specific for any other antigen with which the animal has previously been

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immunized. [NIH] Antithymocyte globulin: A protein used to reduce the risk of or to treat graft-versus-host disease. [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Aorta: The main trunk of the systemic arteries. [NIH] Aortic Valve: The valve between the left ventricle and the ascending aorta which prevents backflow into the left ventricle. [NIH] Aplasia: Lack of development of an organ or tissue, or of the cellular products from an organ or tissue. [EU] Apnea: A transient absence of spontaneous respiration. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] 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] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Arteriosus: Circle composed of anastomosing arteries derived from two long posterior ciliary and seven anterior ciliary arteries, located in the ciliary body about the root of the iris. [NIH]

Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU]

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Aseptic: Free from infection or septic material; sterile. [EU] Aspergillosis: Infections with fungi of the genus Aspergillus. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asystole: Cardiac standstill or arrest; absence of a heartbeat; called also Beau's syndrome. [EU]

Atrial: Pertaining to an atrium. [EU] Atrial Flutter: Rapid, irregular atrial contractions due to an abnormality of atrial excitation. [NIH]

Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atropine: A toxic alkaloid, originally from Atropa belladonna, but found in other plants, mainly Solanaceae. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Aura: A subjective sensation or motor phenomenon that precedes and marks the of a paroxysmal attack, such as an epileptic attack on set. [EU] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autopsy: Postmortem examination of the body. [NIH] Avidity: The strength of the interaction of an antiserum with a multivalent antigen. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [NIH]

Axillary Artery: The continuation of the subclavian artery; it distributes over the upper limb, axilla, chest and shoulder. [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] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by

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basic dyes. [NIH] Belladonna: A species of very poisonous Solanaceous plants yielding atropine (hyoscyamine), scopolamine, and other belladonna alkaloids, used to block the muscarinic autonomic nervous system. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the 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] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Bioengineering: The application of engineering principles to the solution of biological problems, for example, remote-handling devices, life-support systems, controls, and displays. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biopsy specimen: Tissue removed from the body and examined under a microscope to determine whether disease is present. [NIH] Bioreactors: Tools or devices for generating products using the synthetic or chemical conversion capacity of a biological system. They can be classical fermentors, cell culture perfusion systems, or enzyme bioreactors. For production of proteins or enzymes, recombinant microorganisms such as bacteria, mammalian cells, or insect or plant cells are usually chosen. [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] Bladder: The organ that stores urine. [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

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heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body Fluids: Liquid components of living organisms. [NIH] Bone Density: The amount of mineral per square centimeter of bone. This is the definition used in clinical practice. Actual bone density would be expressed in grams per milliliter. It is most frequently measured by photon absorptiometry or x-ray computed tomography. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachial: All the nerves from the arm are ripped from the spinal cord. [NIH] Brachial Artery: The continuation of the axillary artery; it branches into the radial and ulnar arteries. [NIH] Brachiocephalic Veins: Large veins on either side of the root of the neck formed by the junction of the internal jugular and subclavian veins. They drain blood from the head, neck, and upper extremities, and unite to form the superior vena cava. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] 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] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchioles: The tiny branches of air tubes in the lungs. [NIH] Bronchiolitis: Inflammation of the bronchioles. [NIH] Bronchiolitis Obliterans: Inflammation of the bronchioles with obstruction by fibrous granulation tissue or bronchial exudate. It may follow inhalation of irritating gases or foreign bodies and it complicates pneumonia. [NIH]

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Bronchoalveolar Lavage: Washing out of the lungs with saline or mucolytic agents for diagnostic or therapeutic purposes. It is very useful in the diagnosis of diffuse pulmonary infiltrates in immunosuppressed patients. [NIH] Bronchoalveolar Lavage Fluid: Fluid obtained by washout of the alveolar compartment of the lung. It is used to assess biochemical and inflammatory changes in and effects of therapy on the interstitial lung tissue. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Calcifediol: The major circulating metabolite of vitamin D3 produced in the liver and the best indicator of the body's vitamin D stores. It is effective in the treatment of rickets and osteomalacia, both in azotemic and non-azotemic patients. Calcifediol also has mineralizing properties. [NIH] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcineurin: A calcium- and calmodulin-binding protein present in highest concentrations in the central nervous system. Calcineurin is composed of two subunits. A catalytic subunit, calcineurin A, and a regulatory subunit, calcineurin B, with molecular weights of about 60 kD and 19 kD, respectively. Calcineurin has been shown to dephosphorylate a number of phosphoproteins including histones, myosin light chain, and the regulatory subunit of cAMP-dependent protein kinase. It is involved in the regulation of signal transduction and is the target of an important class of immunophilin-immunosuppressive drug complexes in T-lymphocytes that act by inhibiting T-cell activation. EC 3.1.3.-. [NIH] Calcitriol: The physiologically active form of vitamin D. It is formed primarily in the kidney by enzymatic hydroxylation of 25-hydroxycholecalciferol (calcifediol). Its production is stimulated by low blood calcium levels and parathyroid hormone. Calcitriol increases intestinal absorption of calcium and phosphorus, and in concert with parathyroid hormone increases bone resorption. [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] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Candidiasis: Infection with a fungus of the genus Candida. It is usually a superficial infection of the moist cutaneous areas of the body, and is generally caused by C. albicans; it most commonly involves the skin (dermatocandidiasis), oral mucous membranes (thrush, def. 1), respiratory tract (bronchocandidiasis), and vagina (vaginitis). Rarely there is a systemic infection or endocarditis. Called also moniliasis, candidosis, oidiomycosis, and formerly blastodendriosis. [EU] Candidosis: An infection caused by an opportunistic yeasts that tends to proliferate and

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become pathologic when the environment is favorable and the host resistance is weakened. [NIH]

Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capsid: The outer protein protective shell of a virus, which protects the viral nucleic acid. [NIH]

Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] 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] Carcinogenic: Producing carcinoma. [EU] Carcinoid: A type of tumor usually found in the gastrointestinal system (most often in the appendix), and sometimes in the lungs or other sites. Carcinoid tumors are usually benign. [NIH]

Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] Cardiac Output: The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). [NIH] Cardiac Surgical Procedures: Surgery performed on the heart. [NIH] Cardiology: The study of the heart, its physiology, and its functions. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiotonic: 1. Having a tonic effect on the heart. 2. An agent that has a tonic effect on the heart. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovirus: A genus of the family Picornaviridae causing encephalitis and myocarditis in rodents. Encephalomyocarditis virus is the type species. [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

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and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. EC 1.11.1.6. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] 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] 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 Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Cycle Proteins: Proteins that control the cell division cycle. This family of proteins includes a wide variety of classes, including cyclin-dependent kinases, mitogen-activated kinases, cyclins, and phosphoprotein phosphatases (phosphoprotein phosphatase) as well as their putative substrates such as chromatin-associated proteins, cytoskeletal proteins, and transcription factors. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell motility: The ability of a cell to move. [NIH] Cell Physiology: Characteristics and physiological processes of cells from cell division to cell death. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Central Nervous System: The main information-processing organs of the nervous system,

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consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chenodeoxycholic Acid: A bile acid, usually conjugated with either glycine or taurine. It acts as a detergent to solubilize fats for intestinal absorption and is reabsorbed by the small intestine. It is used as cholagogue, a choleretic laxative, and to prevent or dissolve gallstones. [NIH] Chest cavity: Space in body surrounding the lungs. [NIH] Chest wall: The ribs and muscles, bones, and joints that make up the area of the body between the neck and the abdomen. [NIH] Chimeras: Organism that contains a mixture of genetically different cells. [NIH] Cholecystitis: Inflammation of the gallbladder. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Choleretic: A choleretic agent. [EU] 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] 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]

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Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chronotropic: Affecting the time or rate, as the rate of contraction of the heart. [EU] Cidofovir: A drug used to treat infection caused by viruses. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical Protocols: Precise and detailed plans for the study of a medical or biomedical problem and/or plans for a regimen of therapy. [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] Clonal Anergy: Functional inactivation of T- or B-lymphocytes rendering them incapable of eliciting an immune response to antigen. This occurs through different mechanisms in the two kinds of lymphocytes and can contribute to self tolerance. [NIH] Clonal Deletion: Removal, via cell death, of immature lymphocytes that interact with antigens during maturation. For T-lymphocytes this occurs in the thymus and ensures that mature T-lymphocytes are self tolerant. B-lymphocytes may also undergo clonal deletion. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU]

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Colloidal: Of the nature of a colloid. [EU] 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] Complement Activation: The sequential activation of serum components C1 through C9, initiated by an erythrocyte-antibody complex or by microbial polysaccharides and properdin, and producing an inflammatory response. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Concentric: Having a common center of curvature or symmetry. [NIH] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Consolidation: The healing process of a bone fracture. [NIH] Constriction: The act of constricting. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and

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the proper method of treatment in a case. [NIH] Contractility: Capacity for becoming short in response to a suitable stimulus. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Conus: A large, circular, white patch around the optic disk due to the exposing of the sclera as a result of degenerative change or congenital abnormality in the choroid and retina. [NIH] 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 Angiography: Radiography of the vascular system of the heart muscle after injection of a contrast medium. [NIH] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary Artery Bypass: Surgical therapy of ischemic coronary artery disease achieved by grafting a section of saphenous vein, internal mammary artery, or other substitute between the aorta and the obstructed coronary artery distal to the obstructive lesion. [NIH] Coronary Disease: Disorder of cardiac function due to an imbalance between myocardial function and the capacity of the coronary vessels to supply sufficient flow for normal function. It is a form of myocardial ischemia (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Coronary Vessels: The veins and arteries of the heart. [NIH] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Coxsackieviruses: A heterogeneous group of the genus enterovirus found in association with various diseases in man and other animals. Two groups (A and B) have been identified

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with a number of serotypes in each. The name is derived from a village in New York State where the virus was first identified. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Creatinine clearance: A test that measures how efficiently the kidneys remove creatinine and other wastes from the blood. Low creatinine clearance indicates impaired kidney function. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cutaneous Fistula: An abnormal passage or communication leading from an internal organ to the surface of the body. [NIH] Cyanosis: A bluish or purplish discoloration of the skin and mucous membranes due to an increase in the amount of deoxygenated hemoglobin in the blood or a structural defect in the hemoglobin molecule. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cyclin-Dependent Kinases: Protein kinases that control cell cycle progression in all eukaryotes and require physical association with cyclins to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events. [NIH]

Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cystathionine beta-Synthase: A multifunctional pyridoxal phosphate enzyme. In the second stage of cysteine biosynthesis it catalyzes the reaction of homocysteine with serine to form cystathionine with the elimination of water. Deficiency of this enzyme leads to hyperhomocysteinemia and homocystinuria. EC 4.2.1.22. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] 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] Cytopenia: A reduction in the number of blood cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]

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Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]

Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Desmin: An intermediate filament protein found predominantly in smooth, skeletal, and cardiac muscle cells. Localized at the Z line. MW 50,000 to 55,000 is species dependent. [NIH] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Dextran Sulfate: Long-chain polymer of glucose containing 17-20% sulfur. It has been used as an anticoagulant and also has been shown to inhibit the binding of HIV-1 to CD4+ Tlymphocytes. It is commonly used as both an experimental and clinical laboratory reagent and has been investigated for use as an antiviral agent, in the treatment of hypolipidemia, and for the prevention of free radical damage, among other applications. [NIH] Diabetes Insipidus: A metabolic disorder due to disorders in the production or release of vasopressin. It is characterized by the chronic excretion of large amounts of low specific gravity urine and great thirst. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diastole: Period of relaxation of the heart, especially the ventricles. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself

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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] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilated cardiomyopathy: Heart muscle disease that leads to enlargement of the heart's chambers, robbing the heart of its pumping ability. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dipyridamole: A drug that prevents blood cell clumping and enhances the effectiveness of fluorouracil and other chemotherapeutic agents. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disparity: Failure of the two retinal images of an object to fall on corresponding retinal points. [NIH] Disposition: A tendency either physical or mental toward certain diseases. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] 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] Diuretic: A drug that increases the production of urine. [NIH] Dobutamine: A beta-2 agonist catecholamine that has cardiac stimulant action without evoking vasoconstriction or tachycardia. It is proposed as a cardiotonic after myocardial infarction or open heart surgery. [NIH] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Double-blinded: A clinical trial in which neither the medical staff nor the person knows which of several possible therapies the person is receiving. [NIH]

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Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Drug Toxicity: Manifestations of the adverse effects of drugs administered therapeutically or in the course of diagnostic techniques. It does not include accidental or intentional poisoning for which specific headings are available. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Dystrophin: A muscle protein localized in surface membranes which is the product of the Duchenne/Becker muscular dystrophy gene. Individuals with Duchenne muscular dystrophy usually lack dystrophin completely while those with Becker muscular dystrophy have dystrophin of an altered size. It shares features with other cytoskeletal proteins such as spectrin and alpha-actinin but the precise function of dystrophin is not clear. One possible role might be to preserve the integrity and alignment of the plasma membrane to the myofibrils during muscle contraction and relaxation. MW 400 kDa. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Echocardiography: Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Ejection fraction: A measure of ventricular contractility, equal to normally 65 8 per cent; lower values indicate ventricular dysfunction. [EU] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocardiogram: Measurement of electrical activity during heartbeats. [NIH] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH]

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Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Encephalitis: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see encephalitis, viral) are a relatively frequent cause of this condition. [NIH] Encephalitis, Viral: Inflammation of brain parenchymal tissue as a result of viral infection. Encephalitis may occur as primary or secondary manifestation of Togaviridae infections; Herpesviridae infections; Adenoviridae infections; Flaviviridae infections; Bunyaviridae infections; Picornaviridae infections; Paramyxoviridae infections; Orthomyxoviridae infections; Retroviridae infections; and Arenaviridae infections. [NIH] Encephalomyelitis: A general term indicating inflammation of the brain and spinal cord, often used to indicate an infectious process, but also applicable to a variety of autoimmune and toxic-metabolic conditions. There is significant overlap regarding the usage of this term and encephalitis in the literature. [NIH] Encephalomyocarditis Virus: The type species of cardiovirus causing encephalomyelitis and myocarditis in rodents, pigs, and monkeys. Infection in man has been reported with CNS involvement but without myocarditis. [NIH] Endarterectomy: Surgical excision, performed under general anesthesia, of the atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocarditis: Exudative and proliferative inflammatory alterations of the endocardium, characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary disorder or as a complication of or in association with another disease. [EU] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin

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system and the neurosecretory systems. [NIH] Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxin: Toxin from cell walls of bacteria. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Enterovirus: A genus of the family Picornaviridae whose members preferentially inhabit the intestinal tract of a variety of hosts. The genus contains many species. Newly described members of human enteroviruses are assigned continuous numbers with the species designated "human enterovirus". [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] Enzyme-Linked Immunosorbent Assay: An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH]

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Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]

Epoprostenol: A prostaglandin that is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. It is a potent inhibitor of platelet aggregation. The sodium salt has been also used to treat primary pulmonary hypertension. [NIH] Ergonovine: An ergot alkaloid with uterine and vascular smooth muscle contractile properties. [NIH] Ergot: Cataract due to ergot poisoning caused by eating of rye cereals contaminated by a fungus. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Excipient: Any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug; a vehicle. [EU] 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] Exercise Test: Controlled physical activity, more strenuous than at rest, which is performed in order to allow assessment of physiological functions, particularly cardiovascular and pulmonary, but also aerobic capacity. Maximal (most intense) exercise is usually required but submaximal exercise is also used. The intensity of exercise is often graded, using criteria such as rate of work done, oxygen consumption, and heart rate. Physiological data obtained from an exercise test may be used for diagnosis, prognosis, and evaluation of disease severity, and to evaluate therapy. Data may also be used in prescribing exercise by determining a person's exercise capacity. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exophiala: A normally saprophytic mitosporic Chaetothyriales fungal genus. Infections in humans include phaeohyphomycosis, peritonitis, and chromoblastomycosis. Exophiala jeanselmei (previously Phialophora jeanselmei) is an etiological agent of maduromycosis. [NIH]

Expiration: The act of breathing out, or expelling air from the lungs. [EU] External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture

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dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extracorporeal: Situated or occurring outside the body. [EU] Extravascular: Situated or occurring outside a vessel or the vessels. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from cells. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Facial: Of or pertaining to the face. [EU] Facial Nerve: The 7th cranial nerve. The facial nerve has two parts, the larger motor root which may be called the facial nerve proper, and the smaller intermediate or sensory root. Together they provide efferent innervation to the muscles of facial expression and to the lacrimal and salivary glands, and convey afferent information for taste from the anterior two-thirds of the tongue and for touch from the external ear. [NIH] 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] Femoral: Pertaining to the femur, or to the thigh. [EU] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fibrillation: A small, local, involuntary contraction of muscle, invisible under the skin, resulting from spontaneous activation of single muscle cells or muscle fibres. [EU] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas

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fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] 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] Fistulas: An abnormal passage from one hollow structure of the body to another, or from a hollow structure to the surface, formed by an abscess, disease process, incomplete closure of a wound, or by a congenital anomaly. [NIH] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flatus: Gas passed through the rectum. [NIH] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has

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immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Focal Adhesions: An anchoring junction of the cell to a non-cellular substrate. It is composed of a specialized area of the plasma membrane where bundles of microfilaments terminate and attach to the transmembrane linkers, integrins, which in turn attach through their extracellular domains to extracellular matrix proteins. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Furosemide: A sulfamyl saluretic and diuretic. It has a fast onset and short duration of action and is used in edema and chronic renal insufficiency. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallstones: The solid masses or stones made of cholesterol or bilirubin that form in the gallbladder or bile ducts. [NIH] 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] Gangliosides: Protein kinase C's inhibitor which reduces ischemia-related brain damage. [NIH]

Gangrenous: A circumscribed, deep-seated, suppurative inflammation of the subcutaneous tissue of the eyelid discharging pus from several points. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as

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a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [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 Deletion: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus. [NIH] Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene 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] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Giardiasis: An infection of the small intestine caused by the flagellated protozoan Giardia lamblia. It is spread via contaminated food and water and by direct person-to-person contact. [NIH] Gingival Hyperplasia: A pathological increase in the depth of the gingival crevice surrounding a tooth at the gum margin. [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]

Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH]

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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] 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] Glycolysis: The pathway by which glucose is catabolized into two molecules of pyruvic acid with the generation of ATP. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Gonadal: Pertaining to a gonad. [EU] Gout: Hereditary metabolic disorder characterized by recurrent acute arthritis, hyperuricemia and deposition of sodium urate in and around the joints, sometimes with formation of uric acid calculi. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Graft Survival: The survival of a graft in a host, the factors responsible for the survival and the changes occurring within the graft during growth in the host. [NIH] Graft vs Host Reaction: An immunological attack mounted by a graft against the host because of tissue incompatibility when immunologically competent cells are transplanted to an immunologically incompetent host; the resulting clinical picture is that of graft vs host disease. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Granulation Tissue: A vascular connective tissue formed on the surface of a healing wound,

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ulcer, or inflamed tissue. It consists of new capillaries and an infiltrate containing lymphoid cells, macrophages, and plasma cells. [NIH] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitat: An area considered in terms of its environment, particularly as this determines the type and quality of the vegetation the area can carry. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] 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] Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the major histocompatibility complex. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heart Transplantation: The transference of a heart from one human or animal to another. [NIH]

Heart Valves: Flaps of tissue that prevent regurgitation of blood from the ventricles to the atria or from the pulmonary arteries or aorta to the ventricles. [NIH] Heartbeat: One complete contraction of the heart. [NIH] Helminthiasis: Infestation with parasitic worms of the helminth class. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH]

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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] Hemoglobin M: A group of abnormal hemoglobins in which amino acid substitutions take place in either the alpha or beta chains but near the heme iron. This results in facilitated oxidation of the hemoglobin to yield excess methemoglobin which leads to cyanosis. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [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] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] 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] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [NIH]

Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] 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] Horseradish Peroxidase: An enzyme isolated from horseradish which is able to act as an antigen. It is frequently used as a histochemical tracer for light and electron microscopy. Its antigenicity has permitted its use as a combined antigen and marker in experimental immunology. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or

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bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridoma: A hybrid cell resulting from the fusion of a specific antibody-producing spleen cell with a myeloma cell. [NIH] Hydrochlorothiazide: A thiazide diuretic often considered the prototypical member of this class. It reduces the reabsorption of electrolytes from the renal tubules. This results in increased excretion of water and electrolytes, including sodium, potassium, chloride, and magnesium. It has been used in the treatment of several disorders including edema, hypertension, diabetes insipidus, and hypoparathyroidism. [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] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [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] Hyperhomocysteinemia: An inborn error of methionone metabolism which produces an excess of homocysteine in the blood. It is often caused by a deficiency of cystathionine betasynthase and is a risk factor for coronary vascular disease. [NIH] Hyperlipoproteinemia: Metabolic disease characterized by elevated plasma cholesterol and/or triglyceride levels. The inherited form is attributed to a single gene mechanism. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hyperthyroidism: Excessive functional activity of the thyroid gland. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH]

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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] Hypotensive: Characterized by or causing diminished tension or pressure, as abnormally low blood pressure. [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] Hypothermia: Lower than normal body temperature, especially in warm-blooded animals; in man usually accidental or unintentional. [NIH] Hypoxanthine: A purine and a reaction intermediate in the metabolism of adenosine and in the formation of nucleic acids by the salvage pathway. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Iloprost: An eicosanoid, derived from the cyclooxygenase pathway of arachidonic acid metabolism. It is a stable and synthetic analog of epoprostenol, but with a longer half-life than the parent compound. Its actions are similar to prostacyclin. Iloprost produces vasodilation and inhibits platelet aggregation. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunodominant Epitopes: Subunits of the antigenic determinant that are most easily recognized by the immune system and thus most influence the specificity of the induced antibody. [NIH] Immunoglobulin: A protein that acts as an antibody. [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] Immunophenotyping: Process of classifying cells of the immune system based on structural and functional differences. The process is commonly used to analyze and sort Tlymphocytes into subsets based on CD antigens by the technique of flow cytometry. [NIH] Immunophilin: A drug for the treatment of Parkinson's disease. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incompetence: Physical or mental inadequacy or insufficiency. [EU] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] 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] Induction therapy: Treatment designed to be used as a first step toward shrinking the cancer and in evaluating response to drugs and other agents. Induction therapy is followed by additional therapy to eliminate whatever cancer remains. [NIH] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus,

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or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]

Influenza: An acute viral infection involving the respiratory tract. It is marked by inflammation of the nasal mucosa, the pharynx, and conjunctiva, and by headache and severe, often generalized, myalgia. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inoperable: Not suitable to be operated upon. [EU] Inosine Monophosphate: Inosine 5'-Monophosphate. A purine nucleotide which has hypoxanthine as the base and one phosphate group esterified to the sugar moiety. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] 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]

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Integrins: A family of transmembrane glycoproteins consisting of noncovalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement, and other cells, while their intracellular domains interact with the cytoskeleton. The integrins consist of at least three identified families: the cytoadhesin receptors, the leukocyte adhesion receptors, and the very-late-antigen receptors. Each family contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and oncogenic transformation. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Intubation: Introduction of a tube into a hollow organ to restore or maintain patency if obstructed. It is differentiated from catheterization in that the insertion of a catheter is usually performed for the introducing or withdrawing of fluids from the body. [NIH] Inulin: A starch found in the tubers and roots of many plants. Since it is hydrolyzable to fructose, it is classified as a fructosan. It has been used in physiologic investigation for

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determination of the rate of glomerular function. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Islet: Cell producing insulin in pancreas. [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] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] 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] 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] Leishmaniasis: A disease caused by any of a number of species of protozoa in the genus Leishmania. There are four major clinical types of this infection: cutaneous (Old and New World), diffuse cutaneous, mucocutaneous, and visceral leishmaniasis. [NIH] Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species. [NIH] Leptin: A 16-kD peptide hormone secreted from white adipocytes and implicated in the regulation of food intake and energy balance. Leptin provides the key afferent signal from fat cells in the feedback system that controls body fat stores. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU]

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Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Ligaments: Shiny, flexible bands of fibrous tissue connecting together articular extremities of bones. They are pliant, tough, and inextensile. [NIH] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Lovastatin: A fungal metabolite isolated from cultures of Aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. [NIH] 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] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain

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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] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] 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] Lymphoproliferative: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Maduromycosis: A disease caused by various fungi (Madurella mycetomi) or actinomycetes (Nocardia brasiliensis). It usually affects the foot, hand, and legs with tissues becoming necrosed and swollen after infection. [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] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Mammary: Pertaining to the mamma, or breast. [EU] Marital Status: A demographic parameter indicating a person's status with respect to

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marriage, divorce, widowhood, singleness, etc. [NIH] Mastitis: Inflammatory disease of the breast, or mammary gland. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediastinitis: Inflammation of the mediastinum, the area between the pleural sacs. [NIH] Mediastinum: The area between the lungs. The organs in this area include the heart and its large blood vessels, the trachea, the esophagus, the bronchi, and lymph nodes. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] Medical Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH] 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] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH]

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Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metaphase: The second phase of cell division, in which the chromosomes line up across the equatorial plane of the spindle prior to separation. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Methoxsalen: A naturally occurring furocoumarin compound found in several species of plants, including Psoralea corylifolia. It is a photoactive substance that forms DNA adducts in the presence of ultraviolet A irradiation. [NIH] Metronidazole: Antiprotozoal used in amebiasis, trichomoniasis, giardiasis, and as treponemacide in livestock. It has also been proposed as a radiation sensitizer for hypoxic cells. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985, p133), this substance may reasonably be anticipated to be a carcinogen (Merck, 11th ed). [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Mice Minute Virus: The type species of parvovirus prevalent in mouse colonies and found as a contaminant of many transplanted tumors or leukemias. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiological: Pertaining to microbiology : the science that deals with microorganisms, including algae, bacteria, fungi, protozoa and viruses. [EU] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Microfibrils: Components of the extracellular matrix consisting primarily of fibrillin. They are essential for the integrity of elastic fibers. [NIH] Microfilaments: The smallest of the cytoskeletal filaments. They are composed chiefly of actin. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller than a quart and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same. [NIH] Mineralocorticoids: A group of corticosteroids primarily associated with the regulation of water and electrolyte balance. This is accomplished through the effect on ion transport in renal tubules, resulting in retention of sodium and loss of potassium. Mineralocorticoid secretion is itself regulated by plasma volume, serum potassium, and angiotensin II. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes

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place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocyte: A type of white blood cell. [NIH] Monocyte Chemoattractant Protein-1: A chemokine that is a chemoattractant for human monocytes and may also cause cellular activation of specific functions related to host defense. It is produced by leukocytes of both monocyte and lymphocyte lineage and by fibroblasts during tissue injury. [NIH] Mononuclear: A cell with one nucleus. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Mucocutaneous: Pertaining to or affecting the mucous membrane and the skin. [EU] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Multicenter Studies: Controlled studies which are planned and carried out by several cooperating institutions to assess certain variables and outcomes in specific patient populations, for example, a multicenter study of congenital anomalies in children. [NIH] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]

Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the

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drugs less effective. [NIH] Multivalent: Pertaining to a group of 5 or more homologous or partly homologous chromosomes during the zygotene stage of prophase to first metaphasis in meiosis. [NIH] Muscle Contraction: A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Myalgia: Pain in a muscle or muscles. [EU] Mycophenolate mofetil: A drug that is being studied for its effectiveness in preventing graft-versus-host disease and autoimmune disorders. [NIH] Mycoplasma: A genus of gram-negative, facultatively anaerobic bacteria bounded by a plasma membrane only. Its organisms are parasites and pathogens, found on the mucous membranes of humans, animals, and birds. [NIH] Mycoplasma Infections: Infections with species of the genus Mycoplasma. [NIH] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]

Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH]

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Myofibrils: Highly organized bundles of actin, myosin, and other proteins in the cytoplasm of skeletal and cardiac muscle cells that contract by a sliding filament mechanism. [NIH] Myoglobin: A conjugated protein which is the oxygen-transporting pigment of muscle. It is made up of one globin polypeptide chain and one heme group. [NIH] Myopathy: Any disease of a muscle. [EU] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] Nephrologist: A doctor who treats patients with kidney problems or hypertension. [NIH] Nephrology: A subspecialty of internal medicine concerned with the anatomy, physiology, and pathology of the kidney. [NIH] Nephropathy: Disease of the kidneys. [EU] Nephrotoxic: Toxic or destructive to kidney cells. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers 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] Neuroendocrine tumor: A tumor derived from cells that release a hormone in response to a

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signal from the nervous system. Some examples of neuroendocrine tumors are carcinoid tumors, islet cell tumors, medullary thyroid carcinoma, and pheochromocytoma. These tumors secrete hormones in excess, causing a variety of symptoms. [NIH] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Niche: The ultimate unit of the habitat, i. e. the specific spot occupied by an individual organism; by extension, the more or less specialized relationships existing between an organism, individual or synusia(e), and its environment. [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]

Nosocomial: Pertaining to or originating in the hospital, said of an infection not present or incubating prior to admittance to the hospital, but generally occurring 72 hours after admittance; the term is usually used to refer to patient disease, but hospital personnel may also acquire nosocomial infection. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Omentum: A fold of the peritoneum (the thin tissue that lines the abdomen) that surrounds the stomach and other organs in the abdomen. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH]

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Opacity: Degree of density (area most dense taken for reading). [NIH] Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [NIH] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] 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] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Pacemaker: An object or substance that influences the rate at which a certain phenomenon occurs; often used alone to indicate the natural cardiac pacemaker or an artificial cardiac pacemaker. In biochemistry, a substance whose rate of reaction sets the pace for a series of interrelated reactions. [EU] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Papillomavirus: A genus of Papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans, chimpanzees, cattle, rabbits, dogs, and horses. [NIH]

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Paraffin: A mixture of solid hydrocarbons obtained from petroleum. It has a wide range of uses including as a stiffening agent in ointments, as a lubricant, and as a topical antiinflammatory. It is also commonly used as an embedding material in histology. [NIH] Paralysis: Loss of ability to move all or part of the body. [NIH] Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Parathyroid hormone: A substance made by the parathyroid gland that helps the body store and use calcium. Also called parathormone, parathyrin, or PTH. [NIH] Parotid: The space that contains the parotid gland, the facial nerve, the external carotid artery, and the retromandibular vein. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Particle: A tiny mass of material. [EU] Parvovirus: A genus of the family Parvoviridae, subfamily Parvovirinae, infecting a variety of vertebrates including humans. Parvoviruses are responsible for a number of important diseases but also can be non-pathogenic in certain hosts. The type species is mice minute virus. [NIH] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Patient Selection: Criteria and standards used for the determination of the appropriateness of the inclusion of patients with specific conditions in proposed treatment plans and the criteria used for the inclusion of subjects in various clinical trials and other research protocols. [NIH] Peer Review: An organized procedure carried out by a select committee of professionals in evaluating the performance of other professionals in meeting the standards of their specialty. Review by peers is used by editors in the evaluation of articles and other papers submitted for publication. Peer review is used also in the evaluation of grant applications. It is applied also in evaluating the quality of health care provided to patients. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)-

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L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericardial Effusion: Presence of fluid within the pericardium. [NIH] Pericarditis: Inflammation of the pericardium. [EU] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Perioperative: Around the time of surgery; usually lasts from the time of going into the hospital or doctor's office for surgery until the time the patient goes home. [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] 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] Peritoneal Dialysis: Dialysis fluid being introduced into and removed from the peritoneal cavity as either a continuous or an intermittent procedure. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Peritonitis: Inflammation of the peritoneum; a condition marked by exudations in the peritoneum of serum, fibrin, cells, and pus. It is attended by abdominal pain and tenderness, constipation, vomiting, and moderate fever. [EU] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH]

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Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phosphates: Inorganic salts of phosphoric acid. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [NIH] Phosphodiesterase Inhibitors: Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphoprotein Phosphatase: A group of enzymes removing the serine- or threoninebound phosphate groups from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. (Enzyme Nomenclature, 1992) EC 3.1.3.16. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Photopheresis: A process in which peripheral blood is exposed in an extracorporeal flow system to photoactivated 8-methoxypsoralen (methoxsalen) and ultraviolet light - a procedure known as PUVA therapy. Photopheresis is at present a standard therapy for advanced cutaneous T-cell lymphoma; it shows promise in the treatment of autoimmune diseases. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected

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to the hypothalamus by a short stalk. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [NIH] 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 Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]

Pleural: A circumscribed area of hyaline whorled fibrous tissue which appears on the surface of the parietal pleura, on the fibrous part of the diaphragm or on the pleura in the interlobar fissures. [NIH] Pneumococcal Infections: Infections with bacteria of the species Streptococcus pneumoniae. [NIH]

Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH]

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Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Population Dynamics: The pattern of any process, or the interrelationship of phenomena, which affects growth or change within a population. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Postoperative Complications: Pathologic processes that affect patients after a surgical procedure. They may or may not be related to the disease for which the surgery was done, and they may or may not be direct results of the surgery. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precursor: Something that precedes. In biological processes, a substance from which

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another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Preventive Dentistry: The branch of dentistry concerned with the prevention of disease and the maintenance and promotion of oral health. [NIH] Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Prion: Small proteinaceous infectious particles that resist inactivation by procedures modifying nucleic acids and contain an abnormal isoform of a cellular protein which is a major and necessary component. [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] 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] 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] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is

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PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein 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] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Protozoan Infections: Infections with unicellular organisms of the subkingdom Protozoa. [NIH]

Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH]

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Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary Fibrosis: Chronic inflammation and progressive fibrosis of the pulmonary alveolar walls, with steadily progressive dyspnea, resulting finally in death from oxygen lack or right heart failure. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Pupil: The aperture in the iris through which light passes. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radionuclide Imaging: Process whereby a radionuclide is injected or measured (through tissue) from an external source, and a display is obtained from any one of several rectilinear

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scanner or gamma camera systems. The image obtained from a moving detector is called a scan, while the image obtained from a stationary camera device is called a scintiphotograph. [NIH]

Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reabsorption: 1. The act or process of absorbing again, as the selective absorption by the kidneys of substances (glucose, proteins, sodium, etc.) already secreted into the renal tubules, and their return to the circulating blood. 2. Resorption. [EU] Reactivation: The restoration of activity to something that has been inactivated. [EU] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] 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] Recovery of Function: A partial or complete return to the normal or proper physiologic activity of an organ or part following disease or trauma. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refractory: Not readily yielding to treatment. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regurgitation: A backward flowing, as the casting up of undigested food, or the backward flowing of blood into the heart, or between the chambers of the heart when a valve is incompetent. [EU] Renal Replacement Therapy: Procedures which temporarily or permanently remedy insufficient cleansing of body fluids by the kidneys. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH]

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Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Residual Volume: The volume of air remaining in the lungs at the end of a maximal expiration. Common abbreviation is RV. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Restitution: The restoration to a normal state. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinoids: Derivatives of vitamin A. Used clinically in the treatment of severe cystic acne, psoriasis, and other disorders of keratinization. Their possible use in the prophylaxis and treatment of cancer is being actively explored. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retroperitoneal: Having to do with the area outside or behind the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] Rhabdomyolysis: Necrosis or disintegration of skeletal muscle often followed by myoglobinuria. [NIH] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH]

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Ribose: A pentose active in biological systems usually in its D-form. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Salicylate: Non-steroidal anti-inflammatory drugs. [NIH] Saline: A solution of salt and water. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saphenous: Applied to certain structures in the leg, e. g. nerve vein. [NIH] Saphenous Vein: The vein which drains the foot and leg. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] 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] Self Tolerance: The normal lack of the ability to produce an immunological response to autologous (self) antigens. A breakdown of self tolerance leads to autoimmune diseases. The ability to recognize the difference between self and non-self is the prime function of the immune system. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH]

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Septicaemia: A term originally used to denote a putrefactive process in the body, but now usually referring to infection with pyogenic micro-organisms; a genus of Diptera; the severe type of infection in which the blood stream is invaded by large numbers of the causal. [NIH] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotypes: A cause of haemorrhagic septicaemia (in cattle, sheep and pigs), fowl cholera of birds, pasteurellosis of rabbits, and gangrenous mastitis of ewes. It is also commonly found in atrophic rhinitis of pigs. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Shivering: Involuntary contraction or twitching of the muscles. It is a physiologic method of heat production in man and other mammals. [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]

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] Simvastatin: A derivative of lovastatin and potent competitive inhibitor of 3-hydroxy-3methylglutaryl coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It may also interfere with steroid hormone production. Due to the induction of hepatic LDL receptors, it increases breakdown of LDL-cholesterol (lipoproteins, LDL cholesterol). [NIH] Sinus of Valsalva: The dilatation of the aortic wall behind each of the cusps of the aortic valve. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH]

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Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin graft: Skin that is moved from one part of the body to another. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sleep apnea: A serious, potentially life-threatening breathing disorder characterized by repeated cessation of breathing due to either collapse of the upper airway during sleep or absence of respiratory effort. [NIH] Small 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] Social Support: Support systems that provide assistance and encouragement to individuals with physical or emotional disabilities in order that they may better cope. Informal social support is usually provided by friends, relatives, or peers, while formal assistance is provided by churches, groups, etc. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Sodium Channels: Cell membrane glycoproteins selective for sodium ions. Fast sodium current is associated with the action potential in neural membranes. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatostatin: A polypeptide hormone produced in the hypothalamus, and other tissues and organs. It inhibits the release of human growth hormone, and also modulates important physiological functions of the kidney, pancreas, and gastrointestinal tract. Somatostatin receptors are widely expressed throughout the body. Somatostatin also acts as a neurotransmitter in the central and peripheral nervous systems. [NIH] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] Spasticity: A state of hypertonicity, or increase over the normal tone of a muscle, with heightened deep tendon reflexes. [EU] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU]

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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] Spectrin: A high molecular weight (220-250 kDa) water-soluble protein which can be extracted from erythrocyte ghosts in low ionic strength buffers. The protein contains no lipids or carbohydrates, is the predominant species of peripheral erythrocyte membrane proteins, and exists as a fibrous coating on the inner, cytoplasmic surface of the membrane. [NIH]

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] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. [NIH] 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] Sternum: Breast bone. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Striatum: A higher brain's domain thus called because of its stripes. [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] Stroke Volume: The amount of blood pumped out of the heart per beat not to be confused with cardiac output (volume/time). [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU]

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Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] 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] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Superior vena cava: Vein which returns blood from the head and neck, upper limbs, and thorax. It is formed by the union of the two brachiocephalic veins. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] 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] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Syncope: A temporary suspension of consciousness due to generalized cerebral schemia, a faint or swoon. [EU] Systemic: Affecting the entire body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Tacrolimus: A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the

Dictionary 243

activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. [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] Telepathology: Transmission and interpretation of tissue specimens via remote telecommunication, generally for the purpose of diagnosis or consultation but may also be used for continuing education. [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] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Thioguanine: An antineoplastic compound which also has antimetabolite action. The drug is used in the therapy of acute leukemia. [NIH] Thoracotomy: Surgical incision into the chest wall. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are

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concerned in regulating the metabolic rate of the body. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tophus: A chalky deposit of sodium urate occurring in gout; tophi form most often around joints in cartilage, bone, bursae, and subcutaneous tissue and in the external ear, producing a chronic foreign-body inflammatory response. [EU] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Toxoplasmosis: The acquired form of infection by Toxoplasma gondii in animals and man. [NIH]

Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGFbeta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. [NIH]

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,

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between individuals of the same species, or between individuals of different species. [NIH] Transplantation Immunology: A general term for the complex phenomena involved in alloand xenograft rejection by a host and graft vs host reaction. Although the reactions involved in transplantation immunology are primarily thymus-dependent phenomena of cellular immunity, humoral factors also play a part in late rejection. [NIH] Transplantation Tolerance: An induced state of non-reactivity to grafted tissue from a donor organism that would ordinarily trigger a cell-mediated or humoral immune response. [NIH]

Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Trichomoniasis: An infection with the protozoan parasite Trichomonas vaginalis. [NIH] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Tropism: Directed movements and orientations found in plants, such as the turning of the sunflower to face the sun. [NIH] Tropomyosin: A protein found in the thin filaments of muscle fibers. It inhibits contraction of the muscle unless its position is modified by troponin. [NIH] Troponin: One of the minor protein components of skeletal muscle. Its function is to serve as the calcium-binding component in the troponin-tropomyosin B-actin-myosin complex by conferring calcium sensitivity to the cross-linked actin and myosin filaments. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Univalent: Pertaining to an unpaired chromosome during the zygotene stage of prophase to first metaphase in meiosis. [NIH] 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] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [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

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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] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuole: A fluid-filled cavity within the cytoplasm of a cell. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginitis: Inflammation of the vagina characterized by pain and a purulent discharge. [NIH] Valproic Acid: A fatty acid with anticonvulsant properties used in the treatment of epilepsy. The mechanisms of its therapeutic actions are not well understood. It may act by increasing GABA levels in the brain or by altering the properties of voltage dependent sodium channels. [NIH] Valves: Flap-like structures that control the direction of blood flow through the heart. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilatation: A state of increased calibre of the blood vessels. [EU] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilators: Any nerve or agent which induces dilatation of the blood vessels. [NIH] Vasopressor: 1. Stimulating contraction of the muscular tissue of the capillaries and arteries. 2. An agent that stimulates contraction of the muscular tissue of the capillaries and arteries. [EU]

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] Vena: A vessel conducting blood from the capillary bed to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Ventricular Dysfunction: A condition in which the ventricles of the heart exhibit a decreased functionality. [NIH] Ventricular Function: The hemodynamic and electrophysiological action of the ventricles. [NIH]

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Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [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] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Wound Infection: Invasion of the site of trauma by pathogenic microorganisms. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers'

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and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

249

INDEX A Abdomen, 183, 191, 195, 204, 217, 219, 226, 229, 237, 241, 243 Abdominal, 117, 183, 227, 229, 237 Ablation, 14, 70, 183 Abscess, 183, 207, 238 Acatalasia, 183, 194 Accommodation, 60, 183 Acetylcholine, 183, 195, 226 Acetylcysteine, 116, 183 Acidosis, 87, 183 Actin, 8, 37, 38, 183, 222, 224, 225, 245 Actinin, 183, 202 Acute leukemia, 183, 243 Acute renal, 90, 183 Adaptability, 183, 194 Adenosine, 183, 185, 214, 230 Adenovirus, 5, 136, 183 Adhesions, 8, 183 Adipocytes, 183, 197, 218 Adjustment, 29, 183, 184 Adoptive Transfer, 13, 14, 19, 20, 42, 43, 52, 184 Adrenal Cortex, 184, 198, 233 Adverse Effect, 184, 202, 239 Aerobic, 76, 184, 205, 222 Afferent, 184, 206, 218 Affinity, 30, 31, 54, 184, 240 Afterload, 58, 184 Agar, 184, 231 Age of Onset, 184, 245 Agonist, 184, 201 Airway, 29, 184, 240 Alendronate, 104, 125, 184 Algorithms, 184, 190 Alkaline, 183, 184, 192 Alkaloid, 184, 189, 205 Alleles, 14, 184 Allergen, 185, 238 Allo, 19, 22, 25, 35, 49, 185, 245 Allogeneic, 7, 10, 11, 22, 23, 25, 28, 32, 38, 42, 43, 50, 115, 185, 210 Alternative medicine, 148, 185 Amebiasis, 185, 222 Ameliorated, 31, 185 Ameliorating, 42, 129, 136, 185 Amino Acid Sequence, 185, 187, 209 Amino Acid Substitution, 31, 185, 212

Amino Acids, 185, 186, 209, 227, 228, 229, 232, 234, 239, 242 Amiodarone, 79, 185 Amplification, 56, 185 Ampulla, 185, 204 Anaesthesia, 185, 215 Anal, 185, 207, 219 Analog, 79, 129, 130, 185, 207, 208, 214 Analogous, 9, 27, 185, 244 Anaphylatoxins, 186, 197 Anastomosis, 63, 68, 186 Anatomical, 136, 186, 189, 201, 215, 238 Androgens, 184, 186, 198 Anemia, 114, 186, 208 Anergy, 22, 31, 186 Anesthesia, 184, 186, 203 Aneurysm, 186, 246 Angina, 24, 130, 131, 186, 187 Angiogenesis, 130, 131, 186, 221 Angiogram, 81, 186 Angioplasty, 61, 186, 224 Angiotensin I, 137, 186 Angiotensinogen, 137, 186, 236 Animal model, 5, 14, 20, 33, 34, 42, 48, 59, 186 Anions, 186, 218, 242 Annealing, 186, 232 Anomalies, 186, 223 Anoxia, 47, 186 Antecedent, 30, 187 Antiallergic, 187, 198 Antianginal, 185, 187 Antiarrhythmic, 185, 187 Antibiotic, 3, 170, 187 Antibiotic Prophylaxis, 3, 170, 187 Antibodies, 8, 21, 30, 33, 34, 35, 44, 46, 53, 54, 59, 187, 211, 214, 220, 223, 231 Anticoagulant, 187, 200, 234 Anticonvulsant, 187, 246 Antigen-Antibody Complex, 187, 197 Antigen-presenting cell, 187, 200 Antihypertensive, 138, 187 Anti-inflammatory, 41, 187, 198, 209, 228, 233, 238 Anti-Inflammatory Agents, 187, 198 Antimetabolite, 187, 207, 243 Antimicrobial, 168, 187 Antineoplastic, 118, 187, 198, 207, 243

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Antioxidant, 38, 47, 147, 187, 227 Antiserum, 187, 189 Antithymocyte globulin, 99, 188 Antiviral, 183, 188, 200, 217, 229 Aorta, 16, 188, 198, 211, 246 Aortic Valve, 188, 239 Aplasia, 105, 188 Apnea, 188 Apoptosis, 6, 10, 14, 15, 31, 33, 38, 65, 66, 67, 188, 193 Applicability, 41, 188 Aqueous, 188, 189, 199, 213, 219 Arachidonic Acid, 188, 214, 233 Arginine, 45, 186, 188, 226 Arrhythmia, 58, 187, 188 Arterial, 5, 38, 114, 118, 188, 213, 234, 242 Arteries, 3, 5, 9, 18, 131, 188, 191, 198, 211, 219, 222, 224, 235, 246 Arterioles, 188, 191, 193, 222, 224, 246 Arteriolosclerosis, 188 Arteriosclerosis, 5, 8, 11, 18, 34, 42, 71, 83, 147, 188, 213 Arteriosus, 188, 235 Arteriovenous, 188, 222 Aseptic, 189, 227 Aspergillosis, 10, 90, 107, 189 Assay, 10, 15, 22, 32, 38, 67, 123, 146, 189, 214 Asystole, 63, 189 Atrial, 70, 88, 99, 185, 189 Atrial Flutter, 70, 189 Atrium, 91, 189, 246 Atropine, 90, 189, 190 Attenuated, 128, 129, 136, 189 Aura, 140, 189 Autoimmune disease, 23, 49, 189, 230, 238 Autoimmunity, 46, 49, 189 Autologous, 57, 189, 238 Autopsy, 17, 189 Avidity, 20, 189 Axillary, 189, 191 Axillary Artery, 189, 191 B Bacteria, 187, 189, 190, 203, 204, 206, 220, 222, 224, 231, 236, 244, 246 Bacteriophage, 189, 231, 244 Base, 9, 115, 189, 200, 209, 216, 218, 243 Basement Membrane, 189, 205 Basophils, 189, 211, 219 Belladonna, 189, 190 Benign, 15, 188, 190, 193, 211, 225, 236 Bile, 190, 195, 208, 213, 219, 241, 245

Bioavailability, 5, 190 Biochemical, 33, 47, 55, 185, 187, 190, 192, 207 Bioengineering, 55, 158, 190 Biological response modifier, 190, 217 Biological therapy, 190, 211 Biological Transport, 190, 201 Biopsy, 8, 27, 29, 39, 56, 61, 77, 83, 97, 107, 124, 130, 133, 134, 190, 229 Biopsy specimen, 8, 27, 56, 190 Bioreactors, 55, 190 Biosynthesis, 188, 190, 199, 219, 230, 239 Biotechnology, 60, 64, 148, 159, 190 Bladder, 190, 245 Blood Coagulation, 190, 192, 243 Blood pressure, 69, 99, 100, 110, 138, 146, 170, 187, 190, 193, 213, 214, 223, 235, 240 Blot, 27, 191 Body Fluids, 191, 192, 202, 236, 240 Bone Density, 48, 125, 191 Bone Marrow, 22, 36, 42, 46, 50, 183, 191, 199, 210, 214, 220, 241 Bowel, 20, 58, 185, 191, 201, 216, 217, 229 Bowel Movement, 191, 201 Brachial, 116, 118, 191 Brachial Artery, 116, 191 Brachiocephalic Veins, 191, 242 Brachytherapy, 191, 217, 218, 235, 247 Bradycardia, 98, 191 Bradykinin, 191, 226 Branch, 19, 179, 191, 203, 220, 228, 233, 240, 243 Breakdown, 69, 191, 201, 208, 238, 239 Bronchi, 191, 204, 221 Bronchial, 94, 191 Bronchioles, 191 Bronchiolitis, 29, 191 Bronchiolitis Obliterans, 29, 191 Bronchoalveolar Lavage, 10, 192 Bronchoalveolar Lavage Fluid, 10, 192 Bypass, 39, 192, 224 C Calcifediol, 192 Calcification, 188, 192 Calcineurin, 29, 97, 192 Calcitriol, 125, 192 Calcium, 192, 197, 221, 224, 228, 239, 245 Calmodulin, 192 Candidiasis, 170, 192 Candidosis, 192 Capillary, 95, 191, 193, 209, 246, 247 Capsid, 129, 193

Index 251

Capsules, 193, 209 Carbohydrate, 21, 46, 193, 198, 210, 232 Carbon Dioxide, 193, 207, 237 Carcinogen, 193, 222 Carcinogenic, 193, 216, 226, 233, 241 Carcinoid, 193, 226 Carcinoma, 193, 226 Cardiac Output, 131, 193, 241 Cardiac Surgical Procedures, 41, 193 Cardiomyopathy, 37, 63, 70, 115, 193 Cardiotonic, 193, 201 Cardiovascular, 16, 18, 24, 25, 26, 27, 29, 42, 54, 65, 68, 79, 82, 85, 88, 91, 97, 100, 111, 115, 116, 117, 167, 193, 205 Cardiovascular disease, 16, 24, 25, 54, 193 Cardiovirus, 193, 203 Case report, 68, 72, 96, 102, 105, 106, 110, 118, 193 Caspase, 11, 31, 193 Catalase, 47, 183, 193 Catecholamine, 194, 201 Catheterization, 95, 186, 194, 217, 224 Caudal, 135, 194, 214, 232 Causal, 4, 35, 194, 239 Cause of Death, 40, 54, 58, 130, 131, 194 Cell Cycle, 6, 15, 52, 194, 199 Cell Cycle Proteins, 15, 194 Cell Death, 6, 15, 25, 33, 188, 194, 196, 225 Cell Differentiation, 194, 239 Cell Division, 189, 194, 211, 221, 222, 223, 231, 233 Cell membrane, 190, 194, 200, 230, 240 Cell motility, 194, 212 Cell Physiology, 27, 194 Cell proliferation, 8, 27, 58, 188, 194, 239 Cell Respiration, 194, 222, 237 Cell Size, 194, 207 Cell Survival, 39, 194, 211 Central Nervous System, 44, 183, 192, 194, 195, 211 Central Nervous System Infections, 44, 195, 211 Cerebral, 70, 195, 204, 240, 242 Cerebral Palsy, 195, 240 Cerebrovascular, 193, 195 Cervical, 55, 195 Cervix, 195 Character, 129, 195, 200 Chemokines, 11, 44, 57, 59, 137, 195 Chemotactic Factors, 195, 197 Chemotherapy, 10, 168, 195 Chenodeoxycholic Acid, 195, 245

Chest cavity, 135, 195 Chest wall, 135, 195, 243 Chimeras, 26, 195 Cholecystitis, 72, 195 Cholera, 195, 239 Choleretic, 195, 246 Cholesterol, 44, 165, 190, 195, 198, 208, 213, 219, 239, 241 Choline, 44, 195 Chromatin, 188, 194, 195, 204 Chromosomal, 185, 195, 196 Chromosome, 12, 37, 196, 219, 245 Chronic renal, 196, 208 Chronotropic, 109, 196 Cidofovir, 77, 196 Clinical Medicine, 47, 196, 233 Clinical Protocols, 40, 196 Clinical trial, 4, 29, 30, 47, 55, 57, 123, 125, 159, 196, 198, 199, 201, 223, 228, 234, 236 Clonal Anergy, 22, 196 Clonal Deletion, 22, 196 Cloning, 37, 190, 196 Coagulation, 17, 190, 196, 243 Coenzyme, 196, 219, 239 Cofactor, 196, 234, 243 Colitis, 20, 196, 216 Collagen, 53, 55, 189, 196, 206, 207, 208, 221, 231, 233 Collapse, 191, 196, 240 Colloidal, 197, 203 Complement, 20, 21, 34, 35, 49, 59, 186, 197, 209, 217, 220, 238 Complement Activation, 20, 186, 197 Computational Biology, 159, 197 Concentric, 58, 188, 197 Congestive heart failure, 66, 128, 131, 197 Conjugated, 24, 195, 197, 225 Conjunctiva, 197, 216 Connective Tissue, 4, 191, 196, 197, 207, 208, 210, 220, 221, 238 Connective Tissue Cells, 197 Consciousness, 197, 201, 242 Consolidation, 90, 197 Constriction, 131, 197, 218, 246 Consultation, 197, 243 Contractility, 198, 202 Contraindications, ii, 198 Control group, 4, 198, 233 Controlled study, 64, 198 Conus, 198, 235 Coronary Angiography, 64, 71, 74, 198 Coronary Arteriosclerosis, 198, 224

252

Heart Transplant

Coronary Artery Bypass, 60, 61, 198 Coronary Disease, 24, 64, 198 Coronary heart disease, 193, 198 Coronary Thrombosis, 198, 222, 224 Coronary Vessels, 198 Corticosteroid, 100, 198, 233 Cortisone, 198, 233 Coxsackieviruses, 129, 136, 198 Creatinine, 71, 109, 115, 199 Creatinine clearance, 71, 199 Curative, 199, 243 Cutaneous, 61, 65, 72, 77, 92, 114, 192, 199, 218, 230 Cutaneous Fistula, 65, 199 Cyanosis, 10, 199, 212 Cyclic, 45, 192, 199, 211, 226, 230, 234 Cyclin, 194, 199 Cyclin-Dependent Kinases, 194, 199 Cyclosporine, 4, 29, 41, 69, 76, 80, 83, 86, 87, 88, 90, 91, 98, 100, 103, 108, 114, 117, 124, 132, 199 Cystathionine beta-Synthase, 199, 213 Cysteine, 183, 195, 199, 242 Cytokine, 5, 13, 14, 19, 20, 23, 30, 34, 39, 42, 45, 56, 129, 199 Cytomegalovirus, 14, 56, 58, 61, 63, 67, 72, 82, 95, 96, 102, 118, 199, 208 Cytomegalovirus Infections, 95, 199, 208 Cytopenia, 69, 199 Cytoplasm, 188, 189, 194, 199, 200, 204, 211, 225, 246 Cytoskeletal Proteins, 37, 194, 199, 202 Cytoskeleton, 8, 77, 199, 200, 217 Cytotoxic, 9, 30, 57, 116, 200, 236, 239 Cytotoxicity, 9, 15, 200 D Databases, Bibliographic, 159, 200 De novo, 36, 44, 72, 87, 91, 100, 200 Degenerative, 198, 200, 212 Deletion, 14, 22, 25, 30, 188, 196, 200, 209 Denaturation, 200, 232 Dendrites, 200 Dendritic, 22, 25, 32, 200 Dendritic cell, 22, 25, 32, 200 Density, 47, 191, 200, 207, 219, 227 Depolarization, 200, 239 Desmin, 37, 200 Deuterium, 200, 213 Dextran Sulfate, 20, 200 Diabetes Insipidus, 200, 213 Diabetes Mellitus, 116, 200, 210, 212 Diagnostic procedure, 127, 148, 200

Diastole, 128, 200 Diastolic, 75, 128, 200, 213 Diffusion, 78, 190, 200, 216 Digestion, 190, 191, 201, 217, 219, 241 Digestive system, 126, 201, 223 Dihydrotestosterone, 201, 236 Dilatation, 118, 186, 201, 233, 239, 246 Dilatation, Pathologic, 201, 246 Dilated cardiomyopathy, 32, 36, 201 Dilation, 131, 134, 135, 191, 201, 246 Dipyridamole, 109, 201 Direct, iii, 13, 28, 30, 33, 43, 45, 58, 133, 196, 201, 209, 232, 236 Discrimination, 46, 201 Disease Progression, 59, 201 Disparity, 115, 201 Disposition, 82, 201 Dissociation, 184, 201 Distal, 198, 201, 203, 234 Diuretic, 138, 201, 208, 213 Dobutamine, 74, 81, 89, 90, 104, 201 Dose-dependent, 35, 201 Double-blinded, 29, 201 Drive, ii, vi, 35, 113, 116, 202 Drug Interactions, 152, 202 Drug Tolerance, 202, 244 Drug Toxicity, 12, 202 Duct, 185, 194, 202, 205, 238 Duodenum, 190, 202, 204, 241 Dyspnea, 202, 235 Dystrophin, 37, 202 Dystrophy, 202 E Echocardiography, 74, 81, 88, 90, 91, 99, 104, 202 Edema, 202, 208, 213, 224 Effector, 9, 12, 13, 19, 28, 39, 42, 44, 53, 56, 183, 197, 202, 230 Effector cell, 13, 39, 42, 202 Efficacy, 41, 47, 52, 63, 64, 71, 109, 117, 124, 202 Ejection fraction, 58, 131, 202 Elasticity, 188, 198, 202 Elastin, 196, 202, 206 Elective, 71, 202 Electrocardiogram, 124, 202 Electrocoagulation, 196, 202 Electrode, 26, 203 Electrolyte, 198, 203, 222, 232, 240 Electrons, 187, 189, 203, 218, 227, 235, 236 Electrophoresis, 15, 203 Electrophysiological, 203, 246

Index 253

Embolus, 203, 215 Embryo, 194, 203, 215 Encephalitis, 109, 193, 203 Encephalitis, Viral, 203 Encephalomyelitis, 203 Encephalomyocarditis Virus, 49, 203 Endarterectomy, 186, 203 Endemic, 85, 195, 203 Endocarditis, 192, 203 Endocrine System, 203, 225 Endoscope, 204 Endoscopic, 82, 204 Endothelial cell, 8, 9, 14, 21, 24, 27, 31, 34, 35, 51, 53, 59, 204, 243 Endothelium, 5, 6, 8, 9, 43, 53, 80, 204, 226, 231 Endothelium, Lymphatic, 204 Endothelium, Vascular, 204 Endothelium-derived, 204, 226 Endotoxin, 204, 245 Energy balance, 204, 218 Enterovirus, 198, 204 Environmental Health, 158, 160, 204 Enzymatic, 10, 133, 192, 197, 199, 204, 207, 232, 237 Enzyme-Linked Immunosorbent Assay, 62, 204 Eosinophils, 204, 211, 219 Epigastric, 204, 227 Epinephrine, 204, 245 Epithelial, 53, 190, 205, 212 Epithelial Cells, 53, 205, 212 Epithelium, 189, 204, 205, 227 Epitope, 21, 46, 57, 205 Epoprostenol, 205, 214 Ergonovine, 114, 205 Ergot, 205 Erythrocytes, 186, 191, 205, 236, 238 Esophagus, 201, 205, 221, 229, 241 Eukaryotic Cells, 199, 205, 215, 227 Excipient, 137, 205 Excitation, 189, 205, 207 Exercise Test, 48, 167, 205 Exocrine, 205, 227 Exogenous, 205, 209, 245 Exophiala, 105, 205 Expiration, 205, 237 External-beam radiation, 205, 218, 235, 247 Extracellular, 22, 36, 44, 51, 197, 205, 206, 207, 208, 217, 221, 222, 240

Extracellular Matrix, 36, 51, 197, 205, 206, 207, 208, 217, 221, 222 Extracellular Matrix Proteins, 206, 208, 221 Extracellular Space, 205, 206 Extracorporeal, 206, 230 Extravascular, 137, 206 Extremity, 94, 206 Exudate, 191, 206 Eye Infections, 183, 206 F Facial, 206, 228 Facial Nerve, 206, 228 Family Planning, 159, 206 Fat, 183, 188, 191, 198, 203, 206, 218, 219, 240, 245 Fatigue, 206, 211 Fatty acids, 99, 206, 210, 233 Femoral, 67, 206 Femur, 206 Fibrillation, 110, 206 Fibrin, 27, 190, 206, 207, 229, 231, 243 Fibrinogen, 27, 206, 231, 243 Fibrinolysis, 27, 207 Fibrinolytic, 27, 45, 207 Fibroblasts, 4, 36, 39, 197, 207, 223 Fibronectin, 53, 207 Fibrosis, 9, 11, 17, 29, 36, 38, 47, 207, 235, 238 Fistulas, 91, 207 Fixation, 207, 238 Flatus, 207, 208 Flow Cytometry, 8, 29, 30, 207, 215 Fluorescence, 207 Fluorescent Dyes, 207 Fluorouracil, 201, 207 Focal Adhesions, 8, 208 Folate, 25, 86, 89, 109, 115, 116, 208 Fold, 208, 226 Folic Acid, 208 Forearm, 191, 208 Fungi, 189, 206, 208, 220, 222, 247 Fungus, 192, 205, 208 Furosemide, 138, 208 G Gallbladder, 183, 195, 201, 208 Gallstones, 195, 208, 246 Ganciclovir, 63, 67, 82, 208 Gangliosides, 130, 208 Gangrenous, 208, 239 Gas, 24, 68, 82, 193, 200, 207, 208, 213, 226 Gastrin, 208, 212

254

Heart Transplant

Gastrointestinal, 82, 191, 193, 204, 208, 240, 242 Gastrointestinal tract, 208, 240 Gelatin, 208, 210, 243 Gene Deletion, 38, 209 Gene Expression, 16, 20, 37, 38, 52, 56, 97, 209 Gene Targeting, 50, 209 Genetic Code, 209, 226 Genetic Engineering, 46, 190, 196, 209 Genetic Markers, 40, 209 Genetic testing, 209, 232 Genetics, 16, 37, 40, 209 Genotype, 27, 36, 209, 230 Giardiasis, 209, 222 Gingival Hyperplasia, 4, 209 Gland, 118, 184, 198, 209, 220, 221, 227, 228, 230, 238, 241, 243 Glomerular, 53, 71, 80, 209, 218 Glomerular Filtration Rate, 71, 209 Glomerulus, 209, 225 Glucocorticoid, 83, 103, 104, 209, 233 Glucose, 83, 200, 210, 212, 216, 236, 238 Glucose Intolerance, 200, 210 Glycerol, 210, 230 Glycerophospholipids, 210, 230 Glycine, 25, 195, 210, 239 Glycolysis, 41, 210 Glycoprotein, 43, 206, 207, 210, 223, 243, 245 Gonadal, 210, 241 Gout, 210, 244 Governing Board, 210, 232 Gp120, 210, 229 Grade, 30, 41, 210 Graft Rejection, 3, 13, 19, 22, 25, 28, 35, 49, 56, 74, 77, 132, 210, 215 Graft Survival, 13, 28, 30, 32, 33, 38, 39, 41, 44, 59, 210 Graft vs Host Reaction, 210, 245 Grafting, 60, 198, 210, 215 Graft-versus-host disease, 188, 210, 224 Granulation Tissue, 191, 210 Granulocytes, 211, 239, 247 Growth factors, 25, 211 Guanylate Cyclase, 211, 226 H Habitat, 211, 226 Habitual, 195, 211 Half-Life, 47, 48, 211, 214 Haplotypes, 82, 211 Haptens, 184, 211

Headache, 211, 216 Health Services, iv, 4, 7, 160, 211 Health Status, 48, 116, 211 Heart attack, 131, 193, 211 Heart Valves, 128, 211 Heartbeat, 134, 189, 211 Helminthiasis, 195, 211 Hematopoietic Stem Cells, 22, 42, 211 Heme, 66, 67, 211, 212, 225, 227 Hemoglobin, 186, 199, 205, 211, 212 Hemoglobin M, 199, 212 Hemoglobinopathies, 23, 212 Hemorrhage, 58, 74, 131, 202, 211, 212, 224, 241 Hepatic, 32, 42, 102, 212, 239 Hepatitis, 78, 80, 82, 85, 93, 94, 100, 107, 212, 247 Hepatocyte, 36, 212 Hepatocyte Growth Factor, 36, 212 Heredity, 209, 212 Heterogeneity, 184, 212 Histology, 17, 18, 29, 212, 228 Homeostasis, 6, 44, 69, 116, 212 Homodimer, 212, 244 Homologous, 185, 209, 212, 224, 238, 242 Hormonal, 86, 198, 212 Hormone, 137, 185, 192, 198, 204, 208, 212, 216, 218, 225, 233, 239, 240, 243, 244 Horseradish Peroxidase, 204, 212 Humoral, 19, 54, 210, 212, 245 Humour, 212 Hybrid, 53, 213 Hybridization, 56, 213 Hybridoma, 54, 213 Hydrochlorothiazide, 138, 213 Hydrogen, 26, 138, 183, 189, 193, 200, 206, 213, 219, 223, 226, 227, 229, 234, 242 Hydrogen Peroxide, 193, 213, 219, 242 Hydrolysis, 213, 230, 232, 234 Hydroxylation, 192, 213 Hydroxylysine, 196, 213 Hydroxyproline, 196, 213 Hyperhomocysteinemia, 89, 199, 213 Hyperlipoproteinemia, 213 Hyperplasia, 4, 6, 15, 27, 213 Hypersensitivity, 29, 42, 185, 213, 238 Hypertension, 66, 86, 87, 100, 115, 123, 137, 188, 193, 211, 213, 225 Hyperthyroidism, 79, 213 Hypertriglyceridemia, 27, 213 Hypertrophy, 11, 75, 213, 214 Hypotensive, 138, 214

Index 255

Hypothalamus, 214, 231, 240 Hypothermia, 131, 214 Hypoxanthine, 133, 214, 216 Hypoxia, 10, 214 I Id, 95, 119, 167, 168, 169, 170, 171, 178, 180, 214 Idiopathic, 37, 54, 214 Iloprost, 79, 85, 214 Imidazole, 137, 214 Immune function, 29, 52, 53, 214, 244 Immune Sera, 214 Immune system, 22, 42, 47, 49, 59, 132, 187, 189, 190, 202, 214, 215, 220, 225, 238, 246, 247 Immunity, 12, 32, 49, 52, 55, 214, 244, 245 Immunization, 52, 171, 184, 214, 215, 238 Immunoassay, 10, 204, 214 Immunodominant Epitopes, 15, 214 Immunoglobulin, 35, 62, 63, 187, 214, 223 Immunohistochemistry, 17, 18, 214 Immunologic, 25, 32, 63, 184, 195, 214, 215, 236 Immunology, 6, 14, 20, 40, 43, 56, 72, 74, 103, 106, 129, 184, 207, 212, 215, 245 Immunophenotyping, 36, 215 Immunophilin, 192, 215 Immunosuppressive therapy, 4, 30, 32, 92, 215 Immunotherapy, 57, 184, 190, 215 Impairment, 25, 206, 215, 221 Implant radiation, 215, 217, 218, 235, 247 Implantation, 5, 55, 88, 167, 215 In situ, 20, 38, 56, 215 In Situ Hybridization, 20, 215 In vitro, 9, 11, 14, 19, 20, 22, 24, 31, 33, 35, 37, 39, 43, 50, 51, 53, 54, 55, 57, 59, 215, 232, 243 Incision, 215, 218, 243 Incompetence, 109, 215 Incubation, 215, 218 Incubation period, 215, 218 Indicative, 131, 134, 135, 139, 215, 228, 246 Induction, 6, 10, 12, 22, 23, 28, 29, 31, 38, 42, 44, 46, 51, 53, 56, 57, 59, 71, 87, 93, 98, 99, 186, 215, 239 Induction therapy, 93, 215 Infancy, 40, 215 Infarction, 11, 54, 131, 215, 237 Infiltration, 4, 44, 216 Inflammatory bowel disease, 20, 216 Influenza, 35, 52, 216

Informed Consent, 166, 216 Infusion, 32, 55, 90, 114, 116, 216, 224 Ingestion, 22, 216, 231 Inhalation, 191, 216, 231 Initiation, 34, 43, 56, 216, 244 Inlay, 216, 237 Innervation, 58, 206, 216 Inoperable, 60, 216 Inosine Monophosphate, 89, 216 Inotropic, 100, 131, 216 Insight, 22, 33, 52, 216 Insulin, 138, 216, 218, 245 Insulin-dependent diabetes mellitus, 216 Integrins, 208, 217 Interferon, 98, 217 Interferon-alpha, 217 Interleukin-1, 32, 45, 217 Interleukin-2, 217 Intermittent, 217, 229 Internal Medicine, 9, 44, 116, 117, 217, 225 Internal radiation, 217, 218, 235, 247 Interstitial, 38, 191, 192, 206, 217, 218, 225, 247 Intestinal, 192, 195, 204, 217 Intestine, 191, 217, 218 Intoxication, 217, 247 Intracellular, 11, 37, 41, 44, 51, 216, 217, 226, 232, 234, 239 Intravascular, 46, 61, 64, 74, 81, 168, 169, 217 Intravenous, 22, 216, 217 Intrinsic, 184, 189, 217 Intubation, 194, 217 Inulin, 209, 217 Invasive, 3, 10, 24, 40, 90, 96, 107, 124, 130, 132, 133, 134, 214, 218, 220 Involuntary, 206, 218, 224, 239 Ions, 189, 192, 201, 203, 213, 218, 240 Irradiation, 79, 92, 218, 222, 247 Ischemia, 10, 24, 38, 40, 42, 47, 75, 208, 218, 224, 237 Islet, 7, 12, 218, 226 K Kb, 158, 218 Kidney Disease, 126, 158, 169, 218 Kinetics, 36, 59, 66, 82, 110, 218 L Labile, 197, 218 Large Intestine, 201, 217, 218, 236, 240 Latent, 15, 56, 218 Leishmaniasis, 79, 96, 218 Lentivirus, 5, 15, 218

256

Heart Transplant

Leptin, 88, 218 Lesion, 34, 38, 42, 58, 198, 218, 219 Lethal, 9, 44, 92, 218 Leukocytes, 11, 22, 44, 137, 189, 191, 195, 204, 211, 217, 219, 223, 245 Library Services, 178, 219 Ligaments, 198, 219 Ligands, 12, 32, 35, 59, 217, 219 Ligation, 12, 39, 219 Linkage, 37, 209, 219 Lipid, 6, 44, 53, 92, 130, 131, 188, 195, 210, 216, 219, 227, 245 Lipid Peroxidation, 219, 227 Lipoprotein, 92, 219 Liposome, 52, 219 Liver, 32, 42, 86, 133, 164, 183, 188, 190, 192, 199, 201, 208, 212, 219, 233 Localization, 41, 214, 219 Localized, 183, 200, 202, 207, 216, 219, 231 Longitudinal study, 48, 56, 219 Loop, 43, 219 Lovastatin, 68, 219, 239 Low-density lipoprotein, 68, 219 Luciferase, 53, 219 Lymph, 189, 195, 204, 212, 220, 221 Lymph node, 189, 195, 220, 221 Lymphatic, 204, 216, 220, 221, 241, 243 Lymphatic system, 220, 241, 243 Lymphocyte, 42, 75, 187, 220, 221, 223 Lymphoid, 13, 20, 33, 39, 79, 92, 187, 211, 220 Lymphoma, 15, 61, 75, 106, 111, 118, 220, 230 Lymphoproliferative, 15, 39, 57, 94, 106, 220 Lytic, 116, 220, 239 M Macrophage, 36, 39, 45, 217, 220 Maduromycosis, 205, 220 Magnetic Resonance Imaging, 72, 103, 220 Major Histocompatibility Complex, 22, 211, 220 Malignancy, 40, 220, 227 Malignant, 15, 94, 187, 188, 220, 225, 236, 238 Mammary, 198, 220, 221 Marital Status, 48, 220 Mastitis, 221, 239 Matrix metalloproteinase, 74, 117, 221 Medial, 188, 221 Mediastinitis, 63, 66, 221 Mediastinum, 221

Mediate, 6, 8, 13, 14, 21, 25, 28, 30, 33, 35, 61, 221 Mediator, 24, 53, 217, 221 Medical Records, 124, 221 Medical Staff, 201, 221 MEDLINE, 159, 221 Medullary, 221, 226 Meiosis, 221, 224, 242, 245 Melanin, 221, 230, 245 Memory, 19, 23, 34, 52, 56, 221 Meninges, 195, 221 Mental Disorders, 126, 221 Mental Processes, 201, 221, 234 Mercury, 207, 221 Mesenchymal, 36, 221 Metabolite, 192, 219, 222 Metaphase, 222, 245 Metastasis, 221, 222 Methoxsalen, 222, 230 Metronidazole, 76, 222 MI, 58, 90, 107, 115, 131, 182, 222 Mice Minute Virus, 222, 228 Microbe, 222, 244 Microbiological, 114, 222 Microbiology, 6, 14, 56, 73, 90, 104, 129, 222 Microcirculation, 24, 222, 231 Microfibrils, 51, 222 Microfilaments, 208, 222 Microorganism, 196, 222, 228, 247 Microscopy, 8, 189, 212, 222 Migration, 14, 36, 39, 59, 137, 222 Milliliter, 191, 222 Mineralocorticoids, 184, 198, 222 Mitochondria, 25, 222, 223, 224, 227 Mitochondrial Swelling, 223, 225 Mitosis, 188, 223 Mobility, 32, 223 Modeling, 48, 95, 223 Modification, 5, 6, 52, 209, 223, 235 Monitor, 29, 74, 130, 199, 223, 226 Monoclonal, 8, 20, 35, 50, 106, 218, 223, 235, 247 Monoclonal antibodies, 35, 50, 106, 223 Monocyte, 33, 39, 70, 223 Monocyte Chemoattractant Protein-1, 70, 223 Mononuclear, 42, 133, 223, 245 Morphological, 55, 81, 96, 203, 208, 223 Mucocutaneous, 218, 223 Mucolytic, 183, 192, 223 Mucositis, 10, 223

Index 257

Multicenter Studies, 10, 223 Multicenter study, 80, 223 Multidrug resistance, 43, 223 Multivalent, 136, 189, 224 Muscle Contraction, 202, 224 Muscle Fibers, 224, 225, 245 Myalgia, 216, 224 Mycophenolate mofetil, 75, 84, 86, 87, 89, 96, 97, 101, 103, 115, 117, 224 Mycoplasma, 195, 224 Mycoplasma Infections, 195, 224 Mydriatic, 201, 224 Myeloma, 213, 224 Myocardial infarction, 4, 11, 32, 97, 130, 131, 198, 201, 222, 224 Myocardial Ischemia, 11, 198, 224 Myocardial Reperfusion, 224, 237 Myocardial Reperfusion Injury, 224, 237 Myocarditis, 49, 54, 193, 203, 224 Myocardium, 5, 11, 18, 31, 38, 54, 222, 224 Myofibrils, 202, 225 Myoglobin, 37, 225 Myopathy, 70, 103, 225 Myosin, 37, 49, 192, 224, 225, 245 N Naive, 7, 19, 22, 80, 225 Nasal Mucosa, 216, 225 NCI, 1, 125, 157, 225 Necrosis, 10, 31, 67, 73, 131, 188, 215, 222, 224, 225, 237 Neonatal, 55, 60, 225 Neoplasm, 225, 238 Neoplastic, 220, 225 Nephritis, 20, 225 Nephrologist, 43, 225 Nephrology, 20, 43, 225 Nephropathy, 218, 225 Nephrotoxic, 20, 53, 137, 225 Nerve, 165, 186, 200, 206, 216, 221, 225, 232, 237, 238, 241, 244, 246 Nervous System, 184, 190, 194, 195, 221, 225, 226, 229 Networks, 10, 42, 225 Neural, 184, 212, 225, 240 Neuroendocrine, 72, 225 Neuroendocrine tumor, 72, 225 Neutrons, 218, 226, 235 Neutrophil, 45, 226 Niche, 21, 226 Nitric Oxide, 5, 31, 37, 45, 56, 85, 87, 123, 226 Nosocomial, 61, 62, 226

Nuclear, 39, 40, 89, 203, 205, 225, 226, 245 Nuclei, 203, 209, 220, 223, 226, 234 Nucleic acid, 128, 129, 136, 193, 209, 213, 214, 215, 226, 233, 235 Nucleic Acid Hybridization, 213, 226 Nucleus, 188, 189, 195, 199, 200, 204, 205, 221, 223, 226, 233, 234, 241 O Ointments, 226, 228 Omentum, 130, 131, 226 Oncogene, 212, 226 Oncogenic, 217, 218, 226 Opacity, 200, 227 Open Reading Frames, 218, 227 Opportunistic Infections, 168, 227 Oral Health, 227, 233 Organ Culture, 18, 227 Organ Transplantation, 5, 12, 33, 41, 42, 50, 56, 64, 67, 79, 94, 107, 164, 227 Organelles, 44, 199, 227, 231 Osteoporosis, 47, 104, 117, 124, 125, 184, 227 Outpatient, 73, 100, 227 Oxidation, 187, 212, 219, 227 Oxidative Stress, 40, 56, 78, 227 Oxygen Consumption, 76, 205, 227, 237 Oxygenase, 66, 67, 227 P Pacemaker, 129, 130, 134, 227 Palliative, 40, 227, 243 Pancreas, 133, 164, 183, 201, 216, 218, 227, 240 Papillomavirus, 86, 227 Paraffin, 17, 18, 228 Paralysis, 228, 240 Parasite, 44, 60, 228, 245 Parathyroid, 192, 228 Parathyroid hormone, 192, 228 Parotid, 118, 228 Paroxysmal, 189, 228 Particle, 219, 228, 244 Parvovirus, 105, 222, 228 Patch, 54, 87, 198, 228 Pathogen, 29, 215, 228 Pathogenesis, 14, 18, 21, 33, 35, 38, 41, 51, 53, 101, 228 Pathologic, 18, 28, 183, 188, 190, 193, 198, 213, 228, 232, 237, 246 Pathologic Processes, 188, 228 Pathologies, 24, 42, 228 Pathophysiology, 58, 228 Patient Education, 166, 176, 178, 182, 228

258

Heart Transplant

Patient Selection, 3, 228 Peer Review, 27, 113, 228 Peptide, 15, 18, 28, 30, 43, 49, 57, 99, 109, 136, 137, 218, 228, 232, 234 Peptide T, 15, 228 Percutaneous, 69, 167, 229 Perfusion, 5, 38, 58, 89, 103, 109, 130, 131, 190, 214, 229 Pericardial Effusion, 117, 229 Pericarditis, 81, 229 Pericardium, 229 Perioperative, 26, 167, 229 Peripheral blood, 6, 9, 49, 56, 105, 133, 137, 217, 229, 230 Peripheral Nervous System, 229, 240, 242 Peritoneal, 170, 229 Peritoneal Cavity, 229 Peritoneal Dialysis, 170, 229 Peritoneum, 226, 229, 237 Peritonitis, 205, 229 Petroleum, 228, 229 PH, 69, 107, 191, 229 Phagocytosis, 22, 229 Pharmacologic, 41, 52, 186, 211, 229, 244 Pharynx, 216, 229 Phenotype, 16, 22, 23, 36, 51, 55, 209, 230 Phenyl, 138, 230 Phenylalanine, 230, 245 Phosphates, 41, 230 Phosphodiesterase, 45, 230 Phosphodiesterase Inhibitors, 45, 230 Phospholipases, 230, 239 Phospholipids, 44, 206, 219, 230 Phosphoprotein Phosphatase, 194, 230 Phosphorus, 192, 230 Phosphorylation, 8, 199, 230 Photocoagulation, 196, 230 Photopheresis, 67, 230 Physical Examination, 131, 230 Physiologic, 184, 190, 211, 217, 230, 233, 236, 237, 239 Physiology, 5, 65, 81, 82, 86, 110, 135, 193, 203, 225, 230 Pigment, 225, 230 Pilot study, 124, 230 Pituitary Gland, 198, 230 Plants, 184, 189, 190, 193, 195, 210, 217, 222, 231, 238, 244, 245 Plaque, 131, 186, 231 Plasma cells, 187, 211, 224, 231 Plasmin, 231 Plasminogen, 45, 231

Plasminogen Activators, 231 Plastids, 227, 231 Platelet Activation, 231, 239 Platelet Aggregation, 186, 205, 214, 226, 231 Platelets, 35, 226, 231, 243 Platinum, 219, 231 Pleural, 221, 231 Pneumococcal Infections, 170, 231 Poisoning, 202, 205, 217, 221, 231 Polymerase, 73, 129, 133, 232 Polymerase Chain Reaction, 73, 133, 232 Polymorphic, 30, 232 Polymorphism, 89, 232 Polypeptide, 185, 196, 206, 213, 225, 231, 232, 240, 248 Polysaccharide, 170, 187, 232 Population Dynamics, 19, 232 Posterior, 185, 188, 227, 232 Postmenopausal, 184, 227, 232 Postnatal, 232, 241 Postoperative, 3, 66, 232 Postoperative Complications, 66, 232 Postsynaptic, 232, 239 Potassium, 137, 213, 222, 232 Potentiates, 39, 217, 232 Potentiation, 232, 239 Practice Guidelines, 160, 166, 167, 169, 170, 232 Precursor, 36, 44, 186, 188, 195, 202, 204, 230, 231, 232, 244, 245, 246 Prednisolone, 233 Prednisone, 4, 233 Prevalence, 37, 88, 233 Preventive Dentistry, 4, 233 Primary endpoint, 29, 233 Prion, 195, 233 Probe, 20, 72, 131, 233 Progeny, 25, 36, 55, 233 Progesterone, 233, 241 Progression, 14, 24, 44, 56, 71, 186, 199, 233 Progressive, 38, 42, 63, 108, 128, 135, 188, 194, 196, 202, 211, 225, 231, 233, 235 Proline, 196, 213, 233 Promoter, 11, 20, 38, 53, 233 Prophase, 224, 233, 242, 245 Prophylaxis, 93, 107, 114, 168, 233, 237 Proportional, 204, 233 Prospective study, 219, 233 Prostaglandin, 31, 114, 205, 233 Prostaglandins A, 234

Index 259

Protease, 129, 234 Protein C, 27, 38, 129, 185, 189, 219, 234, 241, 245 Protein S, 27, 190, 209, 234 Proteins, 6, 8, 11, 18, 20, 24, 27, 37, 38, 42, 59, 124, 128, 129, 131, 136, 185, 187, 190, 191, 193, 194, 195, 196, 197, 204, 206, 212, 213, 217, 221, 223, 225, 228, 231, 234, 236, 239, 241, 243, 244, 247 Proteolytic, 11, 197, 207, 231, 234 Protocol, 10, 23, 57, 124, 234 Protons, 213, 234, 235 Protozoa, 218, 222, 234 Protozoan Infections, 195, 234 Proximal, 15, 53, 201, 234, 238 Psychology, 85, 106, 201, 234 Public Policy, 159, 235 Publishing, 60, 235 Pulmonary Artery, 27, 84, 190, 235, 246 Pulmonary Edema, 131, 235 Pulmonary Fibrosis, 9, 235 Pulmonary hypertension, 9, 27, 78, 116, 205, 235 Pulse, 132, 223, 235 Pupil, 201, 224, 235 Purines, 235, 239 Purulent, 81, 235, 246 Q Quality of Life, 48, 81, 86, 95, 121, 135, 235 R Race, 17, 48, 222, 235 Radiation, 205, 207, 217, 218, 222, 235, 236, 247 Radiation therapy, 205, 217, 218, 235, 247 Radioactive, 211, 213, 215, 217, 218, 223, 226, 235, 243, 245, 247 Radiolabeled, 218, 235, 247 Radiological, 229, 235 Radionuclide Imaging, 58, 235 Radiotherapy, 191, 218, 235, 236, 247 Randomized, 29, 63, 64, 77, 118, 202, 236 Reabsorption, 213, 236 Reactivation, 56, 118, 236 Reactive Oxygen Species, 38, 45, 47, 236 Reagent, 200, 220, 236 Receptor, 8, 11, 15, 30, 44, 45, 53, 56, 59, 108, 136, 137, 187, 210, 212, 229, 236, 239 Recombinant, 14, 21, 35, 59, 190, 236, 246 Recombination, 209, 236 Recovery of Function, 11, 236 Rectum, 191, 201, 207, 208, 216, 218, 236 Red blood cells, 84, 205, 227, 236, 238

Reductase, 89, 219, 236, 239 Refer, 1, 129, 197, 207, 208, 219, 225, 226, 236 Refractory, 67, 101, 202, 236 Regimen, 22, 55, 100, 196, 202, 236 Regurgitation, 211, 236 Renal Replacement Therapy, 168, 236 Renin, 115, 137, 186, 236 Reperfusion, 10, 24, 38, 40, 47, 117, 224, 237 Reperfusion Injury, 11, 38, 40, 47, 117, 237 Residual Volume, 135, 237 Resorption, 192, 236, 237 Respiration, 41, 188, 193, 223, 237 Restitution, 81, 237 Restoration, 19, 224, 236, 237, 247 Retina, 198, 237, 238 Retinal, 201, 237 Retinoids, 237 Retinol, 108, 237 Retroperitoneal, 118, 237 Retroviral vector, 36, 237 Reversion, 4, 237 Rhabdomyolysis, 90, 237 Rhinitis, 237, 239 Ribose, 41, 183, 238 Risk factor, 8, 25, 86, 88, 115, 213, 233, 238 Rod, 55, 238 S Salicylate, 38, 238 Saline, 192, 238 Salivary, 118, 199, 201, 206, 238 Salivary glands, 199, 201, 206, 238 Saphenous, 198, 238 Saphenous Vein, 198, 238 Saponins, 238, 241 Sarcoma, 62, 73, 90, 91, 238 Schizoid, 238, 247 Schizophrenia, 238, 247 Schizotypal Personality Disorder, 238, 247 Sclerosis, 14, 17, 39, 58, 115, 188, 238 Screening, 10, 37, 49, 54, 109, 196, 238 Secretion, 14, 23, 34, 44, 198, 213, 216, 222, 238, 244 Secretory, 44, 238 Self Tolerance, 196, 238 Senile, 227, 238 Sensitization, 19, 49, 238 Septal, 96, 238 Septicaemia, 239 Sequence Homology, 229, 239 Sequencing, 232, 239

260

Heart Transplant

Serine, 25, 199, 230, 239 Serologic, 214, 239 Serotypes, 129, 199, 239 Serous, 204, 239 Serum, 19, 20, 46, 56, 71, 89, 106, 146, 184, 186, 187, 197, 214, 219, 222, 229, 239, 245 Shivering, 131, 239 Shock, 38, 239, 245 Side effect, 3, 22, 29, 57, 151, 153, 184, 190, 239, 244 Signal Transduction, 8, 15, 192, 239 Simvastatin, 76, 90, 117, 146, 239 Sinus of Valsalva, 96, 239 Skeletal, 37, 83, 102, 186, 200, 225, 237, 239, 245 Skeleton, 183, 206, 234, 239, 240 Skin graft, 28, 47, 50, 55, 240 Skull, 240, 243 Sleep apnea, 107, 146, 240 Small intestine, 195, 202, 209, 212, 217, 240 Smooth muscle, 8, 14, 18, 27, 34, 38, 42, 51, 58, 186, 197, 205, 240, 242 Social Environment, 235, 240 Social Support, 48, 240 Sodium, 20, 205, 210, 213, 222, 236, 240, 244, 246 Sodium Channels, 240, 246 Soft tissue, 83, 191, 240 Somatic, 212, 221, 223, 229, 240 Somatostatin, 71, 240 Spastic, 131, 240 Spasticity, 240 Specialist, 84, 172, 201, 240 Specificity, 12, 20, 29, 35, 44, 50, 57, 60, 184, 214, 241 Spectrin, 202, 241 Sperm, 186, 196, 241 Spinal cord, 191, 195, 203, 221, 225, 229, 241 Spleen, 23, 199, 213, 220, 241 Staging, 39, 241 Standard therapy, 230, 241 Stem Cells, 26, 36, 55, 210, 241 Sternum, 135, 241 Steroid, 73, 198, 238, 239, 241 Stimulant, 201, 241 Stimulus, 198, 202, 203, 205, 216, 241, 243 Stomach, 183, 201, 205, 208, 212, 226, 229, 240, 241 Strand, 41, 232, 241 Stress, 3, 27, 37, 38, 40, 46, 48, 58, 74, 81, 90, 104, 131, 194, 227, 241

Striatum, 96, 241 Stroke, 126, 131, 158, 193, 241 Stroke Volume, 131, 193, 241 Stromal, 38, 42, 241 Subacute, 216, 241 Subarachnoid, 58, 211, 242 Subclinical, 91, 216, 242 Subcutaneous, 105, 183, 202, 208, 242, 244 Subspecies, 240, 242 Substance P, 222, 238, 242 Substrate, 16, 204, 208, 242 Sulfur, 200, 206, 242 Superior vena cava, 68, 191, 242 Superoxide, 47, 56, 242 Superoxide Dismutase, 47, 242 Supplementation, 71, 115, 242 Suppression, 32, 34, 52, 132, 198, 242 Suppressive, 29, 242 Survival Rate, 3, 137, 242 Synaptic, 239, 242 Syncope, 109, 242 Systemic, 29, 31, 52, 64, 74, 92, 118, 188, 191, 192, 204, 216, 218, 233, 235, 242, 244, 246, 247 Systolic, 58, 213, 242 T Tachycardia, 201, 242 Tacrolimus, 42, 52, 86, 88, 106, 115, 117, 118, 147, 242 Technetium, 58, 243 Telepathology, 89, 243 Temporal, 44, 106, 243 Testosterone, 236, 243 Therapeutics, 20, 123, 152, 243 Thermal, 201, 226, 232, 243 Thigh, 206, 243 Thioguanine, 133, 243 Thoracotomy, 55, 243 Thorax, 183, 242, 243 Threonine, 229, 230, 239, 243 Threshold, 213, 243 Thrombin, 206, 231, 234, 243 Thrombocytes, 231, 243 Thrombolytic, 231, 243 Thrombomodulin, 115, 234, 243 Thrombosis, 46, 217, 234, 241, 243 Thrombus, 131, 198, 215, 224, 231, 243 Thymus, 55, 196, 214, 220, 243, 245 Thyroid, 213, 226, 228, 243, 245 Thyroid Gland, 213, 228, 243 Tolerance, 6, 12, 19, 22, 23, 25, 29, 31, 33, 46, 50, 51, 55, 64, 78, 183, 210, 238, 244

Index 261

Tomography, 191, 244 Tophus, 83, 244 Topical, 213, 228, 244 Torsion, 216, 244 Toxic, iv, 10, 25, 41, 47, 50, 53, 189, 200, 203, 214, 225, 244 Toxicity, 25, 41, 53, 202, 221, 244 Toxicology, 160, 244 Toxins, 187, 203, 216, 223, 244 Toxoplasmosis, 80, 107, 244 Transcription Factors, 39, 194, 244 Transduction, 5, 15, 46, 239, 244 Transfection, 31, 190, 244 Transfer Factor, 214, 244 Transforming Growth Factor beta, 52, 244 Translocation, 8, 10, 39, 244 Transmitter, 183, 221, 244 Transplantation Immunology, 28, 43, 245 Transplantation Tolerance, 23, 50, 245 Trauma, 5, 65, 211, 225, 236, 245, 247 Trichomoniasis, 222, 245 Triglyceride, 213, 245 Tropism, 14, 245 Tropomyosin, 245 Troponin, 37, 69, 83, 245 Tryptophan, 196, 245 Tuberculosis, 79, 114, 245 Tumor Necrosis Factor, 99, 245 Type 2 diabetes, 169, 245 Tyrosine, 8, 245 U Unconscious, 214, 245 Univalent, 136, 227, 245 Uranium, 243, 245 Urethra, 245 Urine, 10, 124, 133, 190, 199, 200, 201, 245 Ursodeoxycholic Acid, 77, 245 Uterus, 195, 233, 246 V Vaccine, 35, 109, 170, 234, 246 Vacuole, 44, 246 Vagina, 192, 195, 246 Vaginitis, 192, 246 Valproic Acid, 115, 246 Valves, 128, 246 Vascular endothelial growth factor, 24, 57, 246

Vascular Resistance, 79, 85, 185, 246 Vasoconstriction, 201, 204, 246 Vasodilatation, 87, 246 Vasodilation, 80, 214, 246 Vasodilators, 226, 246 Vasopressor, 138, 246 Vector, 5, 36, 129, 244, 246 Vein, 124, 186, 188, 217, 226, 228, 238, 242, 246 Vena, 246 Venous, 95, 188, 234, 246 Ventricle, 58, 128, 188, 214, 235, 242, 246 Ventricular, 10, 26, 31, 58, 62, 73, 75, 77, 83, 91, 102, 105, 110, 116, 131, 185, 202, 224, 246 Ventricular Dysfunction, 10, 26, 77, 105, 202, 246 Ventricular Function, 31, 83, 246 Venules, 191, 193, 204, 222, 247 Veterinary Medicine, 159, 247 Viral, 14, 27, 32, 52, 56, 59, 77, 98, 128, 129, 134, 135, 136, 183, 193, 203, 216, 226, 244, 247 Viral Hepatitis, 77, 98, 247 Viral vector, 52, 129, 247 Virulence, 44, 189, 244, 247 Visceral, 79, 218, 229, 247 Viscosity, 183, 247 Vitro, 9, 19, 39, 43, 53, 55, 59, 247 Vivo, 5, 9, 11, 12, 13, 19, 21, 22, 24, 25, 28, 31, 32, 33, 35, 39, 43, 47, 49, 50, 51, 52, 54, 55, 57, 59, 90, 215, 242, 247 W White blood cell, 187, 219, 220, 223, 224, 226, 231, 247 Withdrawal, 47, 247 Wound Healing, 217, 221, 247 Wound Infection, 104, 247 X Xenograft, 21, 54, 59, 186, 245, 247 X-ray, 131, 186, 191, 207, 218, 226, 235, 236, 247 X-ray therapy, 218, 247 Y Yeasts, 192, 208, 230, 247 Z Zymogen, 234, 248

262

Heart Transplant

Index 263

264

Heart Transplant

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