Long QT Syndrome - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

LONG QT SYNDROME A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

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

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

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Long QT Syndrome: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00671-5 1. Long QT Syndrome-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 long QT syndrome. 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 LONG QT SYNDROME .............................................................................. 3 Overview........................................................................................................................................ 3 Federally Funded Research on Long QT Syndrome....................................................................... 3 The National Library of Medicine: PubMed ................................................................................ 38 CHAPTER 2. NUTRITION AND LONG QT SYNDROME .................................................................... 83 Overview...................................................................................................................................... 83 Finding Nutrition Studies on Long QT Syndrome ..................................................................... 83 Federal Resources on Nutrition ................................................................................................... 84 Additional Web Resources ........................................................................................................... 84 CHAPTER 3. ALTERNATIVE MEDICINE AND LONG QT SYNDROME .............................................. 87 Overview...................................................................................................................................... 87 National Center for Complementary and Alternative Medicine.................................................. 87 Additional Web Resources ........................................................................................................... 90 General References ....................................................................................................................... 91 CHAPTER 4. PATENTS ON LONG QT SYNDROME ........................................................................... 93 Overview...................................................................................................................................... 93 Patents on Long QT Syndrome ................................................................................................... 93 Patent Applications on Long QT Syndrome................................................................................ 95 Keeping Current .......................................................................................................................... 97 CHAPTER 5. BOOKS ON LONG QT SYNDROME............................................................................... 99 Overview...................................................................................................................................... 99 Book Summaries: Online Booksellers........................................................................................... 99 CHAPTER 6. PERIODICALS AND NEWS ON LONG QT SYNDROME ............................................... 101 Overview.................................................................................................................................... 101 News Services and Press Releases.............................................................................................. 101 Academic Periodicals covering Long QT Syndrome.................................................................. 103 CHAPTER 7. RESEARCHING MEDICATIONS .................................................................................. 105 Overview.................................................................................................................................... 105 U.S. Pharmacopeia..................................................................................................................... 105 Commercial Databases ............................................................................................................... 106 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 111 Overview.................................................................................................................................... 111 NIH Guidelines.......................................................................................................................... 111 NIH Databases........................................................................................................................... 113 Other Commercial Databases..................................................................................................... 115 APPENDIX B. PATIENT RESOURCES ............................................................................................... 117 Overview.................................................................................................................................... 117 Patient Guideline Sources.......................................................................................................... 117 Associations and Long QT Syndrome ....................................................................................... 119 Finding Associations.................................................................................................................. 119 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 121 Overview.................................................................................................................................... 121 Preparation................................................................................................................................. 121 Finding a Local Medical Library................................................................................................ 121 Medical Libraries in the U.S. and Canada ................................................................................. 121 ONLINE GLOSSARIES................................................................................................................ 127 Online Dictionary Directories ................................................................................................... 128 LONG QT SYNDROME DICTIONARY................................................................................... 129

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INDEX .............................................................................................................................................. 165

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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 long QT syndrome 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 long QT syndrome, 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 long QT syndrome, 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 long QT syndrome. 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 long QT syndrome, 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 long QT syndrome. The Editors

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

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CHAPTER 1. STUDIES ON LONG QT SYNDROME Overview In this chapter, we will show you how to locate peer-reviewed references and studies on long QT syndrome.

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

Project Title: ACCESS ANTIARRHYTHMICS

PATHS

FOR

SODIUM-CHANNEL

BLOCKING

Principal Investigator & Institution: Lee, Peter J.; Medicine; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 05-AUG-2002; Project End 31-JUL-2007

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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Summary: (provided by applicant): The proposal describes a 5-year plan to study the interaction between antiarrhythmic drugs and cardiac sodium channels with an ultimate goal of obtaining insights for a better pharmacologic intervention for deadly arrhythmia. It also serves as a training program for the development of an academic career for the principal investigator as a physician scientist. The principal investigator has completed cardiology and postdoctoral fellowships under the guidance of Dr. Harry A. Fozzard at the University of Chicago and will proceed to lead an independent program in basic cardiac electrophysiology. Dr. Fozzard, who will continue to mentor the principal investigator's development, is one of the pioneers in modern basic cardiac electorphysiology and has trained numerous fellows and students, who have since become prominent researchers throughout the world. The Advisory Committee of highly regarded basic and clinical scientists will provide both scientific and career guidance. Research program focuses on the paths through which antiarrhythmic drugs bind and unbind the voltage-gated sodium channel to modulate the use-dependent block. The proposal builds on the foundations of prior studies in Dr. Fozzard's and other laboratories and uses the framework developed by the principal investigator recently. The specific aims include; 1) the effects of membrane depolarization, often seen in ischemia, on the drug-channel interaction of lidocaine and related compounds, 2) identification of other drug-paths to better characterize the drug-channel interactions and gain further insights into the structure of sodium channel, 3) examine the drugpaths important for use-dependent activities of other classes of antiarrhythmic drugs, and 4) expand into the preliminary findings suggesting that a long-QT mutation in the sodium channel alters drug-paths and consequently use-dependent properties of certain antiarrythmic drugs. The University of Chicago, an institution of international prominence in medical and basic science provides a rigorous academic environment with extensive resources for fostering a successful academic career. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANALYSIS OF MINK & MIRP REGULATION OF CARDIAC K CHANNELS Principal Investigator & Institution: Mcdonald, Thomas V.; Professor; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2004; Project Start 15-DEC-2003; Project End 30-NOV-2007 Summary: (provided by applicant): There is increasing awareness of the importance of ion channel accessory proteins in regulating heart rhythm. MinK and the related MiRPs are K+ channel regulators encoded by the KCNE family of genes. They can interact with the two Long QT-associated delayed rectifiers (HERG and KvLQT1 ), pacemaker channels (HCNs) and a variety of voltage gated K+ channels. Their importance is underscored by linkage to hereditary Long QT syndrome and single nucleotide polymorphisms that may sensitize patients to drug-induced arrhythmias. KCNEs each encode small integral membrane proteins with a single transmembrane segment suggesting that they interact with K+ channels in homologous fashion. Their sequence homology however, is fairly divergent with only scattered areas of conservation. Mutations have shown us several of the important sites in KCNE1 & 2 required for function. Controversy remains regarding structure-function relations, stoichiometry and specific protein-protein interactions in vivo. By studying the precise mechanisms of KCNE-channel interaction, a deeper understanding of LQTS, drug-induced and acquired arrhythmias may be gained. To this end we propose to: 1) Determine the specific regions of KvLQT1 and HERG that physically and functionally interact with minK and/or MiRPs. 2) Determine the relative preferences in partners between

Studies

5

minK/MiRPs and HERG or KvLQTI. 3) Determine channel complex stoichiometry using epitope-tagged KCNEs and chimeras in biochemical and electrophysiological studies. 4) Analyze the co-expression pattern of minK/MiRPs against that of HERG and KvLQT1 and their association in cardiac myocytes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CA HANDLING & ARRHYTHMIAS ASSOCIATED WITH LQT SYNDROME Principal Investigator & Institution: Laurita, Kenneth; Co-Director & Assistant Professor; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 30-NOV-2005 Summary: (provided by applicant): Long QT syndrome (LQTS) is a genetic disease characterized by prolonged QT interval and a high incidence of sudden cardiac death (SCD). Despite recent advances in our understanding of the genetic and molecular abnormalities underlying LQTS, the mechanistic relationship between such abnormalities and SCD is not well understood. In patients with LQTS, episodes of syncope and SCD are caused by torsade de pointes (TdP), where afterdepolarizations are believed to play a critically important role. Abnormal management (i.e. handling) of intracellular calcium has been implicated as an important mechanism of afterdepolarizations, including afterdepolarizations that are enhanced by Calcium/calmodulin-dependent protein kinase II (CaM kinase). We hypothesize that heterogeneities of calcium handling are present normally and are enhanced by electrophysiological changes that occur in LQTS. As a result, regional "hot spots" of abnormal calcium handling develop that are prone to the formation of early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs). It is further hypothesized that the location and timing of afterdepolarizations and their interaction with transmural repolarization gradients can critically influence the initiation of TdP. The specific aims of his proposal are to: 1) Determine the regional differences (i.e. heterogeneities) of intracellular calcium handling and action potential duration across the ventricular transmural wall that occur normally and in models of LQTS (i.e. LOT1, LQT2, LQT3). 2): Determine the cellular/molecular mechanisms of calcium handling heterogeneities that occur normally by measuring the level of calcium regulatory protein expression under control conditions. 3) Determine the cellular/molecular mechanisms of enhanced heterogeneities of (i.e. abnormal) intracellular calcium handling and afterdepolarization in models of acquired LQTS, where calcium release from the sarcoplasmic reticulum and CaM klnase are important mechanisms. 4) Determine the mechanistic relationship between the regional occurrence of EADs, repolarization gradients, and episodes of TdP in all three models of acquired LQTS, with an emphasis on the mechanisms of initiation by pauses in cycle length. New optical mapping techniques developed and validated by the PI to measure transmembrane potential and intracellular calcium simultaneously from 256 sites across intact heart preparations will be used. A major advantage of this experimental system is that multiple cellular parameters can be measured during arrhythmia initiation, providing the unique ability to bridge cellular and molecular abnormalities with arrhythmias that are a consequence. The long term objectives of this study are to determine the mechanistic relationship between abnormal intracellular calcium handling and arrhythmias associated with LQTS (i.e. TdP). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Long QT Syndrome

Project Title: CARDIAC CHANNEL MUTATIONS IN SIDS Principal Investigator & Institution: Ackerman, Michael J.; Assistant Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 07-JUN-2002; Project End 31-MAY-2006 Summary: (provided by applicant): Michael J. Ackerman, M.D., Ph.D. is a board eligible pediatric cardiologist and an Assistant Professor of Medicine, Pediatrics, and Molecular Pharmacology & Experimental Therapeutics at Mayo Medical School. Dr. Ackerman is a physician-scientist directing a sudden death genomics laboratory and the Long QT Syndrome Clinic. His long-term objectives are to identify the underlying causes of sudden cardiac death in infants, children, adolescents, and young adults. In this proposal entitled Cardiac Channel Mutations in Sudden Infant Death Syndrome, the applicant sets forth to answer the fundamental question: what percentage of infants suffering a SIDS death possessed putative disease-causing mutations in the genes encoding their cardiac ion channels? Presently, SIDS continues to claim nearly 3000 apparently healthy infants each year in the United States. The fundamental causes underlying SIDS remain poorly understood. In specific aim 1, Dr. Ackerman will perform a mutational analysis of the 5 cardiac channel genes already implicated in a human arrhythmia syndrome, namely congenital long QT syndrome using temperature modulated heteroduplex analysis and denaturing high performance liquid chromatography. In specific aim 2, two non-LQTS arrhythmia syndrome ion channel genes will be investigated by mutational analysis as novel candidate SIDS genes. Finally, in specific aim 3, the possible mutations in the channel genes identified in aims 1 and 2 will be characterized functionally. These mutations will be engineered by site-directed mutagenesis into the wild type channel, expressed in transient and stable transfection cell lines, and characterized using single electrode patch clamp technologies. If the applicant's hypothesis is correct that 10% of infants with SIDS possess cardiac channel mutations, then cardiac channel genes would account for the "underlying vulnerability" for the largest identifiable subset of infants to date. Such a discovery could have significant implications on attempts to further reduce the incidence of SIDS in our country and throughout the world. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CARDIAC EXCITATION AND ARRHYTHMIAS Principal Investigator & Institution: Rudy, Yoram; Professor; Biomedical Engineering; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-FEB-1993; Project End 31-JAN-2003 Summary: (Adapted from the Investigator's Abstract) Abnormalities of the cardiac excitation process that result in cardiac arrhythmias continue to be a major cause of death and disability. In spite of important recent advances in understanding this process (notably, at the molecular level of membrane ion-channels), the mechanisms that underlie arrhythmogenic activity remain incompletely understood. Consequently, treatment (by drugs or non-pharmacological interventions) remains largely empirical with unpredictable outcome in many cases. The overall objective of this project is to further the understanding of mechanisms that underlie cardiac excitation and arrhythmias, and of principles behind interventions that lead to arrhythmia termination and prevention. It is the premise that understanding of mechanisms is imperative to the development of better treatment and prevention of sudden death. As in the previous period of support, the approach is to study these phenomena through the use of theoretical, computer models in close conjunction with experimental observations.

Studies

7

Specific aims are: (1) To develop a model of the cardiac ventricular action potential based on kinetic description of single ion channels. (2) To characterize, using this model, the cellular electrophysiologic consequences of channel-function alteration associated with the Long QT Syndrome. (3) To study the ionic basis of myocardial cellular heterogeneity and its electrophysiologic consequences. (4) To study the effects of regional tissue inhomogeneties (in membrane excitability or tissue architecture) on action potential propagation. (5) To characterize the properties of reentrant propagation and the processes of initiation and termination of reentry in the anisotropic myocardium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CARDIAC POTASSIUM CHANNEL SUBUNITS AND SUDDEN DEATH Principal Investigator & Institution: Tristani-Firouzi, Martin; Pediatrics; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-JUN-1998; Project End 31-MAY-2004 Summary: (Adapted from applicants' abstract) Background: sudden cardiac death is an important cause of cardiovascular mortality in the United States. The long QT syndrome (LQT) is an inherited disorder associated with ventricular arrhythmias and sudden death. Mutations in the gene KVLQT1 cause the most common form of inherited LQT. KvLQT1 proteins coassemble with a regulatory subunit, minK, to form the slowly activating cardiac delayed rectifier (Iks) channel. Iks is an important modulator of cardiac repolarization, and as such, reductions in Iks may promote arrhythmia susceptibility. The goals of this proposal are: (1) To characterize the molecular interactions between Iks channel subunits and (2) To define the molecular pathogenesis of LQT-associated mutations in KVLQT1 and hminK. The studies will be performed using cloned human minK and KvLQT1 proteins heterologously expressed in Xenopus oocytes. Significance: Insight into the molecular pathogenesis of LQT and the molecular mechanisms of K+ channel regulation will facilitate development of novel treatment strategies for life-threatening arrhythmias. Environment: The University of Utah is a preeminent research institution in the field of cardiac ion channel research and the molecular genetics of LQT. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CELLULAR & CLINICAL PHENOTYPES OF NOVEL SCN5A MUTATIONS Principal Investigator & Institution: Makielski, Jonathan C.; Professor of Medicine and Physiology; Medicine; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): SCN5A encodes the alpha subunit of the human voltage-dependent Na channel (hNaV1.5) found in heart. We have made the novel observation that up to four very common variants of NaV1.5 exist in human heart and at least some have functional implications. Mutations in this channel also cause sudden cardiac death in the congenitally acquired long QT syndrome (LQT3) and the Brugada Syndrome (BS). We have recently characterized four novel SCN5A mutations and found: 1) Two in Sudden Infant Death Syndrome (A997S, R1826H) are LQT3.2) LQT3 (M1766L) and BS (G1743) mutations have expression defects "rescued" by antiarrhythmic drugs. 3) M1766L has normal or absent current depending on the variant

8

Long QT Syndrome

NaV1.5 background used to test it. We propose to investigate further the extent and mechanisms of expression defects and their "rescue" and the importance of "background". Through collaboration with Dr. Ackerman at Mayo Clinic we also have >20 additional novel SCN5A mutations to investigate for novel functional defects and arrhythrnia mechanism. We will make and express these channels in cell culture, define function by voltage clamp and immunocytochemistry, and correlate molecular function with clinical phenotype through arrhythmia mechanism. In Aim 1 we will investigate the expression and function of wild type variants, and also how mutant channel expression and function depends upon the background clone. In Aim 2 we will study novel mutants. In Aim 3 we will investigate mutants with "gain of function" and test the hypothesis that late current decay in LQT3 correlates with enhanced rate dependent QT interval adaptation, later onset, and better prognosis than mutations without late current decay. In Aim 4 we will investigate mutations with "loss of function", the mechanism for loss of function including novel trafficking defects, and test the hypothesis that this loss can be "rescued" by drugs. In Aim 5 we will co-express mutations with the beta1 and beta3 subunit, and assess effects of PKA stimulation, to test the hypothesis that these areas are critical to the mechanism of action. These studies on the novel findings will have implications for arrhythmia mechanism and genotypephenotype correlation in both mutation arrhythmia syndromes and more generally for the variants in "normal' hearts that may generate insight into genetic predisposition to acquired arrhythmia. At a more basic level these "natural" experiments will contribute to understanding the structure-function relationship of this important channel. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELLULAR ELECTROPHYSIOLOGY OF REPOLARIZATION Principal Investigator & Institution: Spitzer, Kenneth W.; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002 Summary: The overall objective of this project is to obtain new insight concerning the cellular aspects of ventricular repolarization and their relationship to intracellular Ca2_ regulation and electronic interactions. Studies will be performed on left ventricular myocytes from both normal and disease hearts. Project 3 contains three subprojects. Subproject 3.1 focuses on repolarization abnormalities in myocytes surviving chronic myocardial infarction (post-MI myocytes). The experiments are designed to determine the ionic basis of post-MI-induced changes in repolarization and their reversal by the thyroid hormone analogue, DITPA. The central hypothesis is that repolarization abnormalities and their recovery are mediated by changes in I/Kp Ca2+ uptake by the sarcoplasmic reticulum (SR), I/Ca and I/NaCa. Voltage clamping and fluorescence measurements of intracellular Ca2+ (Ca/i) (confocal and conventional epifluorescence) will be used to test this hypothesis. Subject 3.2 focuses on the relationship between Ca+ influx and triggered Ca2+ release from SR. The central hypotheses is that conditions which promote Na+ entry, as occur in one inherited form of the long QT syndrome, will increase the gain of excitation-contradiction coupling and thus promote Cai-induced arrhythmias. Voltage clamp and fluorescence techniques will be used to test this hypothesis in myocytes exposed to anthopleurin-A which prolongs I/Na inactivation. Subproject 3.3 focuses on the relationship between intercellular communication and repolarization. The central hypothesis is that cell-cell electrical coupling during repolarization modulation action potential propagation and the formation of early afterdepolarizations. This hypothesis will be tested with an electronic circuit which enables

Studies

9

us to electrically connect physically separate myocytes with a variable resistance and thus simulate in vitro change in gap functional resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CENTER FOR EDUCATION AND RESEARCH ON THERAPEUTICS Principal Investigator & Institution: Woosley, Raymond L.; Vice President for Health Sciences; Medicine; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 29-SEP-2007 Summary: (PROVIDED BY APPLICANT):During the initial three years of the Georgetown CERT (GUCERT) the program studied adverse drug interactions (ADIs), particularly those that result in drug-induced cardiac arrhythmias for which women are at increased risk. These original studies have identified new potentially lethal interactions and fostered awareness of ADIs across a wide array of drug classes. Healthcare providers have been unable to prevent ADIs in practice and we have found that curricula of medical schools and medicine residencies contain little information to prepare them to prescribe in ways that avoids harm from ADIs. GUCERT has developed curricula and aides to instruct providers on the range of potential ADIs, and is currently implementing and evaluating these educational programs. With the move to the Arizona Health Sciences Center, the new AzCERT continues the study of drug-drug interactions that result in arrhythmias. The web-based registry, www.QTdrugs.org, continues as the mechanism for initiating these studies. A major finding with life-saving potential is the observation that methadone can induce lethal ventricular arrhythmias. Mechanistic studies performed by AzCERT investigators now make it possible to test preventive measures. Newly proposed projects in this application will include a clinical study of the predictors of methadone-induced QT prolongation. The transition of the GUCERT to the AzCERT creates opportunities to expand the definition and scope of our research and convey this knowledge to healthcare providers and consumers in the multicultural context of the southwest. Our knowledge of the potential contributing factors for ADIs is expanding dramatically and this poses a substantial challenge for all healthcare providers. Our experience during the initial three years has shown that drug interactions must be approached on multiple fronts. We now fully recognize that drug interactions can occur due to systemic failures in which consumers and multiple providers are independently managing therapeutics. Substitution of prescribed drugs, addition of non-prescription, herbal or neutraceutical therapies, and modification of dosing regimens by patients are common. The risk of adverse outcomes grows when providers and consumers do not openly communicate and share in the management of therapies. AzCERT will employ laboratory, clinical and health services research using our broader systemic definition of drug interactions. The entire healthcare delivery system will be examined for weaknesses and potential improvements that are designed to prevent drug-drug and drug-herbal ADIs. Of equal importance, AzCERT will address the provider-consumer dialogue and develop health communication models to minimize risks from these more broadly defined ADIs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CHEMICAL BASIS FOR POTASSIUM CHANNEL MODULATION Principal Investigator & Institution: England, Pamela M.; Pharmaceutical Chemistry; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2003; Project Start 15-JUL-2003; Project End 30-JUN-2007

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Long QT Syndrome

Summary: (provided by applicant): Ion channels are a class of proteins that play critical role in cellular signaling by mediating the excitability of cells. This activity of ion channels is not static, but constantly changes in response to various intracellular and extracellular signals and, in recent years, many of the factors that directly modulate the activity of ion channels have begun to be identified. Understanding the chemical basis for how the activity of these proteins is modulated represents one of the most important areas of modern science as it impacts our understanding of how the nervous system works as well as our ability to pharmacologically manipulate it. The proposed research seeks to characterize several potential modes of modulation of the human ether-a-go-go related gene (HERG) ion channel, a voltage-gated potassium channel found in brain and heart. The activity of HERG channels is modulated by oxygen (02) and reactive oxygen species (ROS) in vitro and it has been proposed that HERG channels function as direct sensors of O2/ROS in vivo. The hypothesis that O2/ROS sensing by HERG channels is mediated by the reversible oxidation of methionine residues within the channel will be evaluated by characterizing the biophysical effects of site-specifically incorporating methionine sulfoxide into the channel on channel biophysics. HERG channel activity is also modulated by various classes of small molecules in vivo. In all but a few cases, the binding site(s) for these compounds have not been identified, however. The hypothesis that small molecules modulate the activity of HERG channels by binding to the Nterminal (PAS) domain will be evaluated using NMR spectroscopy (to detect structural perturbations associated with ligand binding) and electrophysiology (to define biophysical changes associated with ligand binding). Finally, HERG channel activity also appears to be modulated by various protein-protein interactions. To determine the site(s) in HERG that interact with other proteins, photoreactive amino acids capable of forming protein cross-links will be site-specifically incorporated into the HERG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHROMOSOME 7 LINKED LONG QT SYNDROME PHASE II Principal Investigator & Institution: Ethridge, Susan P.; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLINICAL USE OF RESEARCH GENETIC TESTS IN ARRHYTHMIA Principal Investigator & Institution: Freund, Carol L.; Pediatrics; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2003; Project Start 08-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Clinicians and patients often seek to determine the cause of disease, particularly when they believe that knowing the cause will affect management. Both scientific and public media, with their focus on genetics and the promise of individualized medicine, have heightened expectations that greater understanding of genetic information will improve health outcome. At the same time, many bodies, including most recently the Secretary's Advisory Committee on Genetic Testing, have cautioned against the too rapid adoption of genetic testing, calling for evidence of analytic validity, clinical validity, clinical utility, and social implications prior to the inclusion of genetic tests in clinical practice. Anecdotal evidence suggests that there can be a substantial gap between what clinicians and patients desire and what is thought to be appropriate practice. We propose to explore this gap. Our initial

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paradigms for this exploratory grant are Long QT and Brugada syndromes, which often present as sudden death, outcomes that can sometimes be averted by medical intervention. These disorders are genetically complex and as yet incompletely understood and so do not meet general criteria for clinical use. We seek to understand why clinicians nonetheless seek genetic testing for these disorders, and why investigators sometimes provide it. The results of this inquiry will provide insight into how likely it is that clinicians and researchers will adhere to the recommendations of bodies such as the SACGT and legal requirements such as CLIA, insights that could inform the regulatory approach. We also plan to develop instruments that could then be applied to other genetic tests as well to obtain a fuller understanding of the way genetic research is actually translated into practice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOSKELETAL BASIS OF VENTRICULAR ARRHYTHMIAS Principal Investigator & Institution: Vatta, Matteo; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-JUN-2006 Summary: (provided by applicant): Sudden cardiac death accounts for more than 300,000 deaths in the United States alone. Arrhythmias due to primary structural diseases such as dilated cardiomyopathy (DCM) followed by other non-structural cardiac diseases, such as long QT syndrome (LQTS) and Brugada syndrome (BS) must be considered as likely causes of sudden cardiac death. Cytoskeletal proteins such as dystrophin, the major link between the sarcomere and the sarcolemma in cardiac cells, have been involved in sudden cardiac death. Other dystrophin associated proteins, such as alpha1-syntrophin, when altered, could fail to provide correct anchorage and localization for ion channels on the plasma membrane. We hypothesize that alpha1syntrophin mutations can cause both ventricular dysfunction and arrhythmias. In particular our aims are: 1) to evaluate for genetic abnormalities in alpha1-syntrophin as causing DCM, LQTS and BS. We hypothesize that alpha1-syntrophin mutations cause DCM, LQTS and BS. Specific Aim #1: To evaluate for genetic abnormalities in alpha1syntrophin as determinants of ventricular arrhythmias with or without structural damage. Specific Aim #2: To perform functional analysis in alpha1-syntrophin mutant models of cardiomyopathy and ventricular arrhythmias. Specific #3: To evaluate the effect of mechanical unloading on cardiac reverse remodeling in alpha1-syntrophin mutant models. We will screen alpha1-syntrophin gene for mutations in 200 DCM, LQTS and 100 BS probands. We expect to identify mutations in alpha1-syntrophin as the cause of DCM, LQTS and BS; 2) to perform functional analysis in alpha1-syntrophin mutant models of DCM, LQTS or BS. We hypothesize that alpha1-syntrophin mutations cause protein structural changes leading to cytoskeletal network disruption and ion channels displacement. Identifying cytoskeletal mecahnisms involved in malignant arrhythmias, could lead to the design of novel drugs and the employment of therapeutic means, resulting in a better patients management. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEFECTIVE TRAFFICKING MECHANISMS IN A CARDIAC K+ CHANNEL Principal Investigator & Institution: Kupershmidt, Sabina; Pharmacology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007

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Long QT Syndrome

Summary: (provided by applicant): The Long QT Syndrome (LQTS) is a cardiovascular disorder characterized by an abnormality in cardiac repolarization leading to a prolonged QT interval on the ECG. Three of the five genetic loci known to cause the inherited form of the disease code for cardiac potassium channel subunits. One is the Human-ether-a-go-go-related-gene product (HERG) underlying the fast component of the cardiac delayed rectifier IKr. HERG-associated LQT mutations can result either in dysfunctional channels at the plasma membrane, or in incompletely processed channels retained in the endoplasmic reticulum (ER) and then targeted for degradation by ERresident quality control mechanisms. The forward trafficking of ion channels and other multimeric protein complexes can be regulated through assembly-dependent masking of specific ER retention motifs. One recently identified retention motif found in several membrane protein complexes, is 'RXR' where 'R' is arginine and 'X' can be any amino acid. Our preliminary data indicate that RXR is an important regulator of plasma membrane expression of HERG as well. We found that truncation of 147 amino acids from the distal C-terminus of HERG results in the loss of IKr However, IKr could be restored by deleting an RXR signal immediately upstream of the truncated C-terminus. The central hypothesis of our proposal is that the C-terminus of HERG influences IKr by controlling the rate of HERG trafficking through RXR ER retention signals. Thus, Cterminal LQT truncation mutations reduce the number of HERG channels at the membrane because they expose consensus RXRs recognized by the ER quality control system. To test this hypothesis, we have formulated three Specific Aims: 1. To test whether the exposure an RXR signal in HERG C-terminal LQT mutations leads to an IKr defect due to ER retention. We will determine the effect on HERG trafficking of eight RXR signals in the C-terminus. We will further test whether those RXRs cause defective trafficking of associated downstream LQT mutations. 2. To test if decoy peptides can rescue RXR-dependent ER retention mutants. Following up on our findings that RXRdependent intracellular retention of HERG can be reversed by treatment with specific peptides, we will develop peptide-based approaches to alleviate ER retention defects of HERG LQT mutations. 3. To identify the mechanism that permits HERG trafficking. We will investigate the role played by the HERG distal C-terminus in masking an upstream RXR, whether shielding of the RXR is accomplished by an intra- or an intermolecular mechanism. This study will explain important aspects of the biogenesis, intracellular processing, and trafficking of an important cardiac K+ channel. We will develop novel therapeutic strategies designed to correct intracellular processing steps of HERG and possibly other plasma membrane proteins that suffer from defects caused by the same mechanism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DETERMINANTS OF CARDIAC REPOLARIZATION Principal Investigator & Institution: January, Craig T.; Professor of Medicine; Medicine; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: The rapidly activating delayed rectifier K- current (IKr), and the human ether-a-go-related gene (HERG) thought to encode it, play a key role in cardiac repolarization, and mutations in HERG cause congenital long QT syndrome (LQT-2). HERG, IKr and LQT-2 will be studied using molecular and electrophysiological techniques in transfected HEK293 cells and native rabbit myocytes. Specific aim 1 is to study cellular mechanisms of ion channel processing of HERG wild type and LQT-2 mutant channels. We have previously identified normal steps in the processing mechanism for HERG protein as well as abnormal processing for some LQT-2 mutants.

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We will extend these observations by testing three hypotheses: a) the failure of some LQT-2 mutants to function normally involves defects in multiple processing steps, b) coexpression of the minK or minK-related subunits modifies HERG wild type and LQT-2 protein trafficking, c) co-expression of wild type HERG protein with minK LQT mutations (LQT-5) alters the expression of HERG current. We will identify the steps where this occurs. Specific aim 2 is to study cell processes that modify HERG protein production and degradation. We will test the hypothesis that LQT-2 mutant proteins are degraded rapidly, compared with wild type HERG protein, which is of particular importance for newly described LQT-2 mutant channels that form functional channels. Such an increased turnover, if demonstrated, would be a novel mechanism for the expression of the LQT-2 phenotype. We will also test the hypothesis that N- linked glycosylation is a determinant of the stability of expressed HERG protein. We will test the effects of temperature as a determinant of the success and efficiency of trafficking of LQT-2 mutant channels to the surface membrane, and we will identify additional cell processes that might modify HERG protein trafficking. Specific aim 3 is to study the mechanisms of co- assembly of wild type HERG with LQT-2 mutant channel subunits. We will test the hypothesis that protein trafficking abnormalities alter expression of the dominant negative effect. We will test what role, if any, minK, minK-related, and minK mutant (LQT-5) channels have in modifying this. This research will increase our knowledge of molecular mechanisms of ion channel processing and function of HERG and more generally will have implications for all ion channels. More specifically it will have particular relevance to mechanisms of the human disease LQT-2. Elucidating mechanisms in these areas in important in developing new strategies for understanding normal and abnormal arrhythmogenesis and for new strategies for anti-arrhythmic therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ELECTRICAL HETEROGENEITY AND CARDIAC ARRHYTHMIAS Principal Investigator & Institution: Antzelevitch, Charles; Masonic Medical Research Laboratory, Inc 2150 Bleeker St Utica, Ny 13501 Timing: Fiscal Year 2002; Project Start 01-MAY-1993; Project End 31-AUG-2005 Summary: Recent studies by our group and others have demonstrated that ventricular myocardium is not homogeneous as previously thought, but is comprised of at least three electrophysiologically and functionally distinct cell types: epicardium, endocardium and a unique population of cells that we termed M cells, displaying characteristics intermediate between those of ventricular myocardial and Purkinje cells. The three cell types differ with respect to early and late repolarization characteristics. These distinctions have been shown to underlie the various waveforms of the ECG and when amplified create the substrate for the development of life-threatening ventricular arrhythmias, including the polymorphic ventricular arrhythmias associated with the long QT and Brugada syndromes. We and others have recently reported that both syndromes may also be responsible for sudden death in children and infants and may contribute at some level to sudden infant death syndrome (SIDS). Our basis for understanding the mechanisms involved are hampered by the near total absence of data regarding the developmental aspects of electrical heterogeneity in ventricular myocardium of larger mammals. An urgent need to close this gap in our knowledge is the motivating force and the principal aim of this competing renewal. Our objectives are to define the developmental stages at which these heterogeneities normally arise in the canine heart and to probe how ion channel defects known to contribute to the long QT and Brugada syndromes may intervene to disrupt the normal electrical function of the

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Long QT Syndrome

heart and set the stage for malignant arrhythmias in the early stages of life. Our principal goals are to probe the extent to which electrical heterogeneity exists within the heart at each stage of development, to identify the underlying mechanisms as well as the conditions and interventions that amplify or diminish the intrinsic differences in regional electrical behavior and to examine to what extent transmural electrical heterogeneity is responsible for developmental changes in the ECG. To achieve these goals, we propose to use a multilevel approach designed to provide and integrate voltage clamp and action potential data from isolated myocytes, tissues and arterially perfused canine ventricular wedge preparations. Our long-range goal is to generate information that will contribute to our understanding of the causes for arrhythmic death in infants and young children. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EVALUATION OF THE NA+ CHANNEL OUTER VESTIBULE Principal Investigator & Institution: Dudley, Samuel C.; Associate Professor; Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 10-JUN-2000; Project End 31-MAY-2005 Summary: The voltage-gated Na+ channel is the central determinant of muscle excitability. There are seven human disorders associated with gene defects in the Na+ channel or its subunits including the Long QT Syndrome and idiopathic ventricular fibrillation. Drugs that act upon Na+ channels including anticonvulsants, local anesthetics, and antiarrhythmic agents. The aim of the proposed project is to test, refine, and expand a molecular model of the outer vestibule and selectivity filter of the Na+ channel as part of larger effort to understand the structural biology of this channel. Detailed structural information will be necessary to fully understand the function of the channel, to engage in rational drug design, and to consider the possibility of protein engineering in conjunction with gene therapy to ameliorate genetic diseases linked to the Na+ channel. The hypothesis being tested is that a detailed molecular model of a complementary binding surface can be constructed by determining sufficient ligand/substrate interaction points using several ligands of known structure. The experiments will evaluate, refine, and expand a previously described Na+ channel outer vestibule model by testing predictions about the points of interaction with high affinity ligands that bind in this area. The approach is general for ligand/receptor interactions, and an analogy for this approach would be a lock and key where the ligands are the keys and the Na+ channel is the lock. The structure of the lock is determined by looking at the shape of the keys. Specifically, points of interaction between channel amino acids and the ligands will be determined using mutant cycle analysis. The shape of the ligands and the points of interaction are used as constraints when refining computer-generated models of the binding surface. Multiple toxins will used to probe as much of the outer vestibule as possible, to serve as validation of results obtain with other ligands, and to develop sufficient interaction points to constrain adequately the model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FACTORS THAT INITIATE ARRHYTHMIAS IN LONG QT SYNDROME Principal Investigator & Institution: Salama, Guy; Professor; Cell Biology and Physiology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-FEB-1998; Project End 31-JAN-2003

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Summary: (Adapted from applicant's abstract): Patients with congenital and acquired Long QT Syndrome (LQTS) have a high risk for Torsade de Pointe (a variant of polymorphic ventricular tachycardia, VT) and sudden death. A hallmark of LQTS is a prolonged QT interval, a prelude to VT. A number of electrophysiological and cellular abnormalities have been associated with LQTS. Enhanced Dispersion of Repolarization (DR) has been invoked as the arrhythmogenic mechanism based on measurements of QT intervals and T wave changes. Electrode recordings suggest that early afterdepolarizations (EADs) are coincident in time with extra-systolic responses that initiate VT. In turn, EADS can be induced by interventions that increase action potential (AP) durations (APDS) and/or increase cytosolic (Ca+2),; Cai causing cell depolarization. Key to all these issues are the heterogeneities of APDs and Cai transients from cells in different regions of the heart. Other factors may be important to precipitate VT in LQTS, such as Cai load, serum K+, and autonomic imbalance. These mechanisms are poorly understood and remain a matter of conjecture. The aims are: 1) To develop an optical system to simultaneously map APs, DR, and Cai transients by staining hearts with voltage-sensitive and Cai indicator dyes; 2) To develop models of drug-induced LQTS in rabbits using Anthopluerin A (AP-A) and d-Sotasol and characterize the models by mapping APs, Cai and correlating EADS to changes in Cai. Optical maps from different regions of the heart (e.g., the Purkinje fibers on the endocardium, the epicardium and midwall) will identify the sites with the greatest propensity to EADs and/or Cai anomalies. 3) To determine the factors that precipitate LQT-induced arrhythmias by altering the myocardial substrate, interventions (e.g., serum K+, Cai load, alpha and/or beta-agonists) known to increase the incidence of VT in the clinical setting will be applied uniformly in the heart through the coronary perfusate or locally by microinjections at selected sites on the heart to provoke VTs. The project addresses important questions given the high risk of sudden death in patients with LQTS. It will test basic hypothesis that QT prolongation enhances a) the DR, b) the incidence of EADs, c) that the conduction of EADS provokes VT and d) that intervention(s) applied at key sites are needed to trigger EADs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC MODIFIERS OF CONGENITAL LONG QT SYNDROME Principal Investigator & Institution: George, Alfred L.; Director, Division of Genetic Medicine a; Medicine; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant): Ventricular arrhythmias remain the single most important cause of sudden cardiac death (SCD) among adults living in industrialized nations. Genetic factors have substantial effects in determining population-based risk for SCD and may also account for interindividual variability in susceptibility. Great progress has been made in identifying genes underlying various Mendelian disorders associated with inherited arrhythmia susceptibility. The most well studied familial arrhythmia syndrome is the congenital long QT syndrome (LQTS) caused by mutations in genes encoding subunits of myocardial ion channels. Not all mutation carriers have equal risk for experiencing the clinical manifestations of the disease (ie: syncope, sudden death). This observation has raised the possibility that genetic factors other than the primary disease-associated mutation can modify the risk of LQTS manifestations. This proposal outlines an international collaboration designed to investigate the role of candidate modifier genes in determining disease expression in a unique founder population of 17 LQTS families in South Africa. We hypothesize the existence of two

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Long QT Syndrome

types of modifier genes: genes which affect the magnitude of the underlying myocardial arrhythmia substrate, and genes which affect the propensity for triggering events acting through the autonomic nervous system. The primary goals of the study include further ascertainment and extension of the identified pedigrees and to assess a variety of surrogate clinical markers of autonomic function in mutation carriers (Specific Aim 1), to examine multiple candidate modifier genes for their association with symptomatic and asymptomatic disease (Specific Aim 2), and to test the hypothesis that variable transcriptional control of the primary disease gene (KCNQ1) impacts on arrhythmia susceptibility (Specific Aim 3). Identification of LQTS modifiers will enhance our understanding of the pathophysiology of LQTS, provide new and valuable information for counseling patients with this disorder, and will contribute to our understanding of more common arrhythmia syndromes associated with highly prevalent cardiac diseases (e.g. ischemic heart disease and congestive heart failure) that are burdened by a high incidence of SCD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC REGULATION OF MATING BEHAVIOR IN C. ELEGAN MALES Principal Investigator & Institution: Garcia, Luis R.; Biology; Texas A&M University System College Station, Tx 778433578 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): The goal of this project is to understand how a step in a complex behavior is genetically specified. This fundamental problem will be addressed by studying C. elegans male mating behavior. During mating, the male executes a series of stereotyped sub-behaviors that result in the insertion of his copulatory spicules into his mate and the subsequent transfer of sperm. Although C. elegans male mating behavior consists of many steps, this project will focus on dissecting how the male inserts his spicules into his mate's vulva. Spicule insertion behavior is a simple reflex; however, the male nervous system and musculature must regulate many factors. The neurons and muscles must compute when to initiate the behavior and monitor if the behavioral outcome was successful. If an insertion attempt fails, the circuitry must re-initiate the behavior. If penetration is successful, the circuitry keeps the spicules inserted while the next behavioral step proceeds. Males display spicule insertion behavior only during mating. However, mutations can be generated that will cause males to display this behavior abnormally in the absence of mating cues. One of these mutations disrupts the C. elegans unc-103 gene. Unc-103 is the C. elegans homolog of the human h-erg-encoded voltage-gated delayed rectifying K+ channel. In humans, HERG channels regulate cardiac rhythm. Mutations in h-erg that reduce ion channel function can increase the probability of spontaneous lethal heart arrhythmias, a condition called long QT syndrome. Spicule insertion behavior requires coordination between different neurons and muscles. Mutations in unc-103 disrupt that regulation and result in spontaneous seizures of male-specific muscles that are used for copulation. To understand how unc-103 is used to regulate behavior, this project will identify where unc-103 is acting in the behavioral circuitry of males. The project will also determine the identities of mutations that affect candidate genes that may act with or in parallel to unc103 to regulate behavior. Additionally, this project will identify components of activating pathways that must be attenuated by unc-103 during periods between mating. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC SUSCEPTIBILITY IN ACQUIRED LONG QT SYNDROME Principal Investigator & Institution: Murray, Katherine T.; Associate Professor; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HEART AND MUSCLE K+ CHANNELS: ASSEMBLY AND REGULATION Principal Investigator & Institution: Koren, Gideon; Director, Bioelectricity Laboratory; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 08-AUG-1991; Project End 31-JUL-2004 Summary: In excitable cells, voltage-gated K+ channels play an important role in regulating the duration of the action potential. The long-term objective of our research program is to elucidate the mechanisms that regulate cardiac cell excitation. We hypothesize that the cardiac myocytes can respond to prolongation of action potential duration (ADP) by turning on the expression of potassium channel genes that shorten the repolarization period. This compensatory response may be a key to limiting the extent of the prolongation of the ADP and QT intervals. The aims of this proposal are to create mouse models to study electrical remodeling and elucidate the molecular mechanisms that control and regulation the expression of cardiac voltage-gated potassium channel genes. Specifically, the plan over the next five years is: (1) To create mouse models with combined deficiency of several outward potassium currents and to elucidate the molecular basis of the reentrant arrhythmias observed in mice overexpressing KV1.1N206Tag in the heart. (2) To elucidate the mechanisms which regulate the tissue-specific and the level of expression of Kv1.5. To characterize two novel transcription factors (KBF1 and KBF2) that bind to a silencer element (KRE) located in the promoter of Kv1.5. (3) To assess the biological role of KBF1 and KBF2 in the heart. In addition to contributing to our understanding of the basic mechanisms underlying cardiac excitation, these studies may be relevant to the development of new therapy to long QT syndrome and cardiac arrhythmias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INHERITED ION CHANNEL DEFECTS IN ARRHYTHMIAS Principal Investigator & Institution: Grant, Augustus O.; Associate Professor; Medicine; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 05-DEC-2001; Project End 30-NOV-2005 Summary: (provided by applicant): Cardiac arrhythmias account for some 300,000 deaths in the US annually. Although the inherited arrhythmias comprise a small part of the problem, they have proved crucial as models for examination of more complex arrhythmias and have provided important insight into the specific role played by various ion channels in the control of cardiac excitability. This proposal has four specific aims related to the inherited arrhythmias. 1. To determine the mechanism and subgroup specificity of the frequency dependence of the late Na current in LQT3. This aim tests the hypothesis that the APD frequency dependence in LQT3 is mutation specific. 2. To determine whether a new spontaneous mutation in the Na-channel gene identifies the structural basis for closed state inactivation. We have identified a family with a single amino acid deletion in the Ill/IV inter-domain loop that increases closed state

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Long QT Syndrome

inactivation rate almost 20 fold, open state inactivation rate was unchanged. We shall examine the effect of charge and vicinal residues at this locus on closed state inactivation. 3. To determine the impact of expression of the Na-channel and HERG mutants on electrical activity of native cardiac cells in vitro. The functional effects of many LQT mutations are not well understood from their heterologous expression. This aim will test the hypothesis that the complete functional impact of each mutation requires expression in the environment of a cardiac cell. 4. To determine what Nachannel isoforms contribute to the inward current in Purkinje and ventricular cells We have used single cell PCR to clone a Na-channel isoform from Purkinje cells, its aminoacid sequence is identical to the brain III Na channel. Small changes in the expression or kinetics of this channel would cause substantial APD prolongation and LQTS. The experimental approach involves the study of a) wild-type and mutant channels expressed in mammalian cell b) native cardiac cells transfected with recombinant adenoviruses. Isoform expression will be determined by in situ hydridization. The proposed studies will provide new insights into ion channel function, their regulation and possible basis for cardiac arrhythmias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ION CHANNELOPATHIES CO-EXPRESSED IN HEART AND BRAIN Principal Investigator & Institution: Goldman, Alicia M.; Neurology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2004; Project Start 01-AUG-2004; Project End 31-JUL-2009 Summary: (provided by applicant): Neuronal excitability, and thus epileptogenicity, is critically governed by the interaction of voltage-and ligand-gated ion channels and mutations of ion channel genes are now recognized as an important cause of independently defined inherited epilepsy syndromes and cardiac arrhythmias. Recent evidence indicates that a subset of these genes is co-expressed in heart and brain. There is extensive clinical and experimental evidence supporting coexistence of seizures and cardiac arrhythmias, and many clinical reports suggest that "arrhythmogenic epilepsy" is the pathophysiological mechanism of sudden unexplained death in epilepsy (SUDEP). Long QT syndrome (LQTS) has been increasingly recognized as a cause for idiopathic cardiac arrhythmia and sudden cardiac death. Seven LQT loci and six LQT genes (SCN5A, KvLQT1, HERG, KCNE1, KCNE2, KCNJ2) have been identified. Mutations alter electrophysiological properties of a channel thus predisposing the heart towards fatal arrhythmias. Research data originating from our laboratory demonstrated that SCN5A is selectively co-expressed in heart and the brain limbic region, a network inherently prone towards epileptogenesis. HERG, KCNE2 and-KCNJ2 genes are expressed in brain, however they have not yet been regionally localized. This project will extend our preliminary data confirming CNS expression of LQT genes and test their involvement in epilepsy by 1) localizing the known LQT genes (KvLQT1, KCNE1, HERG, KCNE2 and KCNJ2) in mammalian brain using in situ hybridization to permit correlation with neurological phenotypes, 2) analyzing the genomic DNA of epilepsy patient with cardiac arrhythmias, including cases diagnosed as SUDEP, for the presence of mutations in these genes. It is our hypothesis that mutations in ion channel genes coexpressed in heart and brain underlie the clinical phenotype of cardiac arrhythmias and seizures, and may ultimately lead to (SUDEP). During the course of this study we will expand a clinical database of seizure patients with idiopathic epilepsies and utilize it to screen for ion channelopathies. We will analyze the DNA of epilepsy patients with concurrent cardiac history, and the DNA of cases diagnosed as SUDEP. The LQT genes will be studied using PCR, dHPLC, and direct sequencing methods. This research may

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help to determine the roles that LQT genes may play in the etiology of seizures and SUDEP. It may also assist in defining an epilepsy population at risk for sudden death, which would allow initiation of life-saving preventative measures and the design of gene-specific therapy for the affected patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ION CHANNELS AND SUDDEN CARDIAC DEATH Principal Investigator & Institution: Kass, Robert S.; Professor of Pharmaclogy and Chairman; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: The overall goal of the research proposed in this application is to identify the cellular and molecular triggers that initiate fatal cardiac arrhythmias and to determine novel gene-targeted therapeutic strategies to treat them. Our central hypothesis is that one step in this process is perturbation of membrane electrical activity caused by alteration in the biophysical and regulatory properties of surface membrane ion channel proteins and/or in key signaling molecules (in collaboration with Project 1) by diseasedlinked mutations. This changes in channel activity may alter the configuration may alter the configuration 4) and, in turn, triggers arrhythmic. Altered ion channel properties may also confer unique pharmacological properties upon the encoded ion channels and/or signaling molecules linked to the long QT syndrome (LQTS) and Brudaga's syndrome (BrS) as paradigms to test these hypotheses. There are three aims of this project. Aim 1 is to test the hypothesis that there is heterogeneity in biophysical properties of mutant ion channels that are causally related to cellular and disease phenotypes. Aim 2 is to test the hypothesis that heterogeneity in disease-linked channel properties confers beta-receptor/channel coupling either by mutations (polymorphisms) in signaling or in ion channel molecules disrupts channel regulation in a manner that increases the risk of an arrhythmic event. Experiments that are proposed will combine patch clamp measurement of recombinant channel activity transiently expressed in mammalian cells. Theoretical testing of our predictions will be carried out using computer-based simulations of cardiac action potentials that incorporate our patch clamp data. In addition, systemic measurements (ECG) in genetically-altered animal models will be used to test the relationship between changes in ion channel properties and the genesis of arrhythmic activity in the heart. We hypothesize that information gained from these cellular and molecular experiments can be translated directly to improved therapeutic intervention in man. Thus this work has the potential to determine a mechanistic basis for Sudden Cardiac Death (SCD) at the molecular level, and to develop therapeutic strategies in man based on specific properties for mutant gene products. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ION CHANNELS IN THE NERVOUS SYSTEM Principal Investigator & Institution: Caldwell, John H.; Professor; Cellular & Structural Biol; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-AUG-1989; Project End 31-AUG-2004 Summary: Voltage-gated sodium channels (NAChs) are vital for electrical signaling and conduction in the nervous system. There are at least ten NaCh genes in rodents, and each gene has a known ortholog in humans. The specific roles of each NaCh subtype are unknown. One hypothesis is that subtypes are differentially distributed and modulated.

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Long QT Syndrome

This proposal is focused upon the molecular basis for modulation and localization of brain NaCh subtypes. The goal of Aim 1 is to identify proteins that bind to the cytoplasmic domains of brain NaChs (esp. Nav1.6) and are responsible for (a) modulation of channel fiinction and (b) targeting to different subcellular sites. Two complementary methods are being used to find and isolate proteins associated with NaChs: (1) the yeast two-hybrid assay and (2) protein purification/mass spectrometry. Aim 2 is focused upon the interactions of NaChs with calmodulin, which was isolated with the yeast two-hybrid assay. This interaction with brain NaChs will be characterized biochemically and electrophysiologically. Aim 3 utilizes imaging techniques to study the subcellular distribution of brain sodium channels (esp., Nav 1.6) and their binding proteins. After characterizing this distribution, the effects of mutations in NaChs or in the binding proteins identified in Aim I will be studied. This research has both basic science and clinical relevance. Ion channels exist in complexes with other membrane, extracellular, and intracellular proteins. To understand the behavior of these channels, it is important to know which proteins are present in these complexes and hew the proteins interact with the channel. Mutations in muscle NaChs are responsible for some disorders of skeletal muscle and for long QT syndrome in cardiac muscle. It is expected that mutations in brain sodium channels and in the proteins that bind to NaChs will produce CNS disorders in humans, and the proposed studies will contribute to our understanding of these disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ISOLATING AND CHARACTERIZING ATYPICAL ARRHYTHMIA GENES Principal Investigator & Institution: Keating, Mark T.; Professor; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2002; Project Start 01-MAY-1992; Project End 31-MAR-2006 Summary: (provided by applicant): Genetic factors contribute to cardiac arrhythmias. All arrhythmia genes identified to date encode important cardiac ion channel subunits, indicating that ion channel dysfunction underlies arrhythmia susceptibility. Our preliminary data show that several novel arrhythmia genes await discovery, including genes responsible for syndactyly-associated long QT syndrome, Andersen's syndrome, familial sick sinus syndrome and drug-induced long QT syndrome. The goal of this proposal is to define and characterize these genes and encoded proteins with a longterm goal of improving prediction, prevention and treatment. The specific aims are: 1. Define and characterize genes responsible for syndactyly-associated long QT syndrome; 2. Deflne and characterize genes responsible for unlinked Andersen's syndrome; 3. Define and characterize genes responsible for familial sick sinus syndrome; 4. Define and characterize common variants in SCN5A that contribute to drug-induced long QT syndrome. Our preliminary data have defined sufficient patient material for these studies, but we will continue to ascertain and phenotypically characterize individuals and families with these disorders as this will increase the likelihood of success. We have defined specific candidate genes for each of these disorders, including Kir2.4, HCN pacemaker, L-type calcium, T-type calcium, SCN5A and other cardiac ion channel genes. We will test the candidacy of these genes using linkage and mutational analyses. We will identify additional candidate genes using the positional cloning-candidate gene and positional cloning approaches. Once defined, we will characterize each disease gene by Northern analysis of human tissues and by functional expression in Xenopus oocytes. Site-directed mutagenesis will be used to introduce disease-associated mutations in these genes. The physiologic consequences of these mutations will be defined by

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biophysical analysis of wild-type and mutant channels expressed in oocytes and mammalian cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LONG QT SYNDROME: POPULATION, GENETIC & CARDIAC STUDIES Principal Investigator & Institution: Moss, Arthur J.; Professor; Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2003; Project Start 01-FEB-1996; Project End 30-JUN-2007 Summary: (provided by applicant): The proposed research is a multidisciplinary, multicenter, collaborative study to continue the investigation of the clinical, cardiac, and genetic aspects of the Long QT Syndrome (LQTS) - a heritable channelopathy with delayed ventricular repolarization and episodic malignant arrhythmias manifest by syncope and sudden death. Presently, over 300 mutations on 6 ion-channel genes (KCNQ1, HERG, SCNhA, minK, MIRP1, and KCNJ2) have been identified in LQTS. The five-year research activity will: 1) continue to upgrade, expand, and collect clinical and genetic data on 900 active LQTS families (5,508 active family members) currently enrolled in the LQTS Registry; 2) develop a multivariate prognostic risk-scoring system using different time origins (from birth, and from age 10, 20, and 40 years); 3) evaluate the effectiveness and limitations of LQTS therapies; and 4) expand investigations into LQTS genotype-phenotype relationships. Functionally, the grant has four sections: a clinical section involving six clinical centers that have enrolled and are actively following the LQTS families in the Registry; a genotype section involving four experienced molecular genetic laboratories; a biostatistical section that will provide expertise in study design and statistical data analyses; and a central coordination and data center that will provide data management and coordination of the various components of the program. This integrated research program offers a substantial prospect of: 1) improving the diagnosis, management, and treatment of individuals affected with LQTS; and 2) providing a fundamental understanding of the molecular basis of repolarization-related cardiac arrhythmias in patients with a broad spectrum of cardiac disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LONG QT SYNDROME:EMOTIONAL TRIGGERS OF CARDIAC EVENTS Principal Investigator & Institution: Lane, Richard D.; Professor; Psychiatry; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): The role of bio-behavioral factors in the clinical course of the Long QT Syndrome (LQTS) is an understudied phenomenon. The LQTS is a Mendelian-dominant autosomal channelopathy characterized by delayed repolarization, episodic malignant arrhythmias, syncope and sudden death. Substantial progress has been made recently in identifying the genetic and molecular basis for the LQTS. However, there is considerable heterogeneity in the clinical presentation of LQTS that is not well understood. Retrospective studies using relatively insensitive measures suggest that emotions trigger events in all LQTS patients, especially in genotype-2 (LQT2) patients. The proposed research aims to determine whether high intensity negative or positive emotional states increase the likelihood of clinical events in LQTS patients, and whether low intensity negative emotional states increase and low intensity

22

Long QT Syndrome

positive emotional states decrease myocardial electrical instability in LQTS patients, especially in LQT2 patients. If the hypothesized associations between emotional states and clinical variables can be established in LQTS, they would have important implications for clinical management of LQTS and would create a foundation for exploring the mechanisms of sudden death in this and other contexts, such as coronary artery disease. The two proposed projects use will state-of-the-art techniques in emotion research that have not previously been used in the context of LQTS. In Study #1, 250 symptomatic LQTS patients will be interviewed by telephone using the case-crossover method for retrospective recall of emotions and other candidate triggers within 1-6 weeks of syncope or aborted cardiac arrest. This study will determine whether emotional triggers occur more frequently prior to clinical events than control time periods. In Study #2, 200 LQTS patients (100 LQT1 and 100 LQT2; each group balanced for gender) will be studied for three consecutive days during which momentary ratings of emotional state will be randomly elicited 7-10 times per day and ambulatory (Holter) ECG monitor recordings will be continuously obtained. During 5-minute epochs corresponding to each set of momentary emotion ratings, Holter recordings will be assessed for indices of myocardial electrical instability, including beat-to-beat changes in repolarization duration, QTc and the high frequency (vagal) component of heart rate variability. The proposed projects capitalize on a well-established NHLBI-funded LQTS registry, a very cooperative patient population, compelling pilot data supporting the proposed hypotheses, an experienced team of investigators and consultants well suited to conduct the proposed study, and outstanding potential for future studies that aim to elucidate the mechanisms linking emotional states and sudden cardiac death. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MEMBRANE CURRENTS IN CARDIAC MUSCLE Principal Investigator & Institution: Brown, Arthur M.; Professor and Chairman; Physiology and Biophysics; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-DEC-1985; Project End 31-JUL-2004 Summary: The long term goals are to relate the electrical activity of the heart to the genesis and processing of the ion channels responsible for this activity. The specific aims are to: 1) study processing of HERG using misprocessed mutants linked to hLQT2 as probes; 2) test for native chaperones that may interact with HERG during processing and characterize a novel ER resident protein recently discovered by us to interact directly with HERG; 3) expand upon our recent discovery of a novel cytoplasmic protein member of a family of K+ channel chaperones that enhances HERG currents and may be useful as a chaperone to rescue misprocessed mutants; and 4) study the interactions between KvLQT1 and minK during processing using misprocessed mutants linked to hereditary long QT syndrome (hLQTS) as probes. The mutations in KvLQT1/minK and HERG are responsible for most cases of hLQTS and HERG is the target in the majority of cases of the more common acquired LQTS produced by cardiac and non-cardiac antiarrhythmic drugs. An important outcome of our studies will be the identification of trafficking mutants in hLQTS and the discovery of agents which may enhance trafficking of mutant channels. Likewise we may identify drugs which alter trafficking of normal channels to reduce or increase currents thereby mimicking channel blockers or channel activators. The research uses misprocessed mutant HERG and KvLQT1/minK channels to identify sites along the processing pathway are critical for maturation and trafficking and conversely searches for processing proteins that interact with wild type and mutant channels. The methods include patch clamp

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electrophysiology, immunostaining, immunoblotting, immunopurification, pulse-chase labeling, mutagenesis, and yeast two hybrid screens. Our strategy has already led to the discovery of a novel ER-resident protein that interacts with HERG and a novel cytoplasmic protein that enhances HERG currents. Their mechanisms of action together with characterizing the processing of HERG and KvLQT1/minK are the goals of this proposal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MINK-RELATED PEPTIDES(MIRPS): STRUCTURE AND FUNCTION Principal Investigator & Institution: Goldstein, Steve a N.; Professor and Chief; Pediatrics; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-AUG-1996; Project End 31-JUL-2005 Summary: MinK is a small ion channel subunit with a single transmembrane span. It is active only after assembly with a pore-forming subunit. Nonetheless, MinK is required for normal channel function in some tissues. Last period we learned why: MinK determines the gating kinetics, unitary conductance, ion selectivity, regulation and pharmacology of these mixed channel complexes. In the heart and ear, Mink assembles with KCNQ1 to form Iks channels. Inherited Mink mutations are associated with altered IKs function, cardiac arrhythmia and deafness. Mink was thought to be unique until last year when we cloned 3 genes encoding Mink-related peptides (MiRPs). In the last period, we studied the function, dysfunction and structure/function of MinK. We learned how disease-associated mutations altered Mink function and identified residues critical for activity. This allowed isolation of the genes for MiRP1, MiRP2 and MIRP3. We then found that MiRP1 assembled with the pore-forming subunit HERG to reconstitute attributes of cardiac IKr channels. This led to our identification of MIRP1 mutations associated with sporadic long QT syndrome (LQTS), a rare disorder that predisposes to sudden death. More significantly, we later discovered that a MiRP1 polymorphism present in approximately 1.6 percent of healthy individuals places this large group at risk for a common, life-threatening disorder: drug-induced LOTS. Our most recent studies reveal that MiRPs operate not only with KCNQ1 and HERG but also with classical voltage-gated potassium channel subunits throughout the body. The central goal of this application arises directly from our studies of Mink over the last five years: we seek to learn how M1RPs (including Mink) operate in normal and disease states. The four specific aims are designed to evaluate (1) newly identified native MiRPpartner complexes from skeletal muscle, heart and brain; (2) newly identified diseaseassociated mutants; (3) MiRP domains and residues that mediate channel function; and, (4) sites of contact in MiRP-partner complexes. We argue these small subunits merit intense scrutiny. First, they are important to normal physiology and disease pathogenesis. Second, they have potential to reveal mechanisms of ion channel function from a unique vantage point: a peptide intimate with (but not of) the pore-forming subunit. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MODIFIERS OF POTASSIUM CHANNEL FUNCTION AND EXPRESSION Principal Investigator & Institution: Robertson, Gail A.; Associate Professor; Physiology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2006

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Long QT Syndrome

Summary: (provided by applicant): The human ether-a-go-go-related gene (HERG) encodes an ion channel subunit underlying IKr, a potassium current required for the normal repolarization of ventricular cells in the human heart. More than 90 inherited mutations in HERG cause Long QT Syndrome (LQTS), a leading cause of sudden cardiac death. Some mutations alter gating, but more disrupt trafficking. Because the subunit composition of HERG is uncertain, and the mechanisms underlying HERG biogenesis, processing and targeting to the membrane are unknown, we carried out a yeast two-hybrid screen to identify proteins that interact with HERG. Using the carboxy terminus as bait to screen a human heart library, we isolated five genes encoding HERGinteracting proteins ("HIPs"). Two of these proteins have been previously identified: Tara, an actin-binding protein, and GM 130, a peripheral membrane protein of the Golgi apparatus. Little is known about the function of either. Tara co-localizes with HERG to a region in rat cardiac myocytes corresponding to the T-tubules, as determined by confocal immunocytochemistry. Consistent with a stabilizing role at the membrane, Tara enhances expression in HERG when co-expressed in Xenopus oocytes. GM 130 specifically localizes to the Golgi, where a prominent HERG signal is also observed. In contrast to Tara, GM130 suppresses HERG signal in oocytes. Deletion mapping in binary yeast two-hybrid assays reveals that the C terminus contains distinct domains with which the HIPs selectively interact. Certain LQT2 (HERG) mutations selectively disrupt interactions with only two of the proteins. Three of the proteins, Tara, H17 and H3, interact with each other, implying that they function as an interactive complex. Of the HIPs, Tara alone interacts with another cardiac ion channel protein, KvLQT1, in binary yeast two-hybrid assays, but none interacts with Shaker. Each HIP represents a potential target for LQTS to the extent that its expression is required for the normal expression or targeting of HERG channels. The long-range goal of this research is to elucidate the basic biological processes that are disrupted by the disease process. The specific aims of this proposal are: (1) to demonstrate that HERG and the HIPs interact in vivo: (2) to extend our immunocytochemical and electrophysiological analyses, tests for specificity and domain mapping; (3) to determine the necessity of HIP interactions for HERG channels by reciprocal analysis of HERG C terminal truncations and selective disruption of HIPs in native tissues and heterologous systems; and (4) to screen unmapped LQTS families for disease mutations in the genes encoding the HIPs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR AND GENETIC SCREENING FOR ION CHANNEL HEART DI Principal Investigator & Institution: Kyle, John W.; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR MECHANISMS OF CARDIAC ARRHYTHMIAS Principal Investigator & Institution: Wang, Qing; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 30-JUN-2006 Summary: (provided by applicant): Cardiac arrhythmias account for more than 300,000 sudden deaths each year in the U.S. alone. Our laboratory is investigating the pathogenesis of cardiac arrhythmias. We focus on two arrhythmic disorders: long-QT

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syndrome (LQT) and idiopathic ventricular fibrillation (IVF), both of which cause sudden death in the young, otherwise healthy, individuals. During the past 8 years of this project, we focused on genetics and in vitro electrophysiology of LQT and IVF. Together with other scientists, we have defined a genetic pathway for pathogenesis of both LQT and IVF. Further exploration of pathogenic mechanisms of LQT and IVF at the tissue and organ level is impossible because of lack of fresh heart tissues from patients. In the proposed studies we plan to develop and characterize LQT- and IVF-animal models in which SCN5A (the cardiac sodium channel gene) mutations are engineered into the mouse genome to further explore the etiology of arrhythmogenesis. We have successfully established a mouse model for LQT and ventricular arrhythmias by targeting an SCN5A mutation (N1325S). Characterization of our arrhythmic mice has led to the working hypothesis that early and after depolarizations (EADs and DADs) are the substrate for ventricular tachycardia (VT) and ventricular fibrillation (VF). In the proposed studies we plan to continue to study the mouse model for LQT to uncover detailed molecular mechanisms of cardiac arrhythmias, and to generate and characterize mouse models for IVF and acquired LQT. Our specific aims are: (1) To investigate whether over-expression of an LQT-causing mutation of SCN5A in the mouse heart will trigger electrophysiological remodeling; (2) To systematically dissect EADs and DADs induced by a genetic LQT mutation; (3) To systematically determine the effects of representative agents from each class of antiarrhythmic drugs on VT/VF and correlate the findings with results on EADs/DADs; (4) To characterize SCN5A mutations associated with IVF and acquired LQT using the transgenic mouse technology. The successful accomplishment of goals in this proposal will provide a fundamental understanding of the pathogenic mechanisms of cardiac arrhythmias. Evaluation of animal models will help define the physiological and cellular processes involved in arrhythmogenesis, and bridge the gap between the in vitro biophysical defects and the in vivo whole animal phenotype characterized by arrhythmia susceptibility. These studies may provide a new framework for the rational design of therapeutic agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR PHYSIOLOGY OF LONG QT SYNDROME & IDIOPATHIC VENTRICULAR FIBRILLATION Principal Investigator & Institution: Sanguinetti, Michael C.; Professor; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2002 Summary: The long-term goals of this project are to understand the molecular basis of channel dysfunction caused by mutations in ion channel genes that cause cardiac arrhythmia, and to explore potential therapies at the cellular and organ level based on these findings. Subproject 1 will explore the mechanism of action and normalization of cardiac repolarization by an activator of KvLGT1 and cardiac I/Ks channels. A novel benzodiazepine (R-L3) was recently discovered that increases the magnitude of I/Ks and shortens action potential duration. We will study the effects of this compound on KvLGT1 and minK channel subunits heterologously expressed in Xenopus oocytes. We will also determine if this compound can suppress early after depolarizations in rabbit myocytes and prevent torsades de pointes in isolated perfused hearts. Subproject 2 will investigate the biophysical properties of mutations in SCN5A that cause long QT syndrome and idiopathic ventricular fibrillation. Gating and ionic currents recorded from sodium channels heterologously expressed in cultured mammalian cells will be used to understand abnormal channel function of SCN5A mutations. Subproject 3 will characterize mutations in HERG and newly discovered genes that cause long QT

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Long QT Syndrome

syndrome that are identified in Project 1. These studies will utilize both the oocyte and cultured mammalian cell expression systems. We will initially concentrate on mutations in HERG that will provide insights into the structural basis of channel function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MULTI-ANALYTE WAVEGUIDE IMMUNOSENSING Principal Investigator & Institution: Herron, James N.; Associate Professor; Pharmaceutics and Pharmaceutl Chem; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-DEC-1984; Project End 31-JAN-2004 Summary: The goal of this project is to exploit the high reflection density of integrated optical waveguides (IOWs) to develop evanescent wave biosensors for applications in high throughput genetic screening. In particular, the applicants plan to develop nucleic acid hybridization assays (also know as "molecular diagnostics" or "MDx" assays) for use in screening and diagnosis of hereditary cardiovascular disease. Although there are several potential disease targets, they intend to focus on long-QT syndrome (LQTS) because there is a compelling need in this disease for rapid and inexpensive methods for genetic screening of family members of affected individuals. Traditional diagnostic methods (e.g., ECG) are equivocal in about 40% of LQTS cases because the affected individual exhibits either a normal or borderline prolonged QT interval. Such individuals often go undiagnosed, resulting in 3000-4000 sudden deaths per year in the United States. LQTS has been linked to genetic polymorphisms in four genes (KVLQT1,HERG, SCN5A & KCNE1) that encode for cardiac ion channels. Present-day methodology for assessing genetic polymorphism involves isolating genes from afflicted individuals using polymerase chain reaction (PCR), sequencing them, and then cataloging the observed mutations. However, this procedure is too expensive and timeconsuming for use in routine patient screening, which has lead to development of socalled "DNA chips" that contain hundreds to thousands of oligonucleotides immobilized to a single substrate in a microarray. Patient screening with a DNA chip involves isolating the gene of interest from the patient's DNA using PCR and them allowing the PCR product to hybridize to the chip. Hybridization is detected using either an epifluorescence or confocal microscope. The detection process is time-consuming because each array element is imaged sequentially for a few seconds or more. Moreover, the instrumentation required to read the chips is very expensive, costing between $100,000 and $200,000 for a typical setup. Thus, assay time and cost are limiting factors in the application of MDx technology to routine patient screening and diagnosis. The approach taken in this application to this problem is to use an integrated optical waveguide sensor as the immobilization support for a DNA chip. By doing so the applicants can dramatically reduce assay time (to 5 minutes, or less) and instrumentation cost (our prototype analyzer cost about $3,000 to produce, production versions would probably retail for about $10,000) because the entire oligonucleotide array is monitored in real time by charge-coupled device (CCD) camera. Moreover, data acquisition in real time enables us monitoring hybridization kinetics, which is essential for identifying point mutations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEURAL CIRCULATORY CONTROL IN THE LONG QT SYNDROME Principal Investigator & Institution: Somers, Virend K.; Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007

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Summary: (provided by applicant): The long QT syndrome (LQTS) is associated with risk for polymorphic ventricular tachycardia, syncope, and sudden death. Molecular genetic approaches have shown that these syndromes are explained by mutations in cardiac ion channel genes, the commonest known mutations being classified as LQT1, LQT2, and LQT3. The degree of QT prolongation is an independent risk factor for cardiac events. The QT interval is exquisitely sensitive to changes in autonomic nervous system activity. The genotype is further linked to the nature of the trigger for cardiovascular events. Events in patients with LQT1 occur during exertion, particularly during swimming. Excitement and auditory stimuli typically trigger events in LQT2 patients. Most events in LQT3 occur at rest. This interaction between genotype, QT, autonomic status and environment is unclear. We propose the overall hypothesis that patients with LQTS have low sympathetic activation at rest and have potentiated autonomic responses to physical, mental, cold, and chemical stress, and that the autonomic, hemodynamic and/or QT responses to stress in LQTS are differentially affected by genotypes characterizing LQT1, LQT2, and LQT3. We will test the following specific hypotheses: 1. Patients with the LQTS have low levels of sympathetic activation at rest as evidenced by slow heart rates and decreased sympathetic nerve traffic to muscle blood vessels. 2. LQTS individuals have potentiated autonomic and/or QT responses to arousal stimuli such as mental stress and loud noise. 3. Abnormalities in cardiac ion channels causing LQTS are associated with abnormalities in arterial baroreflex regulation of heart rate and sympathetic traffic. 4. LQTS individuals (especially LQT1, who have an increased risk for cardiac events during swimming) have abnormal responses to chemoreflex activation, particularly during apnea, and abnormalities in the diving reflex response. Important and novel strengths of the proposal include an integrated translational approach to understanding autonomic mechanisms that may contribute to sudden death in patients with LQTS. We believe that these studies will provide important and clinically relevant insights into the interaction between the genetics of ion channel dysfunction and associated neural control phenotypes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEURAL REMODELING

MECHANISMS

OF

VENTRICULAR

ELECTRICAL

Principal Investigator & Institution: Adamson, Philip B.; Medicine; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2004 Summary: In the normal heart, when heart rate increases, ventricular repolarization shortens (QT adaptation, normal restitution). This adaptive mechanism prevents the occurrence of excessively long QT intervals at short cycle lengths with the attendant risk for life-threatening arrhythmias. Failure of the QT interval to appropriately adapt to heart rate increases, defined as "ventricular electrical remodeling", may represent one of the key factors in increasing the risk for sudden death in several clinical conditions. One, well defined, is LQT1, the variant of the long QT syndrome with mutations affecting the Iks current. Another, of major social importance, is heart failure. The present proposal is designed to test the hypothesis that different degrees of electrical remodeling (different degrees of loss of repolarization adaptation) represent one of the key targets for interventions destined to alter the progression of ischemic cardiomyopathy toward heart failure and lethal arrhythmias. A novel model of chronic ischemic cardiomyopathy that develops after myocardial infarction, secondary to repeated coronary microembolizations will be used in this project. This model has the unique characteristic

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Long QT Syndrome

to allow chronic study of dogs at high and low risk for spontaneous life-threatening and lethal ventricular tachyarrhythmias. The preparation allows the study of contributions to electrical instability by changes in autonomic tone and reflexes and to assess the concurrent changes in the expression of the ionic currents playing a major role in repolarization. We will evaluate the possibility that specific interventions that are already clinically available, such as beta-blockers or left stellate gangionectomy, or under development, such as activators of repolarizing currents, might prevent or alter favorably this specific type of electrical remodeling. These clinically applicable interventions may modify the natural history of diseases, such as heart failure, characterized by ventricular electrical remodeling leading to a high risk for lethal arrhythmias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROGENETICS OF THE SEIZURE (DERG) POTASSIUM CHANNEL Principal Investigator & Institution: Massa, Enrique; Associate Professor; Texas A&M University-Kingsville Campus Box 104 Kingsville, Tx 78363 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2006 Summary: Potassium channels make up a diverse group of ion channels that play integral in roles action potential generation and fine-tuning of firing properties of excitable cells. The ether-a-go-gorelated (ERG) potassium channels are a relatively new family of potassium channels. The human ERG ismutant in a form of familial Long QT syndrome or sudden cardiac death. The role of ERG in cells is not fully understood and the identification of mutations in this channel warrant the further examination of the function of this ion channel. The previous funding period for this proposal resulted in the characterization of the Drosophila ERG channel which is mutant in the seizure mutation. The seizure (DERG) channel transcriptional start sites were identified and mapped to three distinct promoters which exhibit cell-specific transcriptional regulation patterns. This proposalexamines the promoters of DERG and their control by specific DNA elements. We propose to examine the seizure (DERG) channel gone by transgenic regulation of promotedreporter gone fusions and identificationof conserved regulatory elements acrossthree Drosophilid species. The coordinate transcriptional regulation of seizure (DERG) and gamma-SNAPwill also be examined. The gamma-SNAP gene lies on the opposite DNA strand and transcribes antiparallel to DERG. The most proximal seizure (DERG) promoter overlaps with the promoter of gamma-SNAP. Interestingly, both genes exhibit the same expression profile on Northern blot analysis. We propose to examine this coordinate regulation by identifying the minimal gamma-SNAP promoter and correlating with the minimal regulatory sequences of the proximal seizure (DERG) promoter. We will also utilize genetic screens to identify genes that modify seizure mutantphenotypes and compdse either accessory subunitsor play similar roles in modulating membrane excitability. In addition, electrophysiological analysisand recombination mapping of the identified mutants will be performed on previously identified seizure (DERG) modifiers. The ease of generating mutations in Drosophila and the availability of the annotated genome allows us to combine physiological analyses with genetics approaches to address questions pertaining ion channel regulation and function. These studies may shed light upon the physiological role of ERG and provide evidence of the pathophysiology of LQT syndrome and epilepsy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NON LINEAR EFFECTS OF SR RELEASE TRIGGERS IN HEART Principal Investigator & Institution: Bridge, John H B.; Research Professor of Medicine; Cardiovascular Research and Training Institute; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-MAY-1999; Project End 30-APR-2004 Summary: The applicants' broad and long term objectives are to investigate excitation contraction (EC) coupling and in' particular mechanisms by which sarcoplasmic reticular (SR) Ca release is triggered in mammalian heart. Defects in the mechanism of EC coupling may be central to such health related problems as the long QT syndrome, heart failure and various cardiomypathies. The specific aims mainly involve establishing that the relationship between trigger Ca and SR Ca release is non linear so that two separate triggers e.g. T type Ca current or Na-Ca exchange sum their effects with L type Ca current in a non linear fashion. Thus small triggers might have effects that are disproportionately large. Therefore the influence of small triggers could be significant in regulating SR Ca release. The specific aims are 1) To investigate the relationships between SR Ca release triggers and SR Ca release 2) To investigate the relationship between Ca sparks and SR release triggers and 3) To investigate the effect of Na current on both macroscopic and microscopic gain. These specific aims will be approached with the following basic research design and methods. The relationship between SR Ca release and Ca current will be measured at constant voltage using voltage clamp, fluorescent indicators (Fluo-3) and a rapid solution-changing device. The relationship between SR Ca release and Ca current will be established at several different but constant voltages. For example the relationship will be established at -10 mV and at +50 mV. From these relationships the macroscopic gain of the system will be calculated as the rate of SR Ca release divided by the magnitude of the L type Ca current. The effect of intracellular Na, Na current and reverse Na-Ca exchange on this relationship will be established. Ca sparks will be measured with a confocal microscope operating in line scan mode in both Rabbit and Mouse ventricular myocytes at 36 degrees C using the Ca indicator Fluo-3. The hypothesis that the probability of spark occurrence that is activated by Ca current can be influenced by Na-Ca exchange will be measured by comparing spark occurrence in transgenic mice overexpressing the Na-Ca exchange and wildtype mice which do not. The design of these experiments is such that sparks can be measured in a fixed location in one confocal plane thus greatly simplifying the analysis. Finally the effect of Na, Na-Ca exchange and controlled Na currents on microscopic gain will be tested. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NONINVASIVE & GENETIC DIAGNOSIS OF LONG QT SEGMENT Principal Investigator & Institution: Kaufman, Elizabeth S.; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002 Summary: The Long QT Syndrome (LQTS) is a group of diseases in which patients have prolongation of the QT interval on the electrocardiogram (ECG). This interval represents repolarization of the heart. These patients are at risk of death due to a syndrome that has a genetic basis in most individuals. Genetic typing can identify patients and family members at risk of development of this syndrome. This is important because therapy is available which can effectively treat this problem and significantly reduce the mortality. This protocol will study patients with suspected LQTS and their families by performing a medical history, and ECG and a 24-hour Holter monitoring. In

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Long QT Syndrome

addition, blood will be drawn for analysis of the genetic structure. Subjects will also under go a noninvasive test called T wave alternans analysis, which involves wearing adhesive electrodes for approximately 30 minutes during rest and mild exercise, while a computer detects and quantifies subtle abnormalities of the T wave. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOGENESIS OF HERG MUTATIONS IN HUMAN LONG QT SYNDROME Principal Investigator & Institution: Zhou, Zhengfeng; Medicine; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 05-DEC-2001; Project End 30-NOV-2005 Summary: (provided by applicant): Congenital long QT syndrome (LQTS) is a disease associated with delayed cardiac repolarization and prolonged QT intervals on the electrocardiogram, which can lead to ventricular arrhythmia with cardiac sudden death. One of the major forms of LQTS (LQT2) is caused by mutations in the human ether-ago-go-related gene (HERG) that encodes the rapidly activating delayed rectifier potassium channel. To date, more than 100 HERG mutations have been identified in patients with LQTS. Our previous work has shown that a major mechanism for loss of HERG channel function in LQT2 is defective protein trafficking which results in failure of mutant channels to reach the cell surface. We also showed that high affinity HERG channel blockers can correct defective protein trafficking of some LQT2 mutants. The goals of this proposal are (1) to study the mechanisms of defective protein trafficking of LQT2 mutant channels, and (2) to determine how HERO channel blockers rescue trafficking defective LQT2 mutant channels. Our hypotheses are (1) LQT2 mutations cause misfolding or improper assembly of HERO protein which is recognized by quality control system leading to ER retention and degradation by the proteasome, and (2) drugs that bind to HERO channels with high affinity act as pharmacological chaperones to promote proper folding or assembly in a conformation that permits trafficking to the plasma membrane. We will test these hypotheses by four specific aims: aim I to determine whether LQT2 mutations cause misfolding or improper assembly of mutant channels; aim 2 to study the role of molecular chaperones in the ER retention of LQT2 mutant channels; aim 3 to investigate the mechanisms by which LQT2 mutants are recognized and degraded by the proteasome; and aim 4 to elucidate the mechanisms by which high affinity HERG channel blockers correct defective protein trafficking of LQT2 mutant channels. We will use a combination of biochemical, immunohistochemical and patch clamp techniques to study wild type HERG and LQT2 mutant channels expressed in transfected tissue culture cells and in cell-free systems. These studies will strengthen our knowledge of how misfolded and improperly assembled LQT2 mutant channels are recognized, retained and degraded by the ER quality control system and how HERG channel blockers modify these processes and rescue LQT2 mutant channels. Elucidating these mechanisms is an important step towards the development of pharmacological strategies for therapies of congenital LQTS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: QUALITY CONTROL OF K+ CHANNEL BIOGENESIS Principal Investigator & Institution: Papazian, Diane M.; Professor; Physiology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 02-SEP-2002; Project End 31-AUG-2006

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Summary: (provided by applicant): The long-term goal of this research is to elucidate the mechanisms of quality control that ensure that only properly folded and assembled potassium channels are expressed on the cell surface. Potassium channels adopt their native structures in the ER. Channel proteins that fail to fold or assemble properly are recognized by a stringent quality control system and retained in the ER. This system prevents transport of misfolded or incompletely assembled proteins to locations where aberrant functional properties could disrupt cellular physiology. The proposed research focuses on two aspects of potassium channel quality control. First, how are structurally immature, misfolded, or unassembled potassium channel proteins retained in the ER? Second, what pathways dispose of ER-retained potassium channel proteins? What are the roles of proteasomal degradation and aggresome formation, which have been implicated in the disposal of other ER-retained proteins? The proposed research is relevant to the etiology of channelopathies, such as Long QT Syndrome Type 2, in which channel proteins are retained in the ER and may be subjected to ER-associated degradation. We will accomplish the following specific aims: (1) to determine the role of cytoplasmic domains in ER retention and release during biogenesis of Shaker and Kv1.3 potassium channels; (2) to identify mechanisms used by mammalian cells to dispose of ER-retained potassium channel proteins; and (3) to compare the quality control of HERG channel biogenesis in a mammalian cell line and in cardiac ventricular myocytes. Channel proteins will be expressed in HEK293T cells or cultured ventricular myocytes for studies of protein maturation, stability, protease inhibitors. Experimental approaches will include expression and biochemical analysis of wild type and mutant channel proteins, confocal microscopy, cell surface labeling, and electrophysiology. The proposed research will advance our knowledge of basic aspects of ion channel cell biology and improve our understanding of the etiology of channelopathies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGIONS OF NA CHANNEL INVOLVED IN PERMEATION AND GATING Principal Investigator & Institution: Chiamvimonvat, Nipavan; Associate Professor; Internal Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 956165200 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2004 Summary: The Na+ channel is responsible for the conduction of electrical impulses throughout excitable tissues including the heart. They are the primary targets for local anesthetics as well as related antiarrhythmic drugs. Several hereditary cardiac and muscular diseases have now been linked to mutations in Na+ channels, e.g., one form of congenital long QT syndrome (LQT3). The long-term goals of this proposal are to understand the molecular basis for the function of Na+ channels. We have evidence to suggest that there are significant overlaps in the region which are important for the two fundamental properties of the channels; namely gating and permeation. Specifically, two consecutive residues (W402 and E403) in the 55-56 region (P loop) in Domain I of the mu1 skeletal muscle Na+ channel, both of which have been shown to line the pore of the channel, are important in the gating of the channel. We hypothesize that the negatively charged residues in the pore region of the channel (e.g.,E403 residue) interact with nearby positively charged residues to stabilize the activation gate of the channel. This hypothesis can be directly tested using site-directed mutagenesis combined with heterologous expression in oocytes and a mammalian expression system. We will determine the mechanisms by which the negatively charged residues affect the gating of the channel using cysteine mutagenesis combined with sulfhydryl modifications. Using

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data obtained from the mu1 skeletal muscle Na+ channel as groundwork, we will study the homologous mutations (e.g., E375C) in the hH1 cardiac Na+ channel isoform. The goals are two folds: to determine whether the change in gating seen with e.g., E403C is a generalized phenomenon and to establish whether there are isoform-specific differences in the activation gating machinery between the two channels. We will study the nearby positively charged residues in the S5-S6 linker and S4 transmembrane segment in Domain I, which may interact electrostatically with the negatively charged residues. The combined techniques of molecular cloning and site-directed mutagenesis together with electrophysiologic recording promise to provide new insights into the structure-function relationship of ion channels. Definition of the regions determining ion transport, selectivity and gating hold promises for new and more mechanistic approaches for our diagnosis and therapy of cardiovascular ion channel diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF HERG PROTEINS BY CHEMICAL CHAPERONES Principal Investigator & Institution: Delisle, Brian P.; Medicine; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-AUG-2002 Summary: (provided by applicant): The long-term goal of this project is to investigate the pharmacological rescue of ion channels that fail to traffic normally to the plasma membrane. Failure of protein trafficking underlies ion channelopathies associated with congenital Long QT2 syndrome (LQT2). Drugs that bind to channels with a high affinity can restore the trafficking defects of mutant ion channels. However, the mechanisms that underlie the drug rescue of these channels remain poorly understood. This proposal examines the differences in pharmacological rescue of Long QT2 trafficking defects at the molecular and functional level. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF MOLECULAR CHAPERONES IN HERG PROCESSING Principal Investigator & Institution: Ficker, Eckhard K.; Metrohealth Medical Center Cleveland, Oh 441091998 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): The overall goals are to identify and understand the function of molecular chaperones essential for productive folding, retention and degradation of hERG potassium channels during biosynthesis in the endoplasmic reticulum. The hERG gene encodes the rapid component of the cardiac delayed rectifier current IKr that is crucial for cardiac repolarization and critical to the normal duration and propagation of the cardiac action potential. Mutations in hERG produce functionally impaired or trafficking-deficient channels that reduce IKr current and are linked to hereditary long QT syndrome type2 in which delayed repolarization is associated with torsade de pointes and sudden cardiac death in young people. The specific aims of this study are to: (1) identify the molecular components of the multichaperone folding machinery associated with hERG wildtype channels during synthesis, assembly and maturation in the endoplasmic reticulum (ER), (2) probe remodeling of the multi-chaperone folding machinery associated with misprocessed LQT2 hERG mutations retained in the ER, (3) study the relationship of hERG-chaperone complexes with the ubiquitin/proteasome system and determine how triage decisions towards protein degradation are made, and (4) validate in native cardiomyocytes the physiological role for hERG chaperones and components of the ubiquitin/proteasome

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system identified in heterologous expression systems. An important outcome of this study will be the identification of novel molecular targets that can be exploited to restore trafficking of misfolded LQT2 mutants or increase the folding propensity of wildtype hERG channels to stabilize impaired cardiac action potentials. The research uses pulsechase labeling, immunoprecipitation, autoradiography and immunoblotting to isolate and characterize the multi-chaperone machinery associated with hERG potassium channels. Mass spectrometry is used to identify novel protein components of the cellular chaperone machinery as well as of the proteasomal degradation machinery associated with hERG potassium channels. Patch-clamp electrophysiology, mutagenesis and adenoviral gene transfer of dominant-negative chaperone constructs are used to manipulate chaperone expression in heterologous expression systems as well as in native cardiomyocytes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SCOR IN SUDDEN CARDIAC DEATH Principal Investigator & Institution: Lux, Robert L.; Professor of Medicine; Internal Medicine; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-FEB-1995; Project End 31-DEC-2004 Summary: We propose renewal of the Specialized Center of Research in Sudden Death at the University of Utah. Our long-term objective continues to be an investigation of the relationship between abnormal repolarization and ` arrhythmic death. The goal of this investigation is development of therapies that prevent sudden death through fundamental observations at the bench. To achieve this goal we propose six inter-related research projects supported by four core laboratories. Twenty-two investigators are involved. Molecular Genetics of Ventricular Arrhythmias is led by MT Keating. He will identify new mutations underlying the hereditary long QT syndrome (LQT) and idiopathic ventricular fibrillation (IVF), both of which are caused by ion channel dysfunction during repolarization. MC Sanguinetti and MF Sheet, in Molecular Physiology of LQT and IVF, propose biophysical studies of the mutant and wild type disease genes discovered by Keating. Cellular electrophysiological mechanisms of Repolarization, is headed by KW Spitzer. This explores electrophysiological mechanisms of repolarization-related arryhthmias, including contributions by intercellular coupling defects, intracellular calcium and the sodium/calcium exchanger. Project 4, Measurement of Repolarization led by RL Lux, provides new methods for precise measurement of cardiac repolarization and in homogeneities of recovery in humans which are essential if we are to link the basic science observations in the previous Projects with the human trials of Projects. Project 5, Prognostic Value of Repolarization Measures, headed by LS Green, continues a clinical study initiated in the previous grant cycle with the goal of discovery measures of repolarization that predict subsequent sudden death after acute myocardial infarction. Repolarization-related prognosticators in other conditions are also human treatment component of this SCOR. Gene- based pharmacologic therapies of LQT and IVF are proposed. Administration, Instrumentation, Cell Processing and Signal Processing Core laboratories support the six projects. The structure of this multi-disciplinary research effort has been optimized to develop knowledge from disease gene discoveries and rapidly translate it to prevention of sudden death. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SODIUM CHANNEL ISOFORM EXPRESSION IN THE RETINA Principal Investigator & Institution: Van Wart, Audra M.; Neurobiology and Behavior; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2004; Project Start 08-JAN-2004; Project End 07-JAN-2007 Summary: (provided by applicant): This proposal will investigate the role of voltagedependent sodium channel (Nav) isoforms in retinal visual processing. Nav's play the critical role of supporting the rising phase of the action potential, and despite the strong similarity among the Nav isoforms, misexpression of specific isoforms has been implicated in such disorders as epilepsy, long QT syndrome, multiple sclerosis, and a variety of movement disorders. The proposed studies will examine the Nav expression pattern in the developing retina, and investigate how the isotype-specific distribution of these channels within a neuron influences its cellular properties and responsibilities within the retinal mosaic. The proposed research will build on previous work in this lab showing that specific Nav isoforms are targeted to morphologically and functionally distinct compartments within retinal ganglion cells, and their expression is developmentally regulated. Combinations of tract-tracing and immunohistochemistry will be used to see which Navs localize to retinal ganglion cell terminal endings over development, and to determine which cell types express Navs in the inner retina, lmmunohistochemistry and intracellular recordings will then be used to look at the role of Nav1.6 at the initial segment of retinal ganglion cell axons by examining differences in ganglion cell physiology and Nav distribution in med mice who lack Navl.6. The goal is to not only contribute to our understanding of how visual signals are processed, but also to shed light on the mechanisms behind disease-causing channelopathies of the muscle, heart, and nervous system Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STUDY OF VENTRICULAR REPOLARIZATION IN LONG QT SYNDROME Principal Investigator & Institution: Zareba, Wojciech; Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 21-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): The long QT syndrome (LQTS), a familial disorder caused by mutations of genes encoding myocardial potassium sodium ion channels, is manifest clinically by prolongation of the QT interval in the ECO and by a propensity life-threatening ventricular arrhythmias. Genetic forms of LQTS are caused by mutations of sodium and potassium channel genes and are associated with distinct Twave patterns in the ECG and different clinical outcome over time. However, there is a substantial overlap of ECG patterns and clinical manifestation between LQT1 and LQT2 types caused by mutations of two different potassium channel genes (KVLQT1 and HERG, respectively). Experimental data and some anecdotal clinical observations indicate that in LQT1 and LQT2 conditions, the dynamic response of repolarization various stimuli is a critical factor contributing to arrhythmogenesis. However, there is limited knowledge regarding clinically applicable noninvasive and invasive tests and parameters that reliably identify and quantify the magnitude dynamic repolarization abnormalities in LQTS patients, especially those with LQT1 and LQT2 types that account for majority of patients with known genotype. Therefore, the primary aims of this study are: 1) to improve the clinical accuracy of diagnosing patients with LQTS using noninvasive and invasive electrophysiologic testing; 2) to determine response of ventricular repolarization to physiologic/pharmacologic stimuli in LQTS patients when

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compared to control non-LQTS subjects; 3) to identify differences in ventricular repolarization parameters between LQTS patients with LQT1 and LQT2 gene mutations. These goals will be accomplished by conducting a series of noninvasive and invasive electrophysiologic tests with physiological/pharmacological stimuli in 50 LQT1 carriers, 50 LQT2 carriers, and 50 healthy control non-LQTS subjects as well as noninvasive tests in equivalent numbers of non-carriers from LQT1 and LQT2 families. The secondary aims of this study are: 1) to develop and validate standardized noninvasive and invasive electrophysiologic protocols for evaluating abnormal ventricular repolarization in LQTS; 2) to determine the clinical usefulness of noninvasive and invasive testing to identify LQTS patients with borderline prolonged QTc intervals from non-carriers with similar QTc intervals; 3) to determine the response in ventricular repolarization dynamics to beta-blocker therapy in LQT1 and LQT2 patients; 4) to understand the relationship/association between noninvasive and invasive electrophysiologic findings in LQTS and normal subjects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TARGETING HERG: A MOUSE MODEL OF THE LONG QT SYNDROME Principal Investigator & Institution: London, Barry; Associate Professor of Medicine; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Arrhythmias and sudden death remain a major public health problem. Mutations of the K+ channel HERG, the human ether-a-gogo related gene, cause the long QT syndrome (LQTS), a genetic disorder characterized by lethal ventricular arrhythmias. HERG subunits are expressed in the heart and are responsible for IKr, a K+ current important in the repolarization phase of the cardiac action potential. HERG subunits interact in-vitro with IsK (minK), a K+ channel beta-subunit that coassembles with KvLQT1 to form the cardiac current IKs. It is not known whether HERG mutations affect currents other than IKr. Patients with HERG mutations and arrhythmias can have normal QT intervals. The role of HERG in other tissues and in development is unknown. Limited access to tissue and myocytes from LQTS patients presents a major obstacle towards a full understanding of the role of HERG in the heart. We have characterized Merg1 (the mouse homolog of HERG) and engineered mice with a targeted truncation of Merg1 similar to the HERG mutations that cause LQTS. Homozygous embryos are abnormal and die between embryonic days Ell and E14. Heterozygous mice (Merg1+/-) have decreased transcript levels of Merg1; levels of minK are decreased in neonates but markedly increased in adults. Heterozygotes have prolonged QT intervals as neonates, and although the QT interval normalizes with age, the adults remain susceptible to arrhythmias when treated with the alpha1-agonist methoxamine. We will test the hypotheses that Merg1 mutations cause LQTS and arrhythmias by affecting both IKr and IKs, that the cellular mechanisms that control QT interval are in part distinct from those that lead to arrhythmias, and that Merg1 is essential for cardiovascular development. Specifically, we will 1) Correlate changes in channel expression in Merg1+/- mice of several ages to changes in cardiac K+ currents; 2) Determine whether pharmacological agents that cause arrhythmias in the mice prolong the QT interval; 3) Mate the Merg1+/-mouse to a minK-/-/lacZ mouse to identify areas of altered minK expression and the significance of the Merg1/minK interaction in-vivo; and 4) Study the effects of the loss of Merg1 on embryonic development. A better understanding of the molecular basis of cardiac electrophysiology is an essential first step towards the goal of

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ameliorating the diverse group of diseases known as cardiac arrhythmias. The studies proposed here will extend our knowledge of the role of the HERG gene family in normal cardiac function and help to define the mechanisms by which mutations lead to arrhythmias. Information gained from these studies may help to clarify the mechanisms of the more common arrhythmias that cause sudden death. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE STUDY OF HERG-INTERACTING PROTEINS IN C. ELGANS Principal Investigator & Institution: Petersen, Christina I.; Anesthesiology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2003; Project Start 01-DEC-2001; Project End 30-NOV-2003 Summary: (the applicant?s description verbatim): Mutations in the human ether-a-go-go related gene (HERG) are linked to acquired and inherited forms of the long QT syndrome (LQTS), which can provoke the life-threatening arrythmia, Torsades de Pointes. Acquired LQTS is induced by a variety of drugs, many of which block HERG, underscoring the importance of this voltage-gated K+ channel in the maintenance of normal cardiac rhythm. Accessory proteins (beta subunits) are known to modify the current and drug sensitivity of various voltage-gated K+ channels, including HERG. We will study HERG function and accessory protein interactions in vivo using the model organism, C. elegans. An orthologue of HERG, unc-103, has been identified in C. elegans. We will test the hypothesis that unc-103 possesses biophysical and pharmacologic features characteristic of HERG, and that C. elegans can be used as a model organism for identifying and isolating HERG-interacting proteins. To accomplish this goal we will: 1. Determine if HERG and UNC-l03 have analogous function, using complemenatary approaches of a) electrophysiological characterization of unc-103 biophysics and drug sensitivity, in a heterologous expression system and b) in vivo pharmacologic characterization of worms that carry an unc-103 gain-of-function (gf mutation. 2. Characterize candidate UNC-103-interacting proteins, using similar heterologous electrophysiologic and in vivo assays, and 3. Isolate novel UNC-103 interacting proteins using a genetic mutagenesis screen in the C. elegans unc-103 gf background. These studies will improve our understanding of HERG and HERG/accessory protein interactions, and will facilitate drug design and aid in the prevention of life-threatening arrythmias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THERAPY OF REPOLARIZATION ABNORMALITIES Principal Investigator & Institution: Mason, Jay W.; Professor and Chairman; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002 Summary: In the preceding grant cycle our work on the long QT syndrome (LQTS) progressed rapidly from genetics through ion channel biophysics in clinical studies. The discovery in Keating's laboratory of the gene defect in LQT2 led rapidly to the discovery in Sanguinetti's laboratory that LQT is due to l/Kr defects. Our first clinical study of intravenous potassium in a patient with LQT2 took place within four months of the discovery of the abnormal gene. Project 6 continues our effort to develop gene-specific therapy for arrhythmias secondary to repolarization abnormalities. Subproject 3.1 is a multicenter feasibility trial of potassium for prevention of arrhythmia in patients with l/Kr mutations. We have already shown that acutely increased serum potassium improves repolarization in patients with this form of LQTS. We intend to investigate

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whether this finding can be applied clinically. In this pilot study, we will determine the feasibility of multicenter identification and genotyping of affected families, recruitment of both children and adults with inherited LQTS, compliance with prolonged therapy, and effectiveness of multicenter data collection and protocol enforcement. In a substudy, we will test the specificity of therapies that have been considered gene-specific in LQT2 and LQT3. We hypothesize that QT reduction by non-specific therapy has less therapeutic efficacy than gene-specific therapy, which we expect to effect a much greater improvement in ST segment and T wave (STT) abnormalities than non-specific therapy. Subproject 3.2 is a clinical investigation of idiopathic ventricular fibrillation (IVF) and VF associated with anti-arrhythmic drug pro- arrhythmia (pIVF) in patients displaying the Brugada syndrome phenotype. Many of these patients have SCN5A mutations. We will investigate conduction and transmural repolarization differences in order to understand how presumed sodium channel dysfunction disturbs the normal transmural activation and recovery processes. We will also evaluate the ability of pharmacologic therapy to correct the abnormalities. Some therapies have already been envisioned, while others will be conceptualized on the electrophysiological observations in this Project. We will subsequently evaluate long term efficacy of potential treatments for this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VOLTAGE SENSITIVE SODIUM CHANNELS IN BRAIN Principal Investigator & Institution: Catterall, William A.; Professor and Chairman; Pharmacology; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-DEC-1979; Project End 30-NOV-2003 Summary: The final common pathway of electrical excitability in neurons is generation of conducted action potentials. Action potentials in nerve and muscle are initiated by activation of voltage-gated sodium channels, and the threshold and frequency of firing which encode information in the nervous system are critically dependent on sodium channel properties. The ion conductance activity of sodium channels is controlled on the millisecond time scale by two distinct but coupled gating processes: activation and inactivation. Activation controls the voltage- and time-dependence of conductance increase in response to depolarization, and inactivation controls the voltage- and timedependence of the subsequent return of the sodium conductance to the basal level within one millisecond. Both processes are essential for normal electrical excitability of nerve and muscle cells, and elucidation of their molecular basis is a major challenge for molecular neurobiology. The essential nature of the inactivation process is illustrated by the striking effects of dominant mutations which impair this process in the periodic paralyses of skeletal muscle and long QT syndrome in the heart. One can anticipate that similar hyperexcitability syndromes may be caused by mutations in brain sodium channels and contribute to both inherited and spontaneously arising forms of epilepsy. In the current project period, we have made substantial progress on several topics related to the molecular basis for sodium channel inactivation, its modulation by second messenger- activated protein phosphorylation and by peptide neurotoxins, and its interaction with pore-blocking drugs. We have discovered the key amino acid residues in the inactivation gate which are essential for its function, elucidated the threedimensional structure of the key region of the inactivation gate, identified candidate residues involved in formation of the inactivation gate receptor, defined the phosphorylation sites responsible for regulation of channel gating by protein phosphorylation initiated by the dopamine D1/cAMP-dependent protein kinase signaling pathway and the muscarinic acetylcholine/protein kinase C signaling

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pathway in neurons, and identified important components of the receptor site for scorpion toxins and local anesthetic drugs which interact with the inactivation process. In the next project period, we propose to build on this foundation of molecular information about sodium channel gating and further define the molecular basis of its physiological and pharmacological regulation. Our objectives are to elucidate the molecular interactions of the inactivation gate with the putative inactivation gate receptor, to define the three-dimensional structure of the inactivation gate, to probe the molecular mechanisms by which protein phosphorylation influences sodium channel gating and define the interactions of the relevant phosphorylation sites with the inactivation gate, to determine the molecular basis for high affinity binding of local anesthetics to inactivated channels and for molecular trapping of these drugs in their receptor site by closure of the channel activation and inactivation gates, and to analyze the coupling of movements of the S4 voltage sensors to voltage-dependent activation and inactivation using alpha- and beta-scorpion toxins as specific molecular probes. These proposed studies will give new insight into the molecular mechanisms of sodium channel gating and its modification by second messenger-activated protein phosphorylation and by drugs and neurotoxins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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

A candidate locus approach identifies a long QT syndrome gene mutation. Author(s): Beery TA, Dyment M, Shooner K, Knilans TK, Benson DW. Source: Biological Research for Nursing. 2003 October; 5(2): 97-104. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14531214

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A case series of drug-induced long QT syndrome and Torsade de Pointes. Author(s): Tong KL, Lau YS, Teo WS. Source: Singapore Med J. 2001 December; 42(12): 566-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11989578

3

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 founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics. Author(s): Piippo K, Swan H, Pasternack M, Chapman H, Paavonen K, Viitasalo M, Toivonen L, Kontula K. Source: Journal of the American College of Cardiology. 2001 February; 37(2): 562-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11216980

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A near-fatal case of long QT syndrome in a teenaged male. Author(s): Jones RA, Swor RA. Source: Prehosp Emerg Care. 2001 July-September; 5(3): 296-9. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11446549

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A novel mutation (T65P) in the PAS domain of the human potassium channel HERG results in the long QT syndrome by trafficking deficiency. Author(s): Paulussen A, Raes A, Matthijs G, Snyders DJ, Cohen N, Aerssens J. Source: The Journal of Biological Chemistry. 2002 December 13; 277(50): 48610-6. Epub 2002 September 26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12354768

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A novel mutation in KVLQT1, L122P, found in a family with autosomal dominant long QT syndrome. Author(s): Krahn AD, Wang J, Spindler B, Skanes AC, Yee R, Klein GJ, Hegele RA. Source: American Heart Journal. 2000 July; 140(1): 146-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10874277

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A novel mutation in SCN5A, delQKP 1507-1509, causing long QT syndrome: role of Q1507 residue in sodium channel inactivation. Author(s): Keller DI, Acharfi S, Delacretaz E, Benammar N, Rotter M, Pfammatter JP, Fressart V, Guicheney P, Chahine M. Source: Journal of Molecular and Cellular Cardiology. 2003 December; 35(12): 1513-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14654377

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Acquired long QT syndrome: risk assessment, prudent prescribing and monitoring, and patient education. Author(s): Kunkler K. Source: Journal of the American Academy of Nurse Practitioners. 2002 September; 14(9): 382-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12375357

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Activation-recovery interval as a parameter to assess the intracardiac ventricular repolarization in patients with congenital long QT syndrome. Author(s): Chinushi M, Washizuka T, Hosaka Y, Furushima H, Tanabe Y, Chinushi Y, Aizawa Y. Source: The American Journal of Cardiology. 2002 August 15; 90(4): 432-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12161239

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Altered atrial, atrioventricular, and ventricular conduction in patients with the long QT syndrome caused by the DeltaKPQ SCN5A sodium channel gene mutation. Author(s): Zareba W, Sattari MN, Rosero S, Couderc JP, Moss AJ. Source: The American Journal of Cardiology. 2001 December 1; 88(11): 1311-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11728364

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Altered potassium balance and aldosterone secretion in a mouse model of human congenital long QT syndrome. Author(s): Arrighi I, Bloch-Faure M, Grahammer F, Bleich M, Warth R, Mengual R, Drici MD, Barhanin J, Meneton P. Source: Proceedings of the National Academy of Sciences of the United States of America. 2001 July 17; 98(15): 8792-7. Epub 2001 Jul 03. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11438691

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Amiodarone-induced AV block and ventricular standstill. A forme fruste of an idiopathic long QT syndrome. Author(s): Ravina T, Gutierrez J. Source: International Journal of Cardiology. 2000 August; 75(1): 105-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11203326

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Another role for the sympathetic nervous system in the long QT syndrome? Author(s): Schwartz PJ. Source: Journal of Cardiovascular Electrophysiology. 2001 April; 12(4): 500-2. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11332577

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Are some cases of sudden intrauterine unexplained death due to the long QT syndrome? Author(s): Beinder E, Buheitel G, Hofbeck M. Source: Prenatal Diagnosis. 2003 December 30; 23(13): 1097-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14692000

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Arrhythmias in the congenital long QT syndrome: how often is torsade de pointes pause dependent? Author(s): Viskin S, Fish R, Zeltser D, Belhassen B, Heller K, Brosh D, Laniado S, Barron HV. Source: Heart (British Cardiac Society). 2000 June; 83(6): 661-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10814624

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Assessment for congenital long QT syndrome. Author(s): Heidenreich WF. Source: J Insur Med. 2003; 35(3-4): 196-200. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14971094

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Atrial arrhythmias in the inherited long QT syndrome: laboratory quirk or clinical arrhythmia? Author(s): Vincent GM. Source: Journal of Cardiovascular Electrophysiology. 2003 October; 14(10): 1034-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14521654

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Atrioventricular block in a newborn with acquired long QT syndrome. Author(s): Phillips JR, Case CL, Gillette PC. Source: Cardiology in the Young. 2001 November; 11(6): 680-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11813926

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Beta blockers normalize QT hysteresis in long QT syndrome. Author(s): Krahn AD, Yee R, Chauhan V, Skanes AC, Wang J, Hegele RA, Klein GJ. Source: American Heart Journal. 2002 March; 143(3): 528-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11868061

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Beta2-agonist induced ventricular dysrhythmias secondary to hyperexcitable conduction system in the absence of a long QT syndrome. Author(s): Finn AF Jr, Thompson CM Jr, Banov CH, O'Connor BK, Case CL. Source: Annals of Allergy, Asthma & Immunology : Official Publication of the American College of Allergy, Asthma, & Immunology. 1997 February; 78(2): 230-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9048534

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Biophysical characteristics of a new mutation on the KCNQ1 potassium channel (L251P) causing long QT syndrome. Author(s): Deschenes D, Acharfi S, Pouliot V, Hegele R, Krahn A, Daleau P, Chahine M. Source: Canadian Journal of Physiology and Pharmacology. 2003 February; 81(2): 12934. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12710526

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Bradycardia-dependent long QT syndrome, sudden death and late potentials. Author(s): Surawicz B. Source: Journal of the American College of Cardiology. 1992 March 1; 19(3): 550-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1538008

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Bradycardia-induced long QT syndrome caused by a de novo missense mutation in the S2-S3 inner loop of HERG. Author(s): Yoshida H, Horie M, Otani H, Kawashima T, Onishi Y, Sasayama S. Source: American Journal of Medical Genetics. 2001 February 1; 98(4): 348-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11170080

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Catecholamine-induced T-wave lability in congenital long QT syndrome: a novel phenomenon associated with syncope and cardiac arrest. Author(s): Nemec J, Hejlik JB, Shen WK, Ackerman MJ. Source: Mayo Clinic Proceedings. 2003 January; 78(1): 40-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12528876

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Catecholamine-provoked microvoltage T wave alternans in genotyped long QT syndrome. Author(s): Nemec J, Ackerman MJ, Tester DJ, Hejlik J, Shen WK. Source: Pacing and Clinical Electrophysiology : Pace. 2003 August; 26(8): 1660-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12877697

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Catecholamines in children with congenital long QT syndrome and Brugada syndrome. Author(s): Shimizu W, Kamakura S. Source: Journal of Electrocardiology. 2001; 34 Suppl: 173-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11781952

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Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death. Author(s): Clancy CE, Rudy Y. Source: Cardiovascular Research. 2001 May; 50(2): 301-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11334834

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Cellular mechanisms underlying the long QT syndrome. Author(s): Antzelevitch C, Shimizu W. Source: Current Opinion in Cardiology. 2002 January; 17(1): 43-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11790933

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Cellular mechanisms underlying the long QT syndrome. Author(s): Antzelevitch C, El-Sherif N, Rosenbaum D, Vos M. Source: Journal of Cardiovascular Electrophysiology. 2003 January; 14(1): 114; Author Reply 114-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12625624

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Characterization of a novel Long QT syndrome mutation G52R-KCNE1 in a Chinese family. Author(s): Ma L, Lin C, Teng S, Chai Y, Bahring R, Vardanyan V, Li L, Pongs O, Hui R. Source: Cardiovascular Research. 2003 September 1; 59(3): 612-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14499862

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Characterization of a novel missense mutation E637K in the pore-S6 loop of HERG in a patient with long QT syndrome. Author(s): Hayashi K, Shimizu M, Ino H, Yamaguchi M, Mabuchi H, Hoshi N, Higashida H. Source: Cardiovascular Research. 2002 April; 54(1): 67-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12062363

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Clinical and electrophysiological characterization of a novel mutation (F193L) in the KCNQ1 gene associated with long QT syndrome. Author(s): Yamaguchi M, Shimizu M, Ino H, Terai H, Hayashi K, Mabuchi H, Hoshi N, Higashida H. Source: Clinical Science (London, England : 1979). 2003 April; 104(4): 377-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12653681

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Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Author(s): Khan IA. Source: The American Journal of Medicine. 2002 January; 112(1): 58-66. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11812408

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Clinical features and management of congenital long QT syndrome: a report on 54 patients from a national registry. Author(s): Li C, Hu D, Qin X, Li Y, Li P, Liu W, Li Z, Li L, Wang L. Source: Heart and Vessels. 2004 January; 19(1): 38-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14685754

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Clinical value of electrocardiographic parameters in genotyped individuals with familial long QT syndrome. Author(s): Moennig G, Schulze-Bahr E, Wedekind H, Borggrefe M, Funke H, Toelle M, Kirchhof P, Eckardt L, Assmann G, Breithardt G, Haverkamp W. Source: Pacing and Clinical Electrophysiology : Pace. 2001 April; 24(4 Pt 1): 406-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11341076

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Clinical, genetic, and biophysical characterization of a homozygous HERG mutation causing severe neonatal long QT syndrome. Author(s): Johnson WH Jr, Yang P, Yang T, Lau YR, Mostella BA, Wolff DJ, Roden DM, Benson DW. Source: Pediatric Research. 2003 May; 53(5): 744-8. Epub 2003 March 05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12621127

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Complex electrocardiographic findings in a neonate with long QT syndrome. Author(s): Ann Intern Med. 2002 Dec 17;137(12):I43 Source: Ital Heart J. 2002 October; 3(10): 605-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12484739

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Congenital long QT syndrome and 2:1 atrioventricular block with a mutation of the SCN5A gene. Author(s): Miura M, Yamagishi H, Morikawa Y, Matsuoka R. Source: Pediatric Cardiology. 2003 January-February; 24(1): 70-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12574983

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Congenital Long QT Syndrome presenting as epilepsy. Author(s): S RJ, S PC, Thomas JM, G S. Source: Indian Pediatrics. 2003 December; 40(12): 1201-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14722374

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Congenital long QT syndrome with functionally impaired atrioventricular conduction: successful treatment by mexiletine and propranolol. Author(s): Yao CT, Wang JN, Tsai YC, Lin CS, Wu JM. Source: J Formos Med Assoc. 2002 April; 101(4): 291-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12101867

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Congenital Long QT syndrome. Author(s): Vincent GM, Timothy K, Zhang L. Source: Cardiac Electrophysiology Review. 2002 February; 6(1-2): 57-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11984019

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Congenital long QT syndrome: 50 years of electrophysiological research from cell to bedside. Author(s): Wang L. Source: Acta Cardiol. 2003 April; 58(2): 133-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12715904

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Cosegregation of the Marfan syndrome and the long QT syndrome in the same family leads to a severe cardiac phenotype. Author(s): Probst V, Allouis M, Kyndt F, Lande G, Trochu JN, Schott JJ, Le Marec H. Source: The American Journal of Cardiology. 2003 March 1; 91(5): 635-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12615283

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Dangerous and life-threatening drugs - practical lessons from the long QT syndrome. Author(s): Schutte D, Obel W. Source: Cardiovasc J S Afr. 2002 March-April; 13(2): 54-61. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11981581

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Defective ion channel function in the long QT syndrome: multiple unexpected mechanisms. Author(s): Roden DM. Source: Journal of Molecular and Cellular Cardiology. 2001 February; 33(2): 185-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11162124

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Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing. Author(s): Thomas D, Kiehn J, Katus HA, Karle CA. Source: Cardiovascular Research. 2003 November 1; 60(2): 235-41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14613852

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Delayed sodium channel inactivation mimics long QT syndrome 3. Author(s): Kuhlkamp V, Mewis C, Bosch R, Seipel L. Source: Journal of Cardiovascular Pharmacology. 2003 July; 42(1): 113-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12827035

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Denaturing high-performance liquid chromatography quickly and reliably detects cardiac ion channel mutations in long QT syndrome. Author(s): Ning L, Moss A, Zareba W, Robinson J, Rosero S, Ryan D, Qi M. Source: Genetic Testing. 2003 Fall; 7(3): 249-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14642002

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Device therapy for malignant neonatal long QT syndrome. Author(s): Hoorntje T, Sreeram N, de Vroet R. Source: International Journal of Cardiology. 1999 December 1; 71(3): 289-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10636538

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Diagnostic accuracy of screening electrocardiograms in long QT syndrome I. Author(s): Miller MD, Porter Cb, Ackerman MJ. Source: Pediatrics. 2001 July; 108(1): 8-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11433047

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Diagnostic accuracy of screening electrocardiograms in the long QT syndrome. Author(s): Krovetz LJ. Source: Pediatrics. 2002 May; 109(5): 985. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11986469

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Diagnostic criteria for the long QT syndrome. An update. Author(s): Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Source: Circulation. 1993 August; 88(2): 782-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8339437

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Diagnostic performance of various QTc interval formulas in a large family with long QT syndrome type 3: Bazett's formula not so bad after all. Author(s): Brouwer J, Van Den Berg MP, Grobbee DE, Haaksma J, Wilde AA. Source: Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2003 October; 8(4): 269-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14516281

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Diagnostic value of recovery time measured by body surface mapping in patients with congenital long QT syndrome. Author(s): Shimizu W, Kamakura S, Ohe T, Kurita T, Takaki H, Aihara N, Shimomura K. Source: The American Journal of Cardiology. 1994 October 15; 74(8): 780-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7942549

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Differential effects of beta-blockade on dispersion of repolarization in the absence and presence of sympathetic stimulation between the LQT1 and LQT2 forms of congenital long QT syndrome. Author(s): Shimizu W, Tanabe Y, Aiba T, Inagaki M, Kurita T, Suyama K, Nagaya N, Taguchi A, Aihara N, Sunagawa K, Nakamura K, Ohe T, Towbin JA, Priori SG, Kamakura S. Source: Journal of the American College of Cardiology. 2002 June 19; 39(12): 1984-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12084597

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Differential response of QTU interval to exercise, isoproterenol, and atrial pacing in patients with congenital long QT syndrome. Author(s): Shimizu W, Ohe T, Kurita T, Shimomura K. Source: Pacing and Clinical Electrophysiology : Pace. 1991 November; 14(11 Pt 2): 196670. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1721208

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Differential response of transmural dispersion of repolarization and torsade de pointes to beta-adrenergic agonists and antagonists in three models of the long QT syndrome. Author(s): Shimizu W, Antzelevitch C. Source: Journal of Electrocardiology. 1999; 32 Suppl: 150. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10688318

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Dispersion of regional wall motion abnormality in patients with long QT syndrome. Author(s): Nakayama K, Yamanari H, Otsuka F, Fukushima K, Saito H, Fujimoto Y, Emori T, Matsubara H, Uchida S, Ohe T. Source: Heart (British Cardiac Society). 1998 September; 80(3): 245-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9875083

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Dispersion of the QT interval. A marker of therapeutic efficacy in the idiopathic long QT syndrome. Author(s): Priori SG, Napolitano C, Diehl L, Schwartz PJ. Source: Circulation. 1994 April; 89(4): 1681-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7908611

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Drug-induced long QT syndrome and Torsade de Pointes. Author(s): Chism S, Smith E. Source: J Ark Med Soc. 2004 July; 101(1): 24-6. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15270138

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Drug-induced torsades de pointes in one patient with congenital long QT syndrome. Author(s): Hsieh MH, Chen SA, Chiang CE, Tai CT, Lee SH, Wen ZC, Chang MS. Source: International Journal of Cardiology. 1996 April 19; 54(1): 85-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8792191

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Dynamic relationship between the Q-aT interval and heart rate in patients with long QT syndrome during 24-hour Holter ECG monitoring. Author(s): Emori T, Ohe T, Aihara N, Kurita T, Shimizu W, Kamakura S, Shimomura K. Source: Pacing and Clinical Electrophysiology : Pace. 1995 October; 18(10): 1909-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8539160

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Dysrhythmias controlled with stellate ganglion block in a child with diabetes and a variant of long QT syndrome. Author(s): Mesa A, Kaplan RF. Source: Reg Anesth. 1993 January-February; 18(1): 60-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8095401

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ECG features of microvolt T-wave alternans in coronary artery disease and long QT syndrome patients. Author(s): Pacing Clin Electrophysiol. 1999 Jun;22(6 Pt 1):979-80 Source: Journal of Electrocardiology. 1998; 31 Suppl: 114-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10392405

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Effect of age and overweight on the QT interval and the prevalence of long QT syndrome in children. Author(s): Fukushige T, Yoshinaga M, Shimago A, Nishi J, Kono Y, Nomura Y, Miyata K, Imamura M, Shibata T, Nagashima M, Niimura I. Source: The American Journal of Cardiology. 2002 February 15; 89(4): 395-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11835918

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Effect of atropine on QT prolongation and torsade de pointes induced by intracoronary acetylcholine in the long QT syndrome. Author(s): Furushima H, Niwano S, Chinushi M, Yamaura M, Taneda K, Washizuka T, Aizawa Y. Source: The American Journal of Cardiology. 1999 March 1; 83(5): 714-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10080424

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Effect of phenylephrine provocation on dispersion of repolarization in congenital long QT syndrome. Author(s): Khositseth A, Nemec J, Hejlik J, Shen WK, Ackerman MJ. Source: Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2003 July; 8(3): 208-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14510655

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Effect of the antimalarial drug halofantrine in the long QT syndrome due to a mutation of the cardiac sodium channel gene SCN5A. Author(s): Piippo K, Holmstrom S, Swan H, Viitasalo M, Raatikka M, Toivonen L, Kontula K. Source: The American Journal of Cardiology. 2001 April 1; 87(7): 909-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11274952

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Effects of beta-adrenergic antagonists on the QT measurements from exercise stress tests in pediatric patients with long QT syndrome. Author(s): Kaltman JR, Ro PS, Stephens P, McBride MG, Cohen MI, Tanel RE, Vetter VL, Rhodes LA. Source: Pediatric Cardiology. 2003 November-December; 24(6): 553-8. Epub 2003 September 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12947504

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Effects of cardiac sympathetic innervation on regional wall motion abnormality in patients with long QT syndrome. Author(s): Yamanari H, Nakayama K, Morita H, Miyazi K, Fukushima K, Matsubara H, Emori T, Ohe T. Source: Heart (British Cardiac Society). 2000 March; 83(3): 295-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10677409

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Effects of glucose-induced insulin secretion on ventricular repolarization in patients with congenital long QT syndrome. Author(s): Nishizaki M, Ashikaga T, Yamawake N, Fujii H, Arita M, Sumitomo N, Sakurada H, Hiraoka M. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2002 January; 66(1): 35-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11999663

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Effects of sevoflurane on QT interval in a patient with congenital long QT syndrome. Author(s): Gallagher JD, Weindling SN, Anderson G, Fillinger MP. Source: Anesthesiology. 1998 December; 89(6): 1569-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9856735

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Effects of sympathetic stimulation on various repolarization indices in the congenital long QT syndrome. Author(s): Shimizu W. Source: Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2002 October; 7(4): 332-42. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12431311

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Electrical alternans in long QT syndrome resembling a Brugada syndrome pattern. Author(s): Schulze-Bahr E, Zoelch KA, Eckardt L, Haverkamp W, Breithardt G, Borggrefe M. Source: Pacing and Clinical Electrophysiology : Pace. 2003 October; 26(10): 2033-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14516346

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Electrical behavior of T-wave polarity alternans in patients with congenital long QT syndrome. Author(s): Cruz Filho FE, Maia IG, Fagundes ML, Barbosa RC, Alves PA, Sa RM, Boghossian SH, Ribeiro JC. Source: Journal of the American College of Cardiology. 2000 July; 36(1): 167-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10898429

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Electrocardiographic changes following exercise in the congenitally deaf school children: relationship with Jervell Lange Neilsen syndrome (the Long QT syndrome). Author(s): Srivastava RD, Pramod J, Deep J, Jaison TM, Singh S, Soni K. Source: Indian J Physiol Pharmacol. 1998 October; 42(4): 515-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10874353

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Electrocardiographic features of inherited diseases that predispose to the development of cardiac arrhythmias, long QT syndrome, arrhythmogenic right ventricular cardiomyopathy/dysplasia, and Brugada syndrome. Author(s): Marcus FI. Source: Journal of Electrocardiology. 2000; 33 Suppl: 1-10. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11265707

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Electrocardiographic prediction of abnormal genotype in congenital long QT syndrome: experience in 101 related family members. Author(s): Kaufman ES, Priori SG, Napolitano C, Schwartz PJ, Iyengar S, Elston RC, Schnell AH, Gorodeski EZ, Rammohan G, Bahhur NO, Connuck D, Verrilli L, Rosenbaum DS, Brown AM. Source: Journal of Cardiovascular Electrophysiology. 2001 April; 12(4): 455-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11332568

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Enhancement of closed-state inactivation in long QT syndrome sodium channel mutation DeltaKPQ. Author(s): Chen T, Sheets MF. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2002 September; 283(3): H966-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12181125

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Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome. Author(s): Ackerman MJ, Khositseth A, Tester DJ, Hejlik JB, Shen WK, Porter CB. Source: Mayo Clinic Proceedings. 2002 May; 77(5): 413-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12004990

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Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome. Author(s): Ackerman MJ, Tester DJ, Jones GS, Will ML, Burrow CR, Curran ME. Source: Mayo Clinic Proceedings. 2003 December; 78(12): 1479-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14661677

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Evaluation of QT interval duration and dispersion and proposed clinical criteria in diagnosis of long QT syndrome in patients with a genetically uniform type of LQT1. Author(s): Swan H, Saarinen K, Kontula K, Toivonen L, Viitasalo M. Source: Journal of the American College of Cardiology. 1998 August; 32(2): 486-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9708480

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Evaluation of regional cardiac sympathetic innervation in congenital long QT syndrome using 123I-MIBG scintigraphy. Author(s): Momose M, Kobayashi H, Kasanuki H, Kusakabe K, Tamaki A, Onishi S, Okawa T. Source: Nuclear Medicine Communications. 1998 October; 19(10): 943-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10234674

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Face immersion in cold water induces prolongation of the QT interval and T-wave changes in children with nonfamilial long QT syndrome. Author(s): Yoshinaga M, Kamimura J, Fukushige T, Kusubae R, Shimago A, Nishi J, Kono Y, Nomura Y, Miyata K. Source: The American Journal of Cardiology. 1999 May 15; 83(10): 1494-7, A8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10335770

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Familial and acquired long qt syndrome and the cardiac rapid delayed rectifier potassium current. Author(s): Witchel HJ, Hancox JC. Source: Clinical and Experimental Pharmacology & Physiology. 2000 October; 27(10): 753-66. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11022966

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Familial long QT syndrome: electrical storm and implantable cardioverter device therapy. Author(s): Saxon LA, Shannon K, Wetzel GT, Endler LK, Klitzner TS. Source: American Heart Journal. 1996 May; 131(5): 1037-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8615293

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Famotidine and acquired long QT syndrome. Author(s): Endo T, Katoh T, Kiuchi K, Katsuta Y, Shimizu S, Takano T. Source: The American Journal of Medicine. 2000 April 1; 108(5): 438-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10759110

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Famotidine and long QT syndrome. Author(s): Lee KW, Kayser SR, Hongo RH, Tseng ZH, Scheinman MM. Source: The American Journal of Cardiology. 2004 May 15; 93(10): 1325-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15135720

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Famotidine does not induce long QT syndrome: experimental evidence from in vitro and in vivo test systems. Author(s): Sugiyama A, Satoh Y, Takahara A, Nakamura Y, Shimizu-Sasamata M, Sato S, Miyata K, Hashimoto K. Source: European Journal of Pharmacology. 2003 April 11; 466(1-2): 137-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12679150

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Fetal presentation of congenital long QT syndrome. Author(s): Donofrio MT, Gullquist SD, O'Connell NG, Redwine FO. Source: Pediatric Cardiology. 1999 November-December; 20(6): 441-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10556395

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Fetal sinus bradycardia and the long QT syndrome. Author(s): Beinder E, Grancay T, Menendez T, Singer H, Hofbeck M. Source: American Journal of Obstetrics and Gynecology. 2001 September; 185(3): 743-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11568808

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Fetal ventricular tachycardia in long QT syndrome. Author(s): Yamada M, Nakazawa M, Momma K. Source: Cardiology in the Young. 1998 January; 8(1): 119-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9680283

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Fetus with long QT syndrome manifested by tachyarrhythmia: a case report. Author(s): Ohkuchi A, Shiraishi H, Minakami H, Eguchi Y, Izumi A, Sato I. Source: Prenatal Diagnosis. 1999 October; 19(10): 990-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10521830

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Frequency-dependent electrophysiologic properties of ventricular repolarization in patients with congenital long QT syndrome. Author(s): Hirao H, Shimizu W, Kurita T, Suyama K, Aihara N, Kamakura S, Shimomura K. Source: Journal of the American College of Cardiology. 1996 November 1; 28(5): 1269-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8890826

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Functional effects of mutations in KvLQT1 that cause long QT syndrome. Author(s): Wang Z, Tristani-Firouzi M, Xu Q, Lin M, Keating MT, Sanguinetti MC. Source: Journal of Cardiovascular Electrophysiology. 1999 June; 10(6): 817-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10376919

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Gender differences in the long QT syndrome: effects of beta-adrenoceptor blockade. Author(s): Conrath CE, Wilde AA, Jongbloed RJ, Alders M, van Langen IM, van Tintelen JP, Doevendans PA, Opthof T. Source: Cardiovascular Research. 2002 February 15; 53(3): 770-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11861047

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Gene specific therapy for cardiac disease: the case of long QT syndrome. Author(s): Priori SG. Source: Rev Port Cardiol. 1998 November; 17 Suppl 3: Iii27-38. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9857743

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Gene-specific differences in the circadian variation of ventricular repolarization in the long QT syndrome: a key to sudden death during sleep? Author(s): Stramba-Badiale M, Priori SG, Napolitano C, Locati EH, Vinolas X, Haverkamp W, Schulze-Bahr E, Goulene K, Schwartz PJ. Source: Ital Heart J. 2000 May; 1(5): 323-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10832806

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Gene-specific lethality of arrhythmic events in the long QT syndrome? A message from the International Registry. Author(s): Schwartz PJ. Source: European Heart Journal. 1999 August; 20(16): 1137-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10448016

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Gene-specific response of dynamic ventricular repolarization to sympathetic stimulation in LQT1, LQT2 and LQT3 forms of congenital long QT syndrome. Author(s): Noda T, Takaki H, Kurita T, Suyama K, Nagaya N, Taguchi A, Aihara N, Kamakura S, Sunagawa K, Nakamura K, Ohe T, Horie M, Napolitano C, Towbin JA, Priori SG, Shimizu W. Source: European Heart Journal. 2002 June; 23(12): 975-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12069453

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Genetically defined therapy of inherited long QT syndrome. Author(s): Pinski SL. Source: Circulation. 1997 March 18; 95(6): 1675-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9118555

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Genetics and molecular biology of the inherited long QT syndrome. Author(s): Vincent GM. Source: Annals of Medicine. 1994 December; 26(6): 419-25. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7695867

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Genetics of the long QT syndrome. Author(s): Keating M. Source: Journal of Cardiovascular Electrophysiology. 1994 February; 5(2): 146-53. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8186885

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Genetics, molecular mechanisms and management of long QT syndrome. Author(s): Wang Q, Chen Q, Towbin JA. Source: Annals of Medicine. 1998 February; 30(1): 58-65. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9556090

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Genomic organization and mutational analysis of HERG, a gene responsible for familial long QT syndrome. Author(s): Itoh T, Tanaka T, Nagai R, Kamiya T, Sawayama T, Nakayama T, Tomoike H, Sakurada H, Yazaki Y, Nakamura Y. Source: Human Genetics. 1998 April; 102(4): 435-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9600240

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Genomic organization and mutational analysis of KVLQT1, a gene responsible for familial long QT syndrome. Author(s): Itoh T, Tanaka T, Nagai R, Kikuchi K, Ogawa S, Okada S, Yamagata S, Yano K, Yazaki Y, Nakamura Y. Source: Human Genetics. 1998 September; 103(3): 290-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9799083

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Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1. Author(s): Splawski I, Shen J, Timothy KW, Vincent GM, Lehmann MH, Keating MT. Source: Genomics. 1998 July 1; 51(1): 86-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9693036

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Genotype and severity of long QT syndrome. Author(s): Towbin JA, Wang Z, Li H. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2001 April; 29(4 Pt 2): 574-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11259355

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Genotype and severity of long QT syndrome. Author(s): Towbin JA, Wang Z, Li H. Source: Archives of Pathology & Laboratory Medicine. 2001 January; 125(1): 116-21. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11151064

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Genotype-specific clinical manifestation in long QT syndrome. Author(s): Shimizu W. Source: Expert Rev Cardiovasc Ther. 2003 September; 1(3): 401-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15030268

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Grapefruit and tonic: a deadly combination in a patient with the long QT syndrome. Author(s): Hermans K, Stockman D, Van den Branden F. Source: The American Journal of Medicine. 2003 April 15; 114(6): 511-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12727589

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Heart rate acceleration without changes in the QT interval and severe ventricular tachyarrhythmias: a variant of the long QT syndrome? Author(s): Santinelli V, Chiariello M. Source: International Journal of Cardiology. 1983 August; 4(1): 69-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6618721

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Heart rate variability in patients with congenital long QT syndrome. Author(s): Perkiomaki JS, Zareba W, Couderc JP, Moss AJ. Source: Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2001 October; 6(4): 298-304. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11686910

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Hereditary long QT syndrome associated with cardiac conduction system disease. Author(s): Greenspon AJ, Kidwell GA, Barrasse LD, Hessen SE, Giudici M. Source: Pacing and Clinical Electrophysiology : Pace. 1989 March; 12(3): 479-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2466273

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Hereditary long QT syndrome in the postoperative cardiac patient. Author(s): Klitzner T. Source: Clin Cardiol. 1990 February; 13(2): 139-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2306886

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HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects. Author(s): Zhou Z, Gong Q, Epstein ML, January CT. Source: The Journal of Biological Chemistry. 1998 August 14; 273(33): 21061-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9694858

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Heterogeneity in the inherited long QT syndrome. Author(s): Vincent GM. Source: Journal of Cardiovascular Electrophysiology. 1995 February; 6(2): 137-46. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7780629

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Heterozygous mutation in the pore of potassium channel gene KvLQT1 causes an apparently normal phenotype in long QT syndrome. Author(s): Neyroud N, Denjoy I, Donger C, Gary F, Villain E, Leenhardt A, Benali K, Schwartz K, Coumel P, Guicheney P. Source: European Journal of Human Genetics : Ejhg. 1998 March-April; 6(2): 129-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9781056

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High-rate atrial pacing as an innovative bridging therapy in a neonate with congenital long QT syndrome. Author(s): Tanel RE, Triedman JK, Walsh EP, Epstein MR, DeLucca JM, Mayer JE Jr, Fishberger SB, Saul JP. Source: Journal of Cardiovascular Electrophysiology. 1997 July; 8(7): 812-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9255689

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Holter monitoring in the long QT syndrome of children and adolescents. Author(s): Makarov LM, Belokon NA, Laan MI, Belozerov YuM, Shkol'nikova MI, Krugliakov IV. Source: Cor Vasa. 1990; 32(6): 474-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1707772

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Homozygosity for a HERG potassium channel mutation causes a severe form of long QT syndrome: identification of an apparent founder mutation in the Finns. Author(s): Piippo K, Laitinen P, Swan H, Toivonen L, Viitasalo M, Pasternack M, Paavonen K, Chapman H, Wann KT, Hirvela E, Sajantila A, Kontula K. Source: Journal of the American College of Cardiology. 2000 June; 35(7): 1919-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10841244

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How reliable is asking the "right question" in diagnosing idiopathic long QT syndrome? Author(s): Peeters CM, Wijnberger DE, Kamphuis DJ, Algra A, Benatar A, Peters AC. Source: Lancet. 1995 April 8; 345(8954): 925. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7707830

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Human congenital long QT syndrome: more than previously thought? Author(s): Attali B. Source: Trends in Pharmacological Sciences. 2002 June; 23(6): 249-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12084623

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Hypokalemia-induced long QT syndrome with an underlying novel missense mutation in S4-S5 linker of KCNQ1. Author(s): Kubota T, Shimizu W, Kamakura S, Horie M. Source: Journal of Cardiovascular Electrophysiology. 2000 September; 11(9): 1048-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11021476

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Hypothesis for the molecular physiology of the Romano-Ward long QT syndrome. Author(s): Vincent GM. Source: Journal of the American College of Cardiology. 1992 August; 20(2): 500-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1321848

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Ibutilide-induced long QT syndrome and torsade de pointes. Author(s): Gowda RM, Punukollu G, Khan IA, Patlola RR, Tejani FH, Cosme-Thormann BF, Vasavada BC, Sacchi TJ. Source: American Journal of Therapeutics. 2002 November-December; 9(6): 527-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12424513

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Identical twins with long QT syndrome associated with a missense mutation in the S4 region of the HERG. Author(s): Hayashi K, Shimizu M, Ino H, Okeie K, Yamaguchi M, Yasuda T, Fujino N, Fujii H, Fujita S, Mabuchi H. Source: Japanese Heart Journal. 2000 May; 41(3): 399-404. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10987356

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Identification of a new SCN5A mutation, D1840G, associated with the long QT syndrome. Mutations in brief no. 153. Online. Author(s): Benhorin J, Goldmit M, MacCluer JW, Blangero J, Goffen R, Leibovitch A, Rahat A, Wang Q, Medina A, Towbin J, Kerem B. Source: Human Mutation. 1998; 12(1): 72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10627139

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Identification of specific pore residues mediating KCNQ1 inactivation. A novel mechanism for long QT syndrome. Author(s): Seebohm G, Scherer CR, Busch AE, Lerche C. Source: The Journal of Biological Chemistry. 2001 April 27; 276(17): 13600-5. Epub 2001 January 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11278406

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Idiopathic long QT syndrome masquerading as epilepsy. Author(s): el Mauhoub M, Sabharwal HS, Aggarwal VP, Ben Musa AA, Shembesh AA. Source: Indian Pediatrics. 1988 January; 25(1): 94-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3220531

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Idiopathic long QT syndrome: asking the right question. Author(s): Singh B, al Shahwan SA, Habbab MA, al Deeb SM, Biary N. Source: Lancet. 1993 March 20; 341(8847): 741-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8095637

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Images in cardiology: Visualisation of activation and repolarisation in congenital long QT syndrome. Author(s): Shimizu W, Satomi K, Kamakura S. Source: Heart (British Cardiac Society). 2002 August; 88(2): 190. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12117856

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Implantable cardioverter defibrillator in high-risk long QT syndrome patients. Author(s): Viskin S. Source: Journal of Cardiovascular Electrophysiology. 2003 October; 14(10): 1130-1; Reply 1131. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14521674

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Implantable cardioverter defibrillator in high-risk long QT syndrome patients. Author(s): Zareba W, Moss AJ, Daubert JP, Hall WJ, Robinson JL, Andrews M. Source: Journal of Cardiovascular Electrophysiology. 2003 April; 14(4): 337-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12741701

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Implantable cardioverter defibrillator therapy in a patient with the idiopathic long QT syndrome. Author(s): Gronefeld G, Holtgen R, Hohnloser SH. Source: Pacing and Clinical Electrophysiology : Pace. 1996 August; 19(8): 1260-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8865226

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Implantable cardioverter defibrillator therapy in patients with arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, or no structural heart disease. Author(s): Breithardt G, Wichter T, Haverkamp W, Borggrefe M, Block M, Hammel D, Scheld HH. Source: American Heart Journal. 1994 April; 127(4 Pt 2): 1151-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8160595

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Indapamide induced syncope in a patient with long QT syndrome. Author(s): Wang CP, Guo GB. Source: Pacing and Clinical Electrophysiology : Pace. 2002 September; 25(9): 1397-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12380780

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Interaction with GM130 during HERG ion channel trafficking. Disruption by type 2 congenital long QT syndrome mutations. Human Ether-a-go-go-Related Gene. Author(s): Roti EC, Myers CD, Ayers RA, Boatman DE, Delfosse SA, Chan EK, Ackerman MJ, January CT, Robertson GA. Source: The Journal of Biological Chemistry. 2002 December 6; 277(49): 47779-85. Epub 2002 September 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12270925

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Intracoronary acetylcholine-induced prolongation of monophasic action potential in long QT syndrome. Author(s): Furushima H, Niwano S, Chinushi M, Shiba M, Fujita S, Abe A, Ohhira K, Taneda K, Aizawa Y. Source: Japanese Heart Journal. 1998 March; 39(2): 225-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9687831

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Intraoperative epinephrine-induced torsades de pointes in a child with long QT syndrome. Author(s): Richardson MG, Roark GL, Helfaer MA. Source: Anesthesiology. 1992 April; 76(4): 647-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1550292

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Is exercise testing useful in identifying congenital long QT syndrome? Author(s): Dillenburg RF, Hamilton RM. Source: The American Journal of Cardiology. 2002 January 15; 89(2): 233-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11792352

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Is gender a risk factor for adverse drug reactions? The example of drug-induced long QT syndrome. Author(s): Drici MD, Clement N. Source: Drug Safety : an International Journal of Medical Toxicology and Drug Experience. 2001; 24(8): 575-85. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11480490

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Is long QT syndrome entering the era of molecular diagnosis? Author(s): Priori SG. Source: Heart (British Cardiac Society). 1997 January; 77(1): 5-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9038683

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Is restoration of intracellular trafficking clinically feasible in the long QT syndrome?: The example of HERG mutations. Author(s): Kaufman ES, Ficker E. Source: Journal of Cardiovascular Electrophysiology. 2003 March; 14(3): 320-2. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716119

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Is there a role for implantable cardioverter defibrillators in long QT syndrome? Author(s): Welde AA. Source: Journal of Cardiovascular Electrophysiology. 2002 January; 13(1 Suppl): S110-3. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11852886

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KCNQ1 and KCNH2 mutations associated with long QT syndrome in a Chinese population. Author(s): Liu W, Yang J, Hu D, Kang C, Li C, Zhang S, Li P, Chen Z, Qin X, Ying K, Li Y, Li Y, Li Z, Cheng X, Li L, Qi Y, Chen S, Wang Q. Source: Human Mutation. 2002 December; 20(6): 475-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12442276

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KCNQ1 gene mutations and the respective genotype-phenotype correlations in the long QT syndrome. Author(s): Herbert E, Trusz-Gluza M, Moric E, Smilowska-Dzielicka E, Mazurek U, Wilczok T. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2002 October; 8(10): Ra240-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12388934

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Kearns-Sayre syndrome: association with long QT syndrome? Author(s): Rashid A, Kim MH. Source: Journal of Cardiovascular Electrophysiology. 2002 February; 13(2): 184-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11900295

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KVLQT1 mutations in three families with familial or sporadic long QT syndrome. Author(s): Russell MW, Dick M 2nd, Collins FS, Brody LC. Source: Human Molecular Genetics. 1996 September; 5(9): 1319-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8872472

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Linkage and mutation analysis in two Taiwanese families with long QT syndrome. Author(s): Ko YL, Tai DY, Chen SA, Lee-Chen GJ, Chu CH, Lin MW. Source: J Formos Med Assoc. 2001 November; 100(11): 767-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11802537

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Location of mutation in the KCNQ1 and phenotypic presentation of long QT syndrome. Author(s): Zareba W, Moss AJ, Sheu G, Kaufman ES, Priori S, Vincent GM, Towbin JA, Benhorin J, Schwartz PJ, Napolitano C, Hall WJ, Keating MT, Qi M, Robinson JL, Andrews ML; International LQTS Registry, University of Rochester, Rochester, New York. Source: Journal of Cardiovascular Electrophysiology. 2003 November; 14(11): 1149-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678125

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Long QT interval resembling long QT syndrome in a newborn with electrolyte dysbalance. Author(s): Ayangade-Johnson G, Villafane J. Source: J Ky Med Assoc. 2001 July; 99(7): 285-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11468869

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Long QT syndrome and anaesthesia. Author(s): Booker PD, Whyte SD, Ladusans EJ. Source: British Journal of Anaesthesia. 2003 March; 90(3): 349-66. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12594150

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Long QT syndrome and anaesthesia. Author(s): Wisely NA, Shipton EA. Source: European Journal of Anaesthesiology. 2002 December; 19(12): 853-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12510903

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Long QT syndrome and life threatening arrhythmia in a newborn: molecular diagnosis and treatment response. Author(s): Schulze-Bahr E, Fenge H, Etzrodt D, Haverkamp W, Monnig G, Wedekind H, Breithardt G, Kehl HG. Source: Heart (British Cardiac Society). 2004 January; 90(1): 13-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14676229

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Long QT syndrome caused by noncardiac drugs. Author(s): Viskin S, Justo D, Halkin A, Zeltser D. Source: Progress in Cardiovascular Diseases. 2003 March-April; 45(5): 415-27. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12704598

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Long QT syndrome in children. Author(s): Zareba W, Moss AJ. Source: Journal of Electrocardiology. 2001; 34 Suppl: 167-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11781951

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Long QT syndrome in children: the value of rate corrected QT interval and DNA analysis as screening tests in the general population. Author(s): Allan WC, Timothy K, Vincent GM, Palomaki GE, Neveux LM, Haddow JE. Source: Journal of Medical Screening. 2001; 8(4): 173-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11743032

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Long QT syndrome in children: the value of the rate corrected QT interval in children who present with fainting. Author(s): Allan WC, Timothy K, Vincent GM, Palomaki GE, Neveux LM, Haddow JE. Source: Journal of Medical Screening. 2001; 8(4): 178-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11743033

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Long QT syndrome in neonates: conduction disorders associated with HERG mutations and sinus bradycardia with KCNQ1 mutations. Author(s): Lupoglazoff JM, Denjoy I, Villain E, Fressart V, Simon F, Bozio A, Berthet M, Benammar N, Hainque B, Guicheney P. Source: Journal of the American College of Cardiology. 2004 March 3; 43(5): 826-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14998624

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Long QT syndrome manifesting as pulseless epilepsy. Author(s): Abass FA, Shahi M, Kumar N, Bhargava M, Gupta S, Puliyel JM. Source: Indian J Pediatr. 2003 January; 70(1): 97-100. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12619962

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Long QT syndrome patients may faint due to neurocardiogenic syncope. Author(s): Toft E, Aaroe J, Jensen BT, Christiansen M, Fog L, Thomsen PE, Kanters JK. Source: Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 2003 October; 5(4): 367-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14753633

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Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation. Author(s): Grant AO, Carboni MP, Neplioueva V, Starmer CF, Memmi M, Napolitano C, Priori S. Source: The Journal of Clinical Investigation. 2002 October; 110(8): 1201-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12393856

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Long QT Syndrome. Author(s): Moss AJ. Source: Jama : the Journal of the American Medical Association. 2003 April 23-30; 289(16): 2041-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12709446

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Long QT syndrome: a preventable cause of sudden death in women. Author(s): Engelstein ED. Source: Curr Womens Health Rep. 2003 April; 3(2): 126-34. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12628082

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Long QT syndrome: diagnosis and management. Author(s): Khan IA. Source: American Heart Journal. 2002 January; 143(1): 7-14. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11773906

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Long QT syndrome: first and fatal events provoked by hemodialysis. Author(s): Miller RF, Haley MW, Littmann L. Source: Pacing and Clinical Electrophysiology : Pace. 2003 January; 26(1 Pt 1): 103-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12685147

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Long QT syndrome: novel insights into the mechanisms of cardiac arrhythmias. Author(s): Kass RS, Moss AJ. Source: The Journal of Clinical Investigation. 2003 September; 112(6): 810-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12975462

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Long term follow up of long QT syndrome treated by overdrive pacing. Author(s): Campanelli B, Chaudron JM. Source: Heart (British Cardiac Society). 2001 November; 86(5): E14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11602565

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Malignant familial long QT syndrome. Author(s): Subramanyan R, Venugopalan P. Source: Saudi Med J. 2002 June; 23(6): 738-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12070560

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Management of patients with the hereditary long QT syndrome. Author(s): Moss AJ. Source: Journal of Cardiovascular Electrophysiology. 1998 June; 9(6): 668-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9654236

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Mapping of a gene for long QT syndrome to chromosome 4q25-27. Author(s): Schott JJ, Charpentier F, Peltier S, Foley P, Drouin E, Bouhour JB, Donnelly P, Vergnaud G, Bachner L, Moisan JP, et al. Source: American Journal of Human Genetics. 1995 November; 57(5): 1114-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7485162

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Mechanism of ventricular arrhythmias in the long QT syndrome: on hermeneutics. Author(s): El-Sherif N. Source: Journal of Cardiovascular Electrophysiology. 2001 August; 12(8): 973-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11513452

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Missense mutation in the pore region of HERG causes familial long QT syndrome. Author(s): Benson DW, MacRae CA, Vesely MR, Walsh EP, Seidman JG, Seidman CE, Satler CA. Source: Circulation. 1996 May 15; 93(10): 1791-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8635257

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Mode of onset of torsade de pointes in congenital long QT syndrome. Author(s): Viskin S, Alla SR, Barron HV, Heller K, Saxon L, Kitzis I, Hare GF, Wong MJ, Lesh MD, Scheinman MM. Source: Journal of the American College of Cardiology. 1996 November 1; 28(5): 1262-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8890825

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Modulating effects of age and gender on the clinical course of long QT syndrome by genotype. Author(s): Zareba W, Moss AJ, Locati EH, Lehmann MH, Peterson DR, Hall WJ, Schwartz PJ, Vincent GM, Priori SG, Benhorin J, Towbin JA, Robinson JL, Andrews ML, Napolitano C, Timothy K, Zhang L, Medina A; International Long QT Syndrome Registry. Source: Journal of the American College of Cardiology. 2003 July 2; 42(1): 103-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12849668

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Molecular analysis at the Harvey Ras-1 gene in patients with long QT syndrome. Author(s): Schulze-Bahr E, Haverkamp W, Wiebusch H, Schulte H, Hordt M, Borggrefe M, Breithardt G, Assmann G, Funke H. Source: Journal of Molecular Medicine (Berlin, Germany). 1995 November; 73(11): 565-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8751140

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Molecular biology of heart disease. Synopsis of the pathophysiological basis of cardiac hypertrophy, familial hypertrophic cardiomyopathy, long QT syndrome and Marfan syndrome. Author(s): Kurabayashi M, Yazaki Y. Source: Intern Med. 1996 April; 35(4): 243-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8739775

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Molecular biology of the long QT syndrome: impact on management. Author(s): Priori SG, Napolitano C, Paganini V, Cantu F, Schwartz PJ. Source: Pacing and Clinical Electrophysiology : Pace. 1997 August; 20(8 Pt 2): 2052-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9272507

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Molecular genetics of long QT syndrome from genes to patients. Author(s): Wang Q, Chen Q, Li H, Towbin JA. Source: Current Opinion in Cardiology. 1997 May; 12(3): 310-20. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9243089

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Molecular mechanisms underlying the long QT syndrome. Author(s): Dumaine R, Antzelevitch C. Source: Current Opinion in Cardiology. 2002 January; 17(1): 36-42. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11790932

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Molecular screening of selected long QT syndrome (LQTS) mutations in 165 consecutive bodies found in water. Author(s): Lunetta P, Levo A, Laitinen PJ, Fodstad H, Kontula K, Sajantila A. Source: International Journal of Legal Medicine. 2003 April; 117(2): 115-7. Epub 2003 February 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12690509

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Monophasic action potential recordings during T-wave alternans in congenital long QT syndrome. Author(s): Shimizu W, Yamada K, Arakaki Y, Kamiya T, Shimomura K. Source: American Heart Journal. 1996 September; 132(3): 699-701. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8800049

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Morphological algebraic models of the TU-wave patterns/in idiopathic long QT syndrome. Author(s): Padrini R, Butrous G, Statters D, Camm AJ, Malik M. Source: International Journal of Cardiology. 2001 February; 77(2-3): 151-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11182179

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Multiple single-nucleotide polymorphisms (SNPs) in the Japanese population in six candidate genes for long QT syndrome. Author(s): Iwasa H, Kurabayashi M, Nagai R, Nakamura Y, Tanaka T. Source: Journal of Human Genetics. 2001; 46(3): 158-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11310586

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Multi-undulant T-U-wave, sinus bradycardia and long QT syndrome: a possible phenotype of mutant genes controlling the inward potassium rectifiers. Author(s): Shen CT, Wu YC, Yu SS, Wang NK. Source: Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1997 July-August; 38(4): 26775. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9297927

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Mutation analysis in congenital Long QT Syndrome--a case with missense mutations in KCNQ1 and SCN5A. Author(s): Paulussen A, Matthijs G, Gewillig M, Verhasselt P, Cohen N, Aerssens J. Source: Genetic Testing. 2003 Spring; 7(1): 57-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12820704

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Mutation analysis of potassium channel genes KCNQ1 and KCNH2 in patients with long QT syndrome. Author(s): Liu W, Hu D, Li C, Li P, Li Y, Li Z, Li L, Qin X, Dong W, Qi Y, Chen S, Wang Q. Source: Chinese Medical Journal. 2003 September; 116(9): 1333-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14527360

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Mutation detection in long QT syndrome: a comprehensive set of primers and PCR conditions. Author(s): Syrris P, Murray A, Carter ND, McKenna WM, Jeffery S. Source: Journal of Medical Genetics. 2001 October; 38(10): 705-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11594341

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New insight into repolarization abnormalities in patients with congenital long QT syndrome: the increased transmural dispersion of repolarization. Author(s): Lubinski A, Lewicka-Nowak E, Kempa M, Baczynska AM, Romanowska I, Swiatecka G. Source: Pacing and Clinical Electrophysiology : Pace. 1998 January; 21(1 Pt 2): 172-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9474667

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New missense mutation (G626V) in the predicted selectivity filter of the HERG channel associated with familial long QT syndrome. Author(s): Jahr S, Lewalter T, Hesch RD, Luderitz B, Englisch S. Source: Human Mutation. 2000 June; 15(6): 584. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10862104

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Nicorandil abolished repolarisation alternans in a patient with idiopathic long QT syndrome. Author(s): Fujimoto Y, Morita H, Fukushima KK, Ohe T. Source: Heart (British Cardiac Society). 1999 November; 82(5): E8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10525528

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Nicorandil suppresses a hump on the monophasic action potential and torsade de pointes in a patient with idiopathic long QT syndrome. Author(s): Chinushi M, Aizawa Y, Furushima H, Inuzuka H, Ojima K, Shibata A. Source: Japanese Heart Journal. 1995 July; 36(4): 477-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7474363

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No evidence for linkage of long QT syndrome and chromosome 11p15.5 markers in a Chinese family: evidence for genetic heterogeneity. Author(s): Ko YL, Chen SA, Tang TK, Lin JL, Chiang CE, Chen JJ, Teng MS, Chang MS, Lien WP, Wu CW. Source: Human Genetics. 1994 October; 94(4): 364-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7927330

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Non-invasive testing of acquired long QT syndrome: evidence for multiple arrhythmogenic substrates. Author(s): Chevalier P, Rodriguez C, Bontemps L, Miquel M, Kirkorian G, Rousson R, Potet F, Schott JJ, Baro I, Touboul P. Source: Cardiovascular Research. 2001 May; 50(2): 386-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11334843

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Normalization of ventricular repolarization with flecainide in long QT syndrome patients with SCN5A:DeltaKPQ mutation. Author(s): Windle JR, Geletka RC, Moss AJ, Zareba W, Atkins DL. Source: Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2001 April; 6(2): 153-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11333173

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Novel characteristics of a misprocessed mutant HERG channel linked to hereditary long QT syndrome. Author(s): Ficker E, Thomas D, Viswanathan PC, Dennis AT, Priori SG, Napolitano C, Memmi M, Wible BA, Kaufman ES, Iyengar S, Schwartz PJ, Rudy Y, Brown AM. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2000 October; 279(4): H1748-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11009462

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Novel compound heterozygous mutations in the KCNQ1 gene associated with autosomal recessive long QT syndrome (Jervell and Lange-Nielsen syndrome). Author(s): Ning L, Moss AJ, Zareba W, Robinson J, Rosero S, Ryan D, Qi M. Source: Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2003 July; 8(3): 246-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14510661

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Novel donor splice site mutation in the KVLQT1 gene is associated with long QT syndrome. Author(s): Kanters JK, Larsen LA, Orholm M, Agner E, Andersen PS, Vuust J, Christiansen M. Source: Journal of Cardiovascular Electrophysiology. 1998 June; 9(6): 620-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9654228

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Novel insights in the congenital long QT syndrome. Author(s): Wehrens XH, Vos MA, Doevendans PA, Wellens HJ. Source: Annals of Internal Medicine. 2002 December 17; 137(12): 981-92. Review. Summary for Patients In: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12484714

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Novel missense mutation (G601S) of HERG in a Japanese long QT syndrome family. Author(s): Akimoto K, Furutani M, Imamura S, Furutani Y, Kasanuki H, Takao A, Momma K, Matsuoka R. Source: Human Mutation. 1998; Suppl 1: S184-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9452080

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Novel missense mutation in the cyclic nucleotide-binding domain of HERG causes long QT syndrome. Author(s): Satler CA, Walsh EP, Vesely MR, Plummer MH, Ginsburg GS, Jacob HJ. Source: American Journal of Medical Genetics. 1996 October 2; 65(1): 27-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8914737

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Occult T wave alternans in long QT syndrome. Author(s): Platt SB, Vijgen JM, Albrecht P, Van Hare GF, Carlson MD, Rosenbaum DS. Source: Journal of Cardiovascular Electrophysiology. 1996 February; 7(2): 144-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8853024

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Pause-dependent torsade de pointes following acute myocardial infarction: a variant of the acquired long QT syndrome. Author(s): Halkin A, Roth A, Lurie I, Fish R, Belhassen B, Viskin S. Source: Journal of the American College of Cardiology. 2001 October; 38(4): 1168-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11583899

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Perioperative management of long QT syndrome in a child with congenital heart disease. Author(s): Das SN, Kiran U, Saxena N. Source: Acta Anaesthesiologica Scandinavica. 2002 February; 46(2): 221-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11942876

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Phenotype (ECG)-genotype considerations in long QT syndrome and Brugada syndrome. Author(s): Moss AJ. Source: Journal of Cardiovascular Electrophysiology. 2000 September; 11(9): 1055-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11021477

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Picture of the month. Jervell and Lange-Nielsen syndrome (long QT syndrome). Author(s): Narchi H, Tunnessen WW Jr. Source: Archives of Pediatrics & Adolescent Medicine. 1999 April; 153(4): 425-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10201729

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Polymorphisms in beta-adrenergic receptor genes in the acquired long QT syndrome. Author(s): Kanki H, Yang P, Xie HG, Kim RB, George AL Jr, Roden DM. Source: Journal of Cardiovascular Electrophysiology. 2002 March; 13(3): 252-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11942593

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Positive head-up tilt table test in patients with the long QT syndrome. Author(s): Hermosillo AG, Falcon JC, Marquez MF, Arteaga D, Cardenas M. Source: Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 1999 October; 1(4): 213-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11220556

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Possible bradycardic mode of death and successful pacemaker treatment in a large family with features of long QT syndrome type 3 and Brugada syndrome. Author(s): van den Berg MP, Wilde AA, Viersma TJW, Brouwer J, Haaksma J, van der Hout AH, Stolte-Dijkstra I, Bezzina TCR, Van Langen IM, Beaufort-Krol GC, Cornel JH 2nd, Crijns HJ. Source: Journal of Cardiovascular Electrophysiology. 2001 June; 12(6): 630-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11405394

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Postextrasystolic "T wave hump" augmentation as a marker of increased arrhythmogenic risk in the long QT syndrome. Author(s): Wedekind H, Schulze-Bahr E, Djonlagic H. Source: Heart (British Cardiac Society). 2002 December; 88(6): 633. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12433898

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Potassium and long QT syndrome: a new look at an old therapy. Author(s): Bisinov E, Mitchell JH, January CT. Source: Journal of the American College of Cardiology. 2003 November 19; 42(10): 17834. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14642688

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Prenatal diagnosis and in utero treatment of torsades de pointes associated with congenital long QT syndrome. Author(s): Cuneo BF, Ovadia M, Strasburger JF, Zhao H, Petropulos T, Schneider J, Wakai RT. Source: The American Journal of Cardiology. 2003 June 1; 91(11): 1395-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12767447

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Prenatal diagnosis and successful preterm delivery of a fetus with long QT syndrome. Author(s): Manning N, Anthony JP, Ostman-Smith I, Snyder CS, Burch M. Source: Bjog : an International Journal of Obstetrics and Gynaecology. 2000 August; 107(8): 1049-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10955442

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Prenatal diagnosis and treatment of fetal long QT syndrome: a case report. Author(s): Chang IK, Shyu MK, Lee CN, Kau ML, Ko YH, Chow SN, Hsieh FJ. Source: Prenatal Diagnosis. 2002 December; 22(13): 1209-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12478635

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Prenatal diagnosis of long QT syndrome using fetal magnetocardiography. Author(s): Hamada H, Horigome H, Asaka M, Shigemitsu S, Mitsui T, Kubo T, Kandori A, Tsukada K. Source: Prenatal Diagnosis. 1999 July; 19(7): 677-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10419620

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Prenatal diagnosis of long QT syndrome using magnetocardiography: a case report and review of the literature. Author(s): Hosono T, Kawamata K, Chiba Y, Kandori A, Tsukada K. Source: Prenatal Diagnosis. 2002 March; 22(3): 198-200. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11920893

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Prenatal molecular genetic diagnosis of congenital long QT syndrome by strategic genotyping. Author(s): Tester DJ, McCormack J, Ackerman MJ. Source: The American Journal of Cardiology. 2004 March 15; 93(6): 788-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15019897

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Prevalence of idiopathic long QT syndrome in congenital sensori-neural hearing loss students of Songkhla School for the Deaf. Author(s): Sopontammarak S, Khongphatthanayothin A, Sa-Nguanchua P. Source: J Med Assoc Thai. 2003 December; 86(12): 1149-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14971523

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Preventing deaths from long QT syndrome. Author(s): Pilley SF. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2001 March 20; 164(6): 747-8; Author Reply 748-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11276535

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Prevention of drug-induced long QT syndrome: gender, chemistry, and education. Author(s): Vincent GM. Source: Journal of Cardiovascular Electrophysiology. 2001 May; 12(5): 546-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11386515

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Prevention of ventricular arrhythmias in the congenital long QT syndrome. Author(s): Viskin S, Fish R. Source: Current Cardiology Reports. 2000 November; 2(6): 492-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11060576

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Prolonged atrial action potential durations and polymorphic atrial tachyarrhythmias in patients with long QT syndrome. Author(s): Kirchhof P, Eckardt L, Franz MR, Monnig G, Loh P, Wedekind H, SchulzeBahr E, Breithardt G, Haverkamp W. Source: Journal of Cardiovascular Electrophysiology. 2003 October; 14(10): 1027-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14521653

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QT and JT dispersion in children with long QT syndrome. Author(s): Shah MJ, Wieand TS, Rhodes LA, Berul CI, Vetter VL. Source: Journal of Cardiovascular Electrophysiology. 1997 June; 8(6): 642-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9209965

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Q-T peak dispersion in congenital long QT syndrome: possible marker of mutation of HERG. Author(s): Inoue M, Shimizu M, Ino H, Yamaguchi M, Terai H, Hayashi K, Kiyama M, Sakata K, Hayashi T, Mabuchi H. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2003 June; 67(6): 495-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12808265

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Quantitative analysis of T wave abnormalities and their prognostic implications in the idiopathic long QT syndrome. Author(s): Malfatto G, Beria G, Sala S, Bonazzi O, Schwartz PJ. Source: Journal of the American College of Cardiology. 1994 February; 23(2): 296-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7905012

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Rate adaptation of QT intervals during and after exercise in children with congenital long QT syndrome. Author(s): Swan H, Toivonen L, Viitasalo M. Source: European Heart Journal. 1998 March; 19(3): 508-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9568456

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Recent advances in understanding the mechanisms, diagnosis and treatment of congenital and acquired long QT syndrome. Author(s): Sra J, Akhtar M. Source: Indian Heart J. 1996 November-December; 48(6): 639-51. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9062011

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Recent advances in understanding the molecular mechanisms of the long QT syndrome. Author(s): Roden DM, George AL Jr, Bennett PB. Source: Journal of Cardiovascular Electrophysiology. 1995 November; 6(11): 1023-31. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8589871

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Recurrent syncope in a young patient with long QT syndrome: possible relationship of atrioventricular nodal re-entrant tachycardia with neurally mediated spells? Author(s): Horlitz M, Schley P, Marx R, Klein M, Bufe A, Lapp H, Krakau I, Gulker H, Haverkamp W. Source: Wiener Medizinische Wochenschrift (1946). 2003; 153(1-2): 46-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12621693

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Recurrent syncope. Drug induced long QT syndrome. Author(s): Mansfield RJ, Thomas RD. Source: Postgraduate Medical Journal. 2001 May; 77(907): 344, 352-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11320287

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Relation between ventricular repolarization duration and cardiac cycle length during 24-hour Holter recordings. Findings in normal patients and patients with long QT syndrome. Author(s): Merri M, Moss AJ, Benhorin J, Locati EH, Alberti M, Badilini F. Source: Circulation. 1992 May; 85(5): 1816-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1572038

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Repolarization analysis in children with the long QT syndrome. Author(s): Brockmeier K, Khalil M, Sreeram N, Ulmer HE. Source: Journal of Electrocardiology. 2003; 36 Suppl: 209-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14716636

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Repolarization dynamics in patients with long QT syndrome. Author(s): Perkiomaki JS, Zareba W, Nomura A, Andrews M, Kaufman ES, Moss AJ. Source: Journal of Cardiovascular Electrophysiology. 2002 July; 13(7): 651-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12139286

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Report of a life-threatening arrhythmia after hospital discharge in a liver transplant recipient with previously unknown congenital long QT syndrome. Author(s): Biancofiore G, Valentini C, Cellai F, Filipponi F, Mosca F, Vagelli A. Source: Dig Liver Dis. 2001 June-July; 33(5): 432-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11529656

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Resolution of electrical storms after discontinuation of ICD therapy in a child with long QT syndrome. Author(s): Shah MJ, Rhodes LA. Source: Pediatric Cardiology. 2002 March-April; 23(2): 213-5. Epub 2002 February 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11889538

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Response of the QT interval to mental and physical stress in types LQT1 and LQT2 of the long QT syndrome. Author(s): Paavonen KJ, Swan H, Piippo K, Hokkanen L, Laitinen P, Viitasalo M, Toivonen L, Kontula K. Source: Heart (British Cardiac Society). 2001 July; 86(1): 39-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11410559

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Retention in the endoplasmic reticulum as a mechanism of dominant-negative current suppression in human long QT syndrome. Author(s): Ficker E, Dennis AT, Obejero-Paz CA, Castaldo P, Taglialatela M, Brown AM. Source: Journal of Molecular and Cellular Cardiology. 2000 December; 32(12): 2327-37. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11113008

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Right ventricular monophasic action potentials in patients with long QT syndrome. Author(s): Fenici R. Source: British Heart Journal. 1979 November; 42(5): 615-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=518789

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Right ventricular monophasic action potentials in patients with long QT syndrome. Author(s): Gavrilescu S, Luca C. Source: British Heart Journal. 1978 September; 40(9): 1014-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=708526

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Risk of cardiac events in family members of patients with long QT syndrome. Author(s): Zareba W, Moss AJ, le Cessie S, Locati EH, Robinson JL, Hall WJ, Andrews ML. Source: Journal of the American College of Cardiology. 1995 December; 26(7): 1685-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7594104

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Role of alpha1-blockade in congenital long QT syndrome: investigation by exercise stress test. Author(s): Furushima H, Chinushi M, Washizuka T, Aizawa Y. Source: Japanese Circulation Journal. 2001 July; 65(7): 654-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11446501

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Role of DNA testing for diagnosis, management, and genetic screening in long QT syndrome, hypertrophic cardiomyopathy, and Marfan syndrome. Author(s): Vincent GM. Source: Heart (British Cardiac Society). 2001 July; 86(1): 12-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11410552

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Role of left cardiac sympathetic denervation in the management of congenital long QT syndrome. Author(s): Wang LX. Source: Journal of Postgraduate Medicine. 2003 April-June; 49(2): 179-81. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12867702

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Role of vagotony in sinus node dysfunction in children with symptomatic congenital long QT syndrome. Author(s): Matsuoka S, Akita H, Takahashi Y, Nishioka A, Kuroda Y. Source: Acta Paediatr Jpn. 1993 February; 35(1): 27-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8460541

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Romano-Ward long QT syndrome: identification of a HERG mutation in a Taiwanese kindred. Author(s): Lee-Chen GJ, Tai DY, Chu CH, Teng YN. Source: J Formos Med Assoc. 1999 September; 98(9): 649-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10560244

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Saving lives in congenital long QT syndrome: who benefits from implantable cardioverter defibrillator therapy? Author(s): Kaufman ES. Source: Journal of Cardiovascular Electrophysiology. 2003 April; 14(4): 342-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12741702

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Screening for drug-induced (acquired) long QT syndrome: is it time to apply new methods? Author(s): Puddu PE, Criniti A, Monti F. Source: European Heart Journal. 2001 March; 22(5): 363-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11207077

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Septic cardiomyopathy as a cause of long QT syndrome. Author(s): Varriale P, Ramaprasad S. Source: Journal of Electrocardiology. 1995 October; 28(4): 327-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8551176

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Significance of QT dispersion in the long QT syndrome. Author(s): Napolitano C, Priori SG, Schwartz PJ. Source: Progress in Cardiovascular Diseases. 2000 March-April; 42(5): 345-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10768312

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Single-channel characteristics of wild-type IKs channels and channels formed with two minK mutants that cause long QT syndrome. Author(s): Sesti F, Goldstein SA. Source: The Journal of General Physiology. 1998 December; 112(6): 651-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9834138

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Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects. Author(s): Swan H, Viitasalo M, Piippo K, Laitinen P, Kontula K, Toivonen L. Source: Journal of the American College of Cardiology. 1999 September; 34(3): 823-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10483966

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Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations. Author(s): Wattanasirichaigoon D, Vesely MR, Duggal P, Levine JC, Blume ED, Wolff GS, Edwards SB, Beggs AH. Source: American Journal of Medical Genetics. 1999 October 29; 86(5): 470-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10508990

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Some legal, social, and ethical issues related to the genetic testing revolution, as exemplified in the long QT syndrome. Author(s): Liebman J. Source: Journal of Electrocardiology. 2001; 34 Suppl: 183-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11781954

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Stratification of time-frequency abnormalities in the signal-averaged high-resolution ECG in postinfarction patients with and without ventricular tachycardia and congenital long QT syndrome. Author(s): Couderc JP, Fareh S, Chevalier P, Fayn J, Kirkorian G, Rubel P, Touboul P. Source: Journal of Electrocardiology. 1996; 29 Suppl: 180-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9238397

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Stress-induced polymorphous ventricular tachyarrhythmias in two brothers: unusual pattern of inheritance in the long QT syndrome. Author(s): Pfammatter JP, Gertsch M, Weber JW, Stocker FP, Moser H, Kappenberger L. Source: Clin Cardiol. 1993 June; 16(6): 517-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8358888

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Structural and functional basis for the long QT syndrome: relevance to veterinary patients. Author(s): Finley MR, Lillich JD, Gilmour RF Jr, Freeman LC. Source: J Vet Intern Med. 2003 July-August; 17(4): 473-88. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12892298

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Sudden arrhythmia death syndrome: importance of the long QT syndrome. Author(s): Meyer JS, Mehdirad A, Salem BI, Kulikowska A, Kulikowski P. Source: American Family Physician. 2003 August 1; 68(3): 483-8. Review. Erratum In: Am Fam Physician. 2004 May 15; 69(10): 2324. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12924831

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Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects. Author(s): Laitinen P, Fodstad H, Piippo K, Swan H, Toivonen L, Viitasalo M, Kaprio J, Kontula K. Source: Human Mutation. 2000 June; 15(6): 580-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10862094

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Sustained ventricular tachycardia in long QT syndrome: is propofol the culprit? Author(s): Rewari V, Kaul H. Source: Anesthesiology. 2003 September; 99(3): 764. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12960575

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Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. Author(s): Ackerman MJ, Tester DJ, Porter CJ. Source: Mayo Clinic Proceedings. 1999 November; 74(11): 1088-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10560595

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Sympathetic modulation of the long QT syndrome. Author(s): Antzelevitch C. Source: European Heart Journal. 2002 August; 23(16): 1246-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12175662

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Sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than LQT2 forms of congenital long QT syndrome. Author(s): Tanabe Y, Inagaki M, Kurita T, Nagaya N, Taguchi A, Suyama K, Aihara N, Kamakura S, Sunagawa K, Nakamura K, Ohe T, Towbin JA, Priori SG, Shimizu W. Source: Journal of the American College of Cardiology. 2001 March 1; 37(3): 911-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11693770

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Syncope and long QT syndrome with an initially normal QT interval. Author(s): Garcia-Rubira JC, Aramburu O, Romero D, Valladolid J, Arias JL. Source: International Journal of Cardiology. 1993 July 15; 40(3): 286-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8225664

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Syncope in children and adolescents and the congenital long QT syndrome. Author(s): Khositseth A, Martinez MW, Driscoll DJ, Ackerman MJ. Source: The American Journal of Cardiology. 2003 September 15; 92(6): 746-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12972126

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T wave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmogenicity. Author(s): Yamaguchi M, Shimizu M, Ino H, Terai H, Uchiyama K, Oe K, Mabuchi T, Konno T, Kaneda T, Mabuchi H. Source: Clinical Science (London, England : 1979). 2003 December; 105(6): 671-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12857349

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TDI-echocardiography: a new screening tool for long QT syndrome? Author(s): Tukkie R, Wilde AA. Source: European Journal of Echocardiography : the Journal of the Working Group on Echocardiography of the European Society of Cardiology. 2003 September; 4(3): 157-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12928016

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The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations. Author(s): Ficker E, Obejero-Paz CA, Zhao S, Brown AM. Source: The Journal of Biological Chemistry. 2002 February 15; 277(7): 4989-98. Epub 2001 December 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11741928

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The congenital long QT syndrome. Author(s): Shanbag P, Govindakumar PT, Vaidya M, Joshi V, Shahid SK. Source: Indian J Pediatr. 2002 February; 69(2): 141-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11929030

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The distinct HERG missense mutation L564P causes long QT syndrome in one French Canadian family. Author(s): St-Pierre J, Roy N, Blier L, Plante E, Cote JM, Gilbert M, Chahine M. Source: The Canadian Journal of Cardiology. 2000 March; 16(3): 307-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10744792

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The genetic basis for cardiac dysrhythmias and the long QT syndrome. Author(s): Vizgirda VM. Source: The Journal of Cardiovascular Nursing. 1999 July; 13(4): 34-45. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10386270

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The incorporation of an ion channel gene mutation associated with the long QT syndrome (Q9E-hMiRP1) in a plasmid vector for site-specific arrhythmia gene therapy: in vitro and in vivo feasibility studies. Author(s): Burton DY, Song C, Fishbein I, Hazelwood S, Li Q, DeFelice S, Connolly JM, Perlstein I, Coulter DA, Levy RJ. Source: Human Gene Therapy. 2003 June 10; 14(9): 907-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12828861

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The inherited long QT syndrome: from ion channel to bedside. Author(s): Vincent GM, Timothy K, Fox J, Zhang L. Source: Cardiology in Review. 1999 January-February; 7(1): 44-55. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10348966

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The long QT syndrome and torsade de pointes. Author(s): el-Sherif N, Turitto G. Source: Pacing and Clinical Electrophysiology : Pace. 1999 January; 22(1 Pt 1): 91-110. Review. Erratum In: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9990606

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The long QT syndrome. Author(s): Priori SG, Bloise R, Crotti L. Source: Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 2001 January; 3(1): 16-27. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11271945

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The long QT syndrome: considerations in the athletic population. Author(s): Schulze-Bahr E, Monnig G, Eckardt L, Wedekind H, Wichter T, Breithardt G. Source: Curr Sports Med Rep. 2003 April; 2(2): 72-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12831662

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The role of M cells and the long QT syndrome in cardiac arrhythmias: simulation studies of reentrant excitations using a detailed electrophysiological model. Author(s): Henry H, Rappel WJ. Source: Chaos (Woodbury, N.Y.). 2004 March; 14(1): 172-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15003058

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The use of genotype-phenotype correlations in mutation analysis for the long QT syndrome. Author(s): Van Langen IM, Birnie E, Alders M, Jongbloed RJ, Le Marec H, Wilde AA. Source: Journal of Medical Genetics. 2003 February; 40(2): 141-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12566525

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Tissue Doppler echocardiography in patients with long QT syndrome. Author(s): Savoye C, Klug D, Denjoy I, Ennezat PV, Le Tourneau T, Guicheney P, Kacet S. Source: European Journal of Echocardiography : the Journal of the Working Group on Echocardiography of the European Society of Cardiology. 2003 September; 4(3): 209-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12928025

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Torsades de pointes due to multihormonal deficiency induced long QT syndrome. Author(s): Vythoulkas JS, Hatzizacharias AN, Makris TK, Kyriakidis MK. Source: International Journal of Cardiology. 2000 July 31; 74(2-3): 253-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11203051

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Transmural dispersion of repolarization and arrhythmogenicity: the Brugada syndrome versus the long QT syndrome. Author(s): Antzelevitch C, Yan GX, Shimizu W. Source: Journal of Electrocardiology. 1999; 32 Suppl: 158-65. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10688320

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T-wave patterns associated with the hereditary long QT syndrome. Author(s): Moss AJ. Source: Cardiac Electrophysiology Review. 2002 September; 6(3): 311-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12114857

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Twenty single nucleotide polymorphisms (SNPs) and their allelic frequencies in four genes that are responsible for familial long QT syndrome in the Japanese population. Author(s): Iwasa H, Itoh T, Nagai R, Nakamura Y, Tanaka T. Source: Journal of Human Genetics. 2000; 45(3): 182-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10807545

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Two-to-one AV block associated with the congenital long QT syndrome. Author(s): Pruvot E, De Torrente A, De Ferrari GM, Schwartz PJ, Goy JJ. Source: Journal of Cardiovascular Electrophysiology. 1999 January; 10(1): 108-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9930915

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Unexplained fainting, near drowning and unusual seizures in childhood: screening for long QT syndrome in New Zealand families. Author(s): Bradley T, Dixon J, Easthope R. Source: N Z Med J. 1999 August 13; 112(1093): 299-302. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10493429

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Unsuspected echocardiographic abnormality in the long QT syndrome. Diagnostic, prognostic, and pathogenetic implications. Author(s): Nador F, Beria G, De Ferrari GM, Stramba-Badiale M, Locati EH, Lotto A, Schwartz PJ. Source: Circulation. 1991 October; 84(4): 1530-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1914095

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Unusual presentation of long QT syndrome. Author(s): Cucchiaro G, Rhodes LA. Source: British Journal of Anaesthesia. 2003 June; 90(6): 804-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12765899

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Use of implantable cardioverter-defibrillators in the congenital long QT syndrome. Author(s): Groh WJ, Silka MJ, Oliver RP, Halperin BD, McAnulty JH, Kron J. Source: The American Journal of Cardiology. 1996 September 15; 78(6): 703-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8831415

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Usefulness of the Valsalva maneuver in management of the long QT syndrome. Author(s): Mitsutake A, Takeshita A, Kuroiwa A, Nakamura M. Source: Circulation. 1981 May; 63(5): 1029-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7471361

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Usefulness of Valsalva manoeuvre and cold pressor test for evaluation of arrhythmias in long QT syndrome. Author(s): Rubin SA, Brundage B, Mayer W, Chatterjee K. Source: British Heart Journal. 1979 October; 42(4): 490-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=508482

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Utility of a simplified lidocaine and potassium infusion in diagnosing long QT syndrome among patients with borderline QTc interval prolongation. Author(s): Chauhan VS, Krahn AD, Klein GJ, Skanes AC, Yee R. Source: Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2004 January; 9(1): 12-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14731211

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Value of Holter monitoring in patients with the long QT syndrome. Author(s): Eggeling T, Osterhues HH, Hoeher M, Gabrielsen FG, Weismueller P, Hombach V. Source: Cardiology. 1992; 81(2-3): 107-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1286468

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Variable expression of long QT syndrome among gene carriers from families with five different HERG mutations. Author(s): Benhorin J, Moss AJ, Bak M, Zareba W, Kaufman ES, Kerem B, Towbin JA, Priori S, Kass RS, Attali B, Brown AM, Ficker E. Source: Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2002 January; 7(1): 40-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11844290

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Ventricular fibrillation due to long QT syndrome probably caused by clindamycin. Author(s): Gabel A, Schymik G, Mehmel HC. Source: The American Journal of Cardiology. 1999 March 1; 83(5): 813-5, A11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10080451

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Ventricular fibrillation related to reversal of the neuromuscular blockade in a patient with long QT syndrome. Author(s): Pleym H, Bathen J, Spigset O, Gisvold SE. Source: Acta Anaesthesiologica Scandinavica. 1999 March; 43(3): 352-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10081545

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Ventricular tachyarrhythmias complicating the idiopathic or acquired long QT syndrome: a reentry in the His-Purkinje system? Author(s): Santinelli V, Chiariello M, Condorelli M. Source: Journal of Electrocardiology. 1984 January; 17(1): 103-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6699520

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Ventricular tachycardia during general anesthesia in a patient with congenital long QT syndrome. Author(s): Katz RI, Quijano I, Barcelon N, Biancaniello T. Source: Canadian Journal of Anaesthesia = Journal Canadien D'anesthesie. 2003 April; 50(4): 398-403. English, French. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12670819

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Who is at risk for cardiac events in young patients with long QT syndrome? Author(s): Yoshinaga M, Nagashima M, Shibata T, Niimura I, Kitada M, Yasuda T, Iwamoto M, Kamimura J, Iino M, Horigome H, Seguchi M, Aiba S, Izumida N, Kimura T, Ushinohama H, Nishi J, Kono Y, Nomura Y, Miyata K. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2003 December; 67(12): 1007-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14639015

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CHAPTER 2. NUTRITION AND LONG QT SYNDROME Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and long QT syndrome.

Finding Nutrition Studies on Long QT Syndrome 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.4 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 “long QT syndrome” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

4 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 “long QT syndrome” (or a synonym): •

Long-term (subacute) potassium treatment in congenital HERG-related long QT syndrome (LQTS2). Author(s): Department of Cardiology, University of Amsterdam, Academic Medical Center, The Netherlands. Source: Tan, H L Alings, M Van Olden, R W Wilde, A A J-Cardiovasc-Electrophysiol. 1999 February; 10(2): 229-33 1045-3873

•

Torsade de pointes and long QT syndrome following major blood transfusion. Author(s): Northwick Park Hospital, Harrow, Middlesex. Source: Kulkarni, P Bhattacharya, S Petros, A J Anaesthesia. 1992 February; 47(2): 125-7 0003-2409

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

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

•

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

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

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

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

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

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

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

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

•

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

Nutrition

•

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

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

A dilemma on Orchid Island. Author(s): Weber KT. Source: Cardiovascular Research. 1999 July; 43(1): 2-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10536681

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A new oral therapy for long QT syndrome: long-term oral potassium improves repolarization in patients with HERG mutations. Author(s): Etheridge SP, Compton SJ, Tristani-Firouzi M, Mason JW. Source: Journal of the American College of Cardiology. 2003 November 19; 42(10): 177782. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14642687

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Acquired long QT syndrome and monomorphic ventricular tachycardia after alternative treatment with cesium chloride for brain cancer. Author(s): Dalal AK, Harding JD, Verdino RJ. Source: Mayo Clinic Proceedings. 2004 August; 79(8): 1065-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15301336

•

Acute stress and ventricular arrhythmias. Author(s): Michalsen A, Dobos G. Source: European Heart Journal. 2001 April; 22(8): 712. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11286530

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Association between n-3 fatty acid status in blood and electrocardiographic predictors of arrhythmia risk in healthy volunteers. Author(s): Brouwer IA, Zock PL, van Amelsvoort LG, Katan MB, Schouten EG. Source: The American Journal of Cardiology. 2002 March 1; 89(5): 629-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11867059

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Auditory stimuli as a major cause of syncope in a patient with idiopathic long QT syndrome. Author(s): Nakajima T, Misu K, Iwasawa K, Tamiya E, Segawa K, Matsuo H, Hada K. Source: Japanese Circulation Journal. 1995 April; 59(4): 241-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7658619

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Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). Author(s): Wilde AA, Jongbloed RJ, Doevendans PA, Duren DR, Hauer RN, van Langen IM, van Tintelen JP, Smeets HJ, Meyer H, Geelen JL. Source: Journal of the American College of Cardiology. 1999 February; 33(2): 327-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9973011

•

Comparison of clinical and genetic variables of cardiac events associated with loud noise versus swimming among subjects with the long QT syndrome. Author(s): Moss AJ, Robinson JL, Gessman L, Gillespie R, Zareba W, Schwartz PJ, Vincent GM, Benhorin J, Heilbron EL, Towbin JA, Priori SG, Napolitano C, Zhang L, Medina A, Andrews ML, Timothy K. Source: The American Journal of Cardiology. 1999 October 15; 84(8): 876-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10532503

•

Current Management of Syncope: Treatment Alternatives. Author(s): Morillo CA, Baranchuk A.

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Source: Current Treatment Options in Cardiovascular Medicine. 2004 October; 6(5): 371383. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15324613 •

Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine. Author(s): Nasir JM, Durning SJ, Ferguson M, Barold HS, Haigney MC. Source: Mayo Clinic Proceedings. 2004 August; 79(8): 1059-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15301335

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Impact of sex and gonadal steroids on prolongation of ventricular repolarization and arrhythmias induced by I(K)-blocking drugs. Author(s): Pham TV, Sosunov EA, Gainullin RZ, Danilo P Jr, Rosen MR. Source: Circulation. 2001 May 1; 103(17): 2207-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11331264

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Magnesium treatment of ventricular arrhythmias. Author(s): Roden DM. Source: The American Journal of Cardiology. 1989 April 18; 63(14): 43G-46G. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2650516

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Manipulating the QT interval of the ECG by cognitive effort. Author(s): Huang MH, Ebey J, Wolf S. Source: Pavlov J Biol Sci. 1989 July-September; 24(3): 102-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2771455

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Polymorphic ventricular tachycardia in a woman taking cesium chloride. Author(s): Saliba W, Erdogan O, Niebauer M. Source: Pacing and Clinical Electrophysiology : Pace. 2001 April; 24(4 Pt 1): 515-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11341093

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Primary prevention of sudden death with implantable defibrillator therapy in patients with cardiac disease: Can we afford to do it? (Can we afford not to?). Author(s): Exner DV, Klein GJ, Prystowsky EN. Source: Circulation. 2001 September 25; 104(13): 1564-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11571253

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Studies of magnesium in congenital long QT syndrome. Author(s): Hoshino K, Ogawa K, Hishitani T, Kitazawa R. Source: Pediatric Cardiology. 2002 January-February; 23(1): 41-8. Epub 2002 February 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11922507

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T-wave alternans in LQTS: repolarization-rate dynamics from digital 12-lead Holter data. Author(s): Brockmeier K, Aslan I, Hilbel T, Eberle T, Ulmer HE, Lux RL. Source: Journal of Electrocardiology. 2001; 34 Suppl: 93-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11781942

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Ventricular fibrillation. Author(s): Surawicz B. Source: Journal of the American College of Cardiology. 1985 June; 5(6 Suppl): 43B-54B. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3889113

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Very low calorie diets and pre-fasting prolonged QT interval. A hidden potential danger. Author(s): Thwaites BC, Bose M. Source: The West Indian Medical Journal. 1992 December; 41(4): 169-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1290242

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

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

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

•

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

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

•

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

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

•

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

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

•

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

•

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

•

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

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

•

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

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

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CHAPTER 4. PATENTS ON LONG QT SYNDROME 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.5 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 “long QT syndrome” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on long QT syndrome, we have not necessarily excluded nonmedical patents in this bibliography.

Patents on Long QT Syndrome By performing a patent search focusing on long QT syndrome, 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. 5Adapted

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

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The following is an example of the type of information that you can expect to obtain from a patent search on long QT syndrome: •

Mutations in and genomic structure of HERG--a long QT syndrome gene Inventor(s): Keating; Mark T. (Salt Lake City, UT), Splawski; Igor (Salt Lake City, UT) Assignee(s): University of Utah Research Foundation (Salt Lake City, UT) Patent Number: 6,207,383 Date filed: January 6, 1999 Abstract: The invention relates to the determination of the genomic structure of HERG which is a gene associated with long QT syndrome. The sequences of the 15 intron/exon junctions has been determined and this information is useful in devising primers for amplifying and sequencing across all of the exons of the gene. This is useful for determining the presence or absence of mutations which are known to cause long QT syndrome. Also disclosed are many new mutations in HERG which have been found to be associated with long QT syndrome. Excerpt(s): The present invention is directed to a process for the diagnosis of long QT syndrome (LQT). LQT has been associated with specific genes including HERG, SCN5A, KVLQT1 and KCNE1. LQT may be hereditary and due to specific mutations in the above genes or it may be acquired, e.g., as a result of treatment with drugs given to treat cardiac arrhythmias or of treatment with other types of medications such as antihistamines or antibiotics such as erythromycin. The acquired form of LQT is the more prevalent form of the disorder. It had previously been shown that the HERG gene encodes a K.sup.+ channel which is involved in the acquired form of LQT. It is shown that increasing the K.sup.+ levels in patients taking drugs to prevent cardiac arrhythmias may decrease the chances of the acquired form of LQT from developing and can be used as a preventive measure. Also, this knowledge can now be used to develop drugs which may activate this K.sup.+ channel and which could be given in conjunction with the drugs presently used to treat cardiac arrhythmias. Activation of the K.sup.+ channel should decrease the risk of developing LQT and torsade de pointes. The publications and other materials used herein to illuminate the background of the invention or provide additional details respecting the practice, are incorporated by reference, and for convenience are respectively grouped in the appended List of References. Although sudden death from cardiac arrhythmias is thought to account for 11% of all natural deaths, the mechanisms underlying arrhythmias are poorly understood (Kannel, 1987; Willich et al., 1987). One form of long QT syndrome (LQT) is an inherited cardiac arrhythmia that causes abrupt loss of consciousness, syncope, seizures and sudden death from ventricular tachyarrhythmias, specifically torsade de pointes and ventricular fibrillation (Ward, 1964; Romano, 1965; Schwartz et al., 1975; Moss et al., 1991). This disorder usually occurs in young, otherwise healthy individuals (Ward, 1964; Romano, 1965; Schwartz, 1975). Most LQT gene carriers manifest prolongation of the QT interval on electrocardiograms, a sign of abnormal cardiac repolarization (Vincent et al., 1992). The clinical features of LQT result from episodic cardiac arrhythmias, specifically torsade de pointes, named for the characteristic undulating nature of the electrocardiogram in this arrhythmia. Torsade de pointes may degenerate into ventricular fibrillation, a particularly lethal arrhythmia. Although LQT is not a common diagnosis, ventricular arrhythmias are very common; more than 300,000 United States citizens die suddenly every year (Kannel et al., 1987; Willich et al., 1987) and, in many cases, the underlying mechanism may be aberrant cardiac

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repolarization. LQT, therefore, provides a unique opportunity to study life-threatening cardiac arrhythmias at the molecular level. A more common form of this disorder is called "acquired LQT" and it can be induced by many different factors, particularly treatment with certain medications and reduced serum K.sup.+ levels (hypokalemia). Web site: http://www.delphion.com/details?pn=US06207383__

Patent Applications on Long QT Syndrome As of December 2000, U.S. patent applications are open to public viewing.6 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 long QT syndrome: •

Alterations in the long QT syndrome genes KVLQT1 and SCN5A and methods for detecting same Inventor(s): Keating, Mark T.; (Brookline, MA), Splawski, Igor; (Allston, MA) Correspondence: Rothwell, Figg, Ernst & Manbeck, P.C.; 555 13th Street, N.W.; Suite 701, East Tower; Washington; DC; 20004; US Patent Application Number: 20020061524 Date filed: April 24, 2001 Abstract: Long QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on electrocardiogram and presence of syncope, seizures and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS. These genes are KVLQT1, HERG, SCN5A, KCNE1 and KCNE2. Mutations in KVLQt1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion. Mutational analyses were used to screen 262 unrelated individuals with LQTS for mutations in the five defined genes. A total of 134 mutations were observed of which eighty were novel. Excerpt(s): The present invention is related to provisional application Ser. No. 60/190,057 filed Mar. 17, 2000, and is also related to provisional application Ser. No. 60/147,488 filed Aug. 9, 1999, both of which are incorporated herein by reference. Long QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on electrocardiogram and presence of syncope, seizures and sudden death, usually in young, otherwise healthy individuals (Jervell and Lange-Nielsen, 1957; Romano et al., 1963; Ward, 1964). The clinical features of LQTS result from episodic ventricular tachyarrhythmias, such as torsade de pointes and ventricular fibrillation (Schwartz et al., 1975; Moss et al., 1991). Two inherited forms of LQTS exist. The more common form, Romano-Ward syndrome (RW), is not associated with other phenotypic abnormalities and is inherited as an autosomal dominant trait with variable penetrance (Roman et al., 1963; Ward, 1964). Jervell and Lange-Nielsen syndrome (JLN) is characterized by the presence of deafness, a phenotypic abnormality inherited as an autosomal recessive trait (Jervell and Lange-Nielsen, 1957). LQTS can also be acquired, usually as a result of pharmacologic therapy. In previous studies, we mapped LQTS loci to chromosomes 11p15.5 (LQT1) (Keating et al., 1991), 7 q35-36 (LQT2) (Jiang et al., 1994)

6

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

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and LQT3 to 3p21-24 (Jiang et al., 1994). A fourth locus (LQT4) was mapped to 4q25-27 (Schott et al., 1995). Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS. These genes are KVLQT1 (LQT1) (Wang Q. et al., 1996a), HERG (LQT2) (Curran et al., 1995), SCN5A (LQT3) (Wang et al., 1995a), and two genes located at 21q22-KCNE1 (LQT5) (Splawski et al., 1997a) and KCNE2 (LQT6) (Abbott et al., 1999). Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Mutations in the KCNE1 gene encoding human minK which cause arrhythmia susceptibility thereby establishing KCNE1 as an LQT gene Inventor(s): Keating, Mark T.; (Brookline, MA), Sanguinetti, Michael C.; (Salt Lake City, UT), Splawski, Igor; (Boston, MA) Correspondence: Rothwell, Figg, Ernst & Manbeck, P.C.; 1425 K Street, N.W.; Suite 800; Washington; DC; 20005; US Patent Application Number: 20030054380 Date filed: May 6, 2002 Abstract: The genomic structure including the sequence of the intron/exon junctions is disclosed for KVLQT1 and KCNE1 which are genes associated with long QT syndrome. Additional sequence data for the two genes ARE also disclosed. Also disclosed are newly found mutations in KVLQT1 which result in long QT syndrome. The intron/exon junction sequence data allow for the design of primer pairs to amplify and sequence across all of the exons of the two genes. This can be used to screen persons for the presence of mutations which cause long QT syndrome. Assays can be performed to screen persons for the presence of mutations in either the DNA or proteins. The DNA and proteins may also be used in assays to screen for drugs which will be useful in treating or preventing the occurrence of long QT syndrome. Excerpt(s): The present application is a divisional of application Ser. No. 09/444,295 filed Nov. 22, 1999, which is a divisional of application Ser. No. 09/135,020 filed Aug. 17, 1998, now U.S. Pat. No. 6,274,332, which is continuation-in-part of application Ser. No. 08/921,068 filed Aug. 29, 1997, now abandoned, which is a continuation-in-part of application Ser. No. 08/739,383 filed Oct. 29, 1996, now abandoned, all of which are incorporated herein by reference. The present application is also related to and claims priority under 35 USC.sctn.119(e) to provisional patent application Ser. No. 60/019,014 filed Dec. 22, 1995 and No. 60/094,477 filed Jul. 29, 1998, both of which are incorporated herein by reference. The present invention is directed to genes and gene products associated with long QT syndrome (LQT) and to a process for the diagnosis of LQT. LQT is diagnosed in accordance with the present invention by analyzing the DNA sequence of the KVLQT1 or KCNE1 gene of an individual to be tested and comparing the respective DNA sequence to the known DNA sequence of a normal KVLQT1 or KCNE1 gene. Alternatively, the KVLQT1 or KCNE1 gene of an individual to be tested can be screened for mutations which cause LQT. Prediction of LQT will enable practitioners to prevent this disorder using existing medical therapy. This invention is further directed to the discovery that the KVLQT1 and KCNE1 (also known as minK) proteins coassemble to form a cardiac I.sub.Ks potassium channel. This knowledge can be used to coexpress these two proteins in a cell and such a transformed cell can be used for screening for drugs which will be useful in treating or preventing LQT. The

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invention is further directed to mutations in the human KCNE1 gene (which gene encodes human minK protein) which have been discovered in families with LQT. The publications and other materials used herein to illuminate the background of the invention or provide additional details respecting the practice, are incorporated by reference, and for convenience are respectively grouped in the appended List of References. 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 long QT syndrome, 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 “long QT syndrome” (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 long QT syndrome. You can also use this procedure to view pending patent applications concerning long QT syndrome. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 5. BOOKS ON LONG QT SYNDROME Overview This chapter provides bibliographic book references relating to long QT syndrome. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on long QT syndrome 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 “long QT syndrome” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “long QT syndrome” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “long QT syndrome” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

The Long QT Syndrome (Clinical Approaches to Tachyarrhythmias, V. 7) by Peter J. Schwartz; ISBN: 0879936800; http://www.amazon.com/exec/obidos/ASIN/0879936800/icongroupinterna

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CHAPTER 6. PERIODICALS AND NEWS ON LONG QT SYNDROME Overview In this chapter, we suggest a number of news sources and present various periodicals that cover long QT syndrome.

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

Gene For Long QT Syndrome Identified Source: Reuters Medical News Date: January 02, 1996

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Therapy For Long QT Syndrome Targets Specific Gene Mutation Involved Source: Reuters Medical News Date: December 18, 1995 The NIH

Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “long QT syndrome” (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 “long QT syndrome” (or synonyms). If you know the name of a company that is relevant to long QT syndrome, 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 “long QT syndrome” (or synonyms).

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

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CHAPTER 7. 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 long QT syndrome. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a non-profit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI Advice for the Patient can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with long QT syndrome. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.).

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The following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to long QT syndrome: Amiodarone •

Systemic - U.S. Brands: Cordarone; Cordarone I.V. http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202029.html

Cisapride •

Systemic - U.S. Brands: Propulsid http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202672.html

Erythromycin •

Ophthalmic - U.S. Brands: Ilotycin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202220.html

Ketoconazole •

Topical - U.S. Brands: Nizoral A-D Shampoo; Nizoral Cream; Nizoral Shampoo http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202317.html

Phenothiazines •

Systemic - U.S. Brands: Chlorpromazine Hydrochloride Intensol; Compazine; Compazine Spansule; Mellaril; Mellaril Concentrate; Mellaril-S; Permitil; Permitil Concentrate; Prolixin; Prolixin Concentrate; Prolixin Decanoate; Prolixin Enanthate; Serentil; Serentil Concentrate; Stelazine; Stelazine Concentrate; Thorazine; Thorazine Spansule; Trilafon; Trilafon Concentrate; Vesprin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202457.html

Procainamide •

Systemic - U.S. Brands: Procan SR; Promine; Pronestyl; Pronestyl-SR http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202483.html

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

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

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PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee. 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 Institute7: •

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

7

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

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•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.8 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:9 •

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

8

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). 9 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 Gateway10 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.11 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “long QT syndrome” (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 2880 10 405 2 31 3328

HSTAT12 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.13 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.14 Simply search by “long QT syndrome” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

10

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

11

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). 12 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 13 14

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 Biologists15 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.16 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.17 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/.

15 Adapted 16

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. 17 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 long QT syndrome can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internetbased services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to long QT syndrome. 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 long QT syndrome. 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 “long QT syndrome”:

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Adrenal Gland Disorders http://www.nlm.nih.gov/medlineplus/adrenalglanddisorders.html Arrhythmia http://www.nlm.nih.gov/medlineplus/arrhythmia.html Congenital Heart Disease http://www.nlm.nih.gov/medlineplus/congenitalheartdisease.html Marfan Syndrome http://www.nlm.nih.gov/medlineplus/marfansyndrome.html Prader-Willi Syndrome http://www.nlm.nih.gov/medlineplus/praderwillisyndrome.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The 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 long QT syndrome. 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

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Associations and Long QT Syndrome The following is a list of associations that provide information on and resources relating to long QT syndrome: •

International Long QT Syndrome Registry Telephone: (585) 275-5391 Fax: (585) 273-5283 Email: [email protected] Background: The International Long QT Syndrome Registry is a research organization that maintains an international database on long QT syndrome. The aim of the registry is to improve understanding of the genetics and natural history of this rare heart disorder. It also seeks to improve treatments for affected individuals. Efforts toward improved treatments are aided by families with the disorder and physicians who participate in this worldwide registry program. The registry also publishes in the peerreviewed medical literature. Relevant area(s) of interest: Long QT Syndrome

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to long QT syndrome. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with long QT syndrome. 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 long QT syndrome. 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 “long QT syndrome” (or a synonym), and you will receive information on all relevant organizations listed in the database.

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Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “long QT syndrome”. 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 “long QT syndrome” (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 “long QT syndrome” (or a synonym) into the search box, and click “Submit Query.”

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

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.18

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

18

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)19: •

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

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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/

19

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

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•

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

•

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

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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/

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

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•

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

•

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

•

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

•

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

•

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

•

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

•

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

•

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

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

•

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

•

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

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

•

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

•

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

•

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

•

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

•

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

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

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

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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

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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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

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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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

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•

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

•

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

•

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

•

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

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

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

•

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

•

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

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

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

•

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

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on long QT syndrome: •

Basic Guidelines for Long QT Syndrome Hypokalemia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000479.htm

•

Signs & Symptoms for Long QT Syndrome Syncope Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003092.htm

•

Diagnostics and Tests for Long QT Syndrome ALT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003473.htm ECG Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003868.htm Stress test Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003878.htm

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•

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Background Topics for Long QT Syndrome Asymptomatic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002217.htm

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

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

•

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

•

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

•

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

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LONG QT SYNDROME DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abducens: A striated, extrinsic muscle of the eyeball that originates from the annulus of Zinn. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] ACE: Angiotensin-coverting enzyme. A drug used to decrease pressure inside blood vessels. [NIH]

Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] 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] Action Potentials: The electric response of a nerve or muscle to its stimulation. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adrenergic Agonists: Drugs that bind to and activate adrenergic receptors. [NIH] Adrenergic Antagonists: Drugs that bind to but do not activate adrenergic receptors. Adrenergic antagonists block the actions of the endogenous adrenergic transmitters epinephrine and norepinephrine. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH]

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Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] 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] Aldosterone: (11 beta)-11,21-Dihydroxy-3,20-dioxopregn-4-en-18-al. A hormone secreted by the adrenal cortex that functions in the regulation of electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] 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] Alternans: Ipsilateral abducens palsy and facial paralysis and contralateral hemiplegia of the limbs, due to a nuclear or infranuclear lesion in the pons. [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] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] 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

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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] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] 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] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Anomalies: Birth defects; abnormalities. [NIH] Antiarrhythmic: An agent that prevents or alleviates cardiac arrhythmia. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] 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.

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Abbreviated Ag. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Apnea: A transient absence of spontaneous respiration. [NIH] Aponeurosis: Tendinous expansion consisting of a fibrous or membranous sheath which serves as a fascia to enclose or bind a group of muscles. [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] Arrhythmogenic: Producing or promoting arrhythmia. [EU] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asymptomatic: Having no signs or symptoms of disease. [NIH] Atrial: Pertaining to an atrium. [EU] Atrial Fibrillation: Disorder of cardiac rhythm characterized by rapid, irregular atrial impulses and ineffective atrial contractions. [NIH] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atropine: A toxic alkaloid, originally from Atropa belladonna, but found in other plants, mainly Solanaceae. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Auditory: Pertaining to the sense of hearing. [EU] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Autoradiography: A process in which radioactive material within an object produces an image when it is in close proximity to a radiation sensitive emulsion. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls,

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multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bacteriostatic: 1. Inhibiting the growth or multiplication of bacteria. 2. An agent that inhibits the growth or multiplication of bacteria. [EU] Baroreflex: A negative feedback system which buffers short-term changes in blood pressure. Increased pressure stretches blood vessels which activates pressoreceptors (baroreceptors) in the vessel walls. The net response of the central nervous system is a reduction of central sympathetic outflow. This reduces blood pressure both by decreasing peripheral vascular resistance and by lowering cardiac output. Because the baroreceptors are tonically active, the baroreflex can compensate rapidly for both increases and decreases in blood pressure. [NIH]

Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [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] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biogenesis: The origin of life. It includes studies of the potential basis for life in organic compounds but excludes studies of the development of altered forms of life through mutation and natural selection, which is evolution. [NIH] Biophysics: The science of physical phenomena and processes in living organisms. [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 heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood transfusion: The administration of blood or blood products into a blood vessel. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH]

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Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blotting and transferred to strips of nitrocellulose paper. The blots are then detected by radiolabeled antibody probes. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bone 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] Bradycardia: Excessive slowness in the action of the heart, usually with a heart rate below 60 beats per minute. [NIH] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchodilator: A drug that relaxes the smooth muscles in the constricted airway. [NIH] Buffers: A chemical system that functions to control the levels of specific ions in solution. When the level of hydrogen ion in solution is controlled the system is called a pH buffer. [NIH]

Bupivacaine: A widely used local anesthetic agent. [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] 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] Carboxy: Cannabinoid. [NIH] Carcinogenic: Producing carcinoma. [EU] Cardiac: Having to do with the heart. [NIH] Cardiac arrest: A sudden stop of heart function. [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

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(volume per beat). [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] Cardioselective: Having greater activity on heart tissue than on other tissue. [EU] Cardiotonic: 1. Having a tonic effect on the heart. 2. An agent that has a tonic effect on the heart. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardioversion: Electrical reversion of cardiac arrhythmias to normal sinus rhythm, formerly using alternatic current, but now employing direct current. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Physiology: Characteristics and physiological processes of cells from cell division to cell death. [NIH] Cellular Structures: Components of a cell. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU]

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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] Chaperonins: A class of sequence-related molecular chaperones found in bacteria, mitochondria, and plastids. Chaperonins are abundant constitutive proteins that increase in amount after stresses such as heat shock, bacterial infection of macrophages, and an increase in the cellular content of unfolded proteins. Bacterial chaperonins are major immunogens in human bacterial infections because of their accumulation during the stress of infection. Two members of this class of chaperones are chaperonin 10 and chaperonin 60. [NIH] Chimeras: Organism that contains a mixture of genetically different cells. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clindamycin: An antibacterial agent that is a semisynthetic analog of lincomycin. [NIH] Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Coitus: Sexual intercourse. [NIH]

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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] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU]

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Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constriction: The act of constricting. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contralateral: Having to do with the opposite side of the body. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Copulation: Sexual contact of a male with a receptive female usually followed by emission of sperm. Limited to non-human species. For humans use coitus. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary 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] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] 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] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]

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]

Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH]

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De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decongestant: An agent that reduces congestion or swelling. [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] 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] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Dilated cardiomyopathy: Heart muscle disease that leads to enlargement of the heart's chambers, robbing the heart of its pumping ability. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [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] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH]

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Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Design: The molecular designing of drugs for specific purposes (such as DNAbinding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] 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] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Electrocardiogram: Measurement of electrical activity during heartbeats. [NIH] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] 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] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory

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laboratory test results. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocardium: The innermost layer of the heart, comprised of endothelial cells. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] 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] 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]

Erythromycin: A bacteriostatic antibiotic substance produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. [NIH] Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH]

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Excitability: Property of a cardiac cell whereby, when the cell is depolarized to a critical level (called threshold), the membrane becomes permeable and a regenerative inward current causes an action potential. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] 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] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Extracellular: Outside a cell or cells. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Facial: Of or pertaining to the face. [EU] Facial Paralysis: Severe or complete loss of facial muscle motor function. This condition may result from central or peripheral lesions. Damage to CNS motor pathways from the cerebral cortex to the facial nuclei in the pons leads to facial weakness that generally spares the forehead muscles. Facial nerve diseases generally results in generalized hemifacial weakness. Neuromuscular junction diseases and muscular diseases may also cause facial paralysis or paresis. [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]

Feasibility Studies: Studies to determine the advantages or disadvantages, practicability, or capability of accomplishing a projected plan, study, or project. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [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] Flecainide: A potent anti-arrhythmia agent, effective in a wide range of ventricular and atrial arrhythmias and tachycardias. Paradoxically, however, in myocardial infarct patients with either symptomatic or asymptomatic arrhythmia, flecainide exacerbates the arrhythmia and is not recommended for use in these patients. [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] Fold: A plication or doubling of various parts of the body. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized

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connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Screening: Searching a population or individuals for persons possessing certain genotypes or karyotypes that: (1) are already associated with disease or predispose to disease; (2) may lead to disease in their descendants; or (3) produce other variations not known to be associated with disease. Genetic screening may be directed toward identifying phenotypic expression of genetic traits. It includes prenatal genetic screening. [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] Genital: Pertaining to the genitalia. [EU] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]

Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] 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]

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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] 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] Glycoproteins: Conjugated protein-carbohydrate compounds including mucins, mucoid, and amyloid glycoproteins. [NIH] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heartbeat: One complete contraction of the heart. [NIH] Heat-Shock Proteins: Proteins which are synthesized in eukaryotic organisms and bacteria in response to hyperthermia and other environmental stresses. They increase thermal tolerance and perform functions essential to cell survival under these conditions. [NIH] Heat-Shock Proteins 90: A class of molecular chaperones whose members act in the mechanism of signal transduction by steroid receptors. [NIH] Hemiplegia: Severe or complete loss of motor function on one side of the body. This condition is usually caused by BRAIN DISEASES that are localized to the cerebral hemisphere opposite to the side of weakness. Less frequently, BRAIN STEM lesions; cervical spinal cord diseases; peripheral nervous system diseases; and other conditions may manifest as hemiplegia. The term hemiparesis (see paresis) refers to mild to moderate weakness involving one side of the body. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] 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.

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[NIH]

Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] 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] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [NIH]

Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [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] Hypertrophic cardiomyopathy: Heart muscle disease that leads to thickening of the heart walls, interfering with the heart's ability to fill with and pump blood. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] 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] Idiopathic: Describes a disease of unknown cause. [NIH] Immersion: The placing of a body or a part thereof into a liquid. [NIH] Immunoblotting: Immunologic methods for isolating and quantitatively measuring immunoreactive substances. When used with immune reagents such as monoclonal antibodies, the process is known generically as western blot analysis (blotting, western). [NIH]

Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunology: The study of the body's immune system. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU]

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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] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] 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] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [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] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Interindividual: Occurring between two or more individuals. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active or passive. Passive ion transport (facilitated diffusion) derives its energy from

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the concentration gradient of the ion itself and allows the transport of a single solute in one direction (uniport). Active ion transport is usually coupled to an energy-yielding chemical or photochemical reaction such as ATP hydrolysis. This form of primary active transport is called an ion pump. Secondary active transport utilizes the voltage and ion gradients produced by the primary transport to drive the cotransport of other ions or molecules. These may be transported in the same (symport) or opposite (antiport) direction. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoproterenol: Isopropyl analog of epinephrine; beta-sympathomimetic that acts on the heart, bronchi, skeletal muscle, alimentary tract, etc. It is used mainly as bronchodilator and heart stimulant. [NIH] Karyotypes: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [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] Kinetic: Pertaining to or producing motion. [EU] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an osseous and a membranous portion. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leukemia: Cancer of blood-forming tissue. [NIH] Lidocaine: A local anesthetic and cardiac depressant used as an antiarrhythmia agent. Its actions are more intense and its effects more prolonged than those of procaine but its duration of action is shorter than that of bupivacaine or prilocaine. [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] Limbic: Pertaining to a limbus, or margin; forming a border around. [EU] Lincomycin: (2S-trans)-Methyl 6,8-dideoxy-6-(((1-methyl-4-propyl-2pyrrolidinyl)carbonyl)amino)-1-thio-D-erythro-alpha-D-galacto-octopyranoside. An antibiotic produced by Streptomyces lincolnensis var. lincolnensis. It has been used in the treatment of staphylococcal, streptococcal, and Bacteroides fragilis infections. [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] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood

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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] 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] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Health: The state wherein the person is well adjusted. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methoxamine: An alpha-adrenergic agonist that causes prolonged peripheral vasoconstriction. It has little if any direct effect on the central nervous system. [NIH] Mexiletine: Antiarrhythmic agent pharmacologically similar to lidocaine. It may have some anticonvulsant properties. [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] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Chaperones: A family of cellular proteins that mediate the correct assembly or

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disassembly of other polypeptides, and in some cases their assembly into oligomeric structures, but which are not components of those final structures. It is believed that chaperone proteins assist polypeptides to self-assemble by inhibiting alternative assembly pathways that produce nonfunctional structures. Some classes of molecular chaperones are the nucleoplasmins, the chaperonins, the heat-shock proteins 70, and the heat-shock proteins 90. [NIH] Molecular Probes: A group of atoms or molecules attached to other molecules or cellular structures and used in studying the properties of these molecules and structures. Radioactive DNA or RNA sequences are used in molecular genetics to detect the presence of a complementary sequence by molecular hybridization. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Mucinous: Containing or resembling mucin, the main compound in mucus. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Muscle 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 Relaxation: That phase of a muscle twitch during which a muscle returns to a resting position. [NIH] Muscular Diseases: Acquired, familial, and congenital disorders of skeletal muscle and smooth muscle. [NIH] Musculature: The muscular apparatus of the body, or of any part of it. [EU] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the

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blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] 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] Natural selection: A part of the evolutionary process resulting in the survival and reproduction of the best adapted individuals. [NIH] Near Drowning: Non-fatal immersion or submersion in water. The subject is resuscitable. [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] Neonatal: Pertaining to the first four weeks after birth. [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] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Blockade: The intentional interruption of transmission at the neuromuscular junction by external agents, usually neuromuscular blocking agents. It is distinguished from nerve block in which nerve conduction is interrupted rather than neuromuscular transmission. Neuromuscular blockade is commonly used to produce muscle relaxation as an adjunct to anesthesia during surgery and other medical procedures. It is also often used as an experimental manipulation in basic research. It is not strictly speaking anesthesia but is grouped here with anesthetic techniques. The failure of neuromuscular transmission as a result of pathological processes is not included here. [NIH] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxins: Toxic substances from microorganisms, plants or animals that interfere with the functions of the nervous system. Most venoms contain neurotoxic substances. Myotoxins are included in this concept. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a

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widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [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]

Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [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]

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Palsy: Disease of the peripheral nervous system occurring usually after many years of increased lead absorption. [NIH] 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] Paradoxical: Occurring at variance with the normal rule. [EU] Paralyses: Loss or impairment of muscle function or sensation. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] 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] 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]

Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Pharmacokinetics: Dynamic and kinetic mechanisms of exogenous chemical and drug absorption, biotransformation, distribution, release, transport, uptake, and elimination as a function of dosage, and extent and rate of metabolic processes. It includes toxicokinetics, the pharmacokinetic mechanism of the toxic effects of a substance. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] 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] Phenylephrine: An alpha-adrenergic agonist used as a mydriatic, nasal decongestant, and cardiotonic agent. [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] 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] Pigments: Any normal or abnormal coloring matter in plants, animals, or micro-organisms. [NIH]

Pilot study: The initial study examining a new method or treatment. [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

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regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [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]

Pneumonia: Inflammation of the lungs. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] 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] Pons: The part of the central nervous system lying between the medulla oblongata and the mesencephalon, ventral to the cerebellum, and consisting of a pars dorsalis and a pars ventralis. [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] Postoperative: After surgery. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [NIH]

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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 another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Pressoreceptors: Receptors in the vascular system, particularly the aorta and carotid sinus, which are sensitive to stretch of the vessel walls. [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] 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] Procaine: A local anesthetic of the ester type that has a slow onset and a short duration of action. It is mainly used for infiltration anesthesia, peripheral nerve block, and spinal block. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1016). [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Propofol: A widely used anesthetic. [NIH] Propranolol: A widely used non-cardioselective beta-adrenergic antagonist. Propranolol is used in the treatment or prevention of many disorders including acute myocardial infarction, arrhythmias, angina pectoris, hypertension, hypertensive emergencies, hyperthyroidism, migraine, pheochromocytoma, menopause, and anxiety. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Engineering: Procedures by which nonrandom single-site changes are introduced into structural genes (site-specific mutagenesis) in order to produce mutant genes which can be coupled to promoters that direct the synthesis of a specifically altered protein, which is then analyzed for structural and functional properties and then compared with the predicted and sought-after properties. The design of the protein may be assisted by

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computer graphic technology and other advanced molecular modeling techniques. [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] 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] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Pulmonary: Relating to 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]

Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radioactive: Giving off radiation. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] 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] Reentry: Reexcitation caused by continuous propagation of the same impulse for one or more cycles. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of

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treatment. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Restitution: The restoration to a normal state. [NIH] Reticular: Coarse-fibered, netlike dermis layer. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Ganglion Cells: Cells of the innermost nuclear layer of the retina, the ganglion cell layer, which project axons through the optic nerve to the brain. They are quite variable in size and in the shapes of their dendritic arbors, which are generally confined to the inner plexiform layer. [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] Retrospective: Looking back at events that have already taken place. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] 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] Saccule: The smaller of the 2 sacs within the vestibule of the ear. [NIH] Sarcolemma: The plasma membrane of a smooth, striated, or cardiac muscle fiber. [NIH] Sarcomere: The repeating structural unit of a striated muscle fiber. [NIH] Sarcoplasmic Reticulum: A network of tubules and sacs in the cytoplasm of skeletal muscles that assist with muscle contraction and relaxation by releasing and storing calcium ions. [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

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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] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Sensibility: The ability to receive, feel and appreciate sensations and impressions; the quality of being sensitive; the extend to which a method gives results that are free from false negatives. [NIH] Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] 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] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Sick Sinus Syndrome: Dysfunction of the sinoatrial node manifested by persistent sinus bradycardia, sinus arrest, sinoatrial exit block, chronic atrial fibrillation and inability of the heart to resume sinus rhythm following cardioversion for atrial fibrillation. [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] Sinoatrial Node: The small mass of modified cardiac muscle fibers located at the junction of the superior vena cava and right atrium. Contraction impulses probably start in this node, spread over the atrium and are then transmitted by the atrioventricular bundle to the ventricle. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [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,

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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] Solitary Nucleus: Gray matter located in the dorsomedial part of the medulla oblongata associated with the solitary tract. The solitary nucleus receives inputs from most organ systems including the terminations of the facial, glossopharyngeal, and vagus nerves. It is a major coordinator of autonomic nervous system regulation of cardiovascular, respiratory, gustatory, gastrointestinal, and chemoreceptive aspects of homeostasis. The solitary nucleus is also notable for the large number of neurotransmitters which are found therein. [NIH] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] 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]

Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stellate: Star shaped. [NIH] Stellate Ganglion: A paravertebral sympathetic ganglion formed by the fusion of the inferior cervical and first thoracic ganglia. [NIH] Steroids: Drugs used to relieve swelling and inflammation. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other

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excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] 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] Sudden cardiac death: Cardiac arrest caused by an irregular heartbeat. [NIH] Sudden death: Cardiac arrest caused by an irregular heartbeat. The term "death" is somewhat misleading, because some patients survive. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] Syncope: A temporary suspension of consciousness due to generalized cerebral schemia, a faint or swoon. [EU]

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Systemic: Affecting the entire body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tachyarrhythmia: Tachycardia associated with an irregularity in the normal heart rhythm. [EU]

Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Tendon: A discrete band of connective tissue mainly composed of parallel bundles of collagenous fibers by which muscles are attached, or two muscles bellies joined. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thoracic: Having to do with the chest. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonic: 1. Producing and restoring the normal tone. 2. Characterized by continuous tension. 3. A term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Torsades de Pointes: A ventricular tachycardia characterized by periodic twisting of the points of the QRS complexes and rates between 200 and 250 beats per minute. It may be selflimited or may progress to ventricular fibrillation. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH]

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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] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Triage: The sorting out and classification of patients or casualties to determine priority of need and proper place of treatment. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] 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] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Vagal: Pertaining to the vagus nerve. [EU] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Vagus Nerve: The 10th cranial nerve. The vagus is a mixed nerve which contains somatic

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afferents (from skin in back of the ear and the external auditory meatus), visceral afferents (from the pharynx, larynx, thorax, and abdomen), parasympathetic efferents (to the thorax and abdomen), and efferents to striated muscle (of the larynx and pharynx). [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venoms: Poisonous animal secretions forming fluid mixtures of many different enzymes, toxins, and other substances. These substances are produced in specialized glands and secreted through specialized delivery systems (nematocysts, spines, fangs, etc.) for disabling prey or predator. [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 fibrillation: Rapid, irregular quivering of the heart's ventricles, with no effective heartbeat. [NIH] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vestibule: A small, oval, bony chamber of the labyrinth. The vestibule contains the utricle and saccule, organs which are part of the balancing apparatus of the ear. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [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] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral Afferents: The sensory fibers innervating the viscera. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] 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]

Dictionary 163

Vivo: Outside of or removed from the body of a living organism. [NIH] Voltage-gated: It is opened by the altered charge distribution across the cell membrane. [NIH]

Vulva: The external female genital organs, including the clitoris, vaginal lips, and the opening to the vagina. [NIH] Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

165

INDEX A Abducens, 129, 130 Aberrant, 31, 94, 129 Acceptor, 129, 151, 161 ACE, 51, 129 Acetylcholine, 37, 48, 59, 129, 150 Actin, 24, 129, 149, 150 Actinin, 129, 140 Action Potentials, 19, 33, 37, 74, 129 Adaptation, 8, 27, 72, 129 Adjustment, 129 Adrenal Cortex, 129, 130 Adrenal Medulla, 129, 135, 141, 150 Adrenergic, 47, 49, 69, 129, 139, 141, 148, 152, 154, 159 Adrenergic Agonists, 47, 129 Adrenergic Antagonists, 49, 129 Adverse Effect, 129, 157 Aerobic, 130, 142 Affinity, 14, 30, 32, 38, 130, 157 Agonist, 35, 41, 130, 139, 148, 152 Aldosterone, 40, 130 Algorithms, 130, 133 Alimentary, 130, 147 Alkaline, 130, 134 Alkaloid, 130, 132 Alternans, 30, 42, 48, 49, 50, 65, 67, 69, 90, 130 Alternative medicine, 102, 130 Ameliorating, 36, 130 Amino acid, 10, 12, 14, 17, 37, 77, 130, 131, 132, 138, 141, 142, 143, 144, 148, 152, 153, 155, 157, 159, 161 Amino Acid Sequence, 130, 131, 142, 143 Anaesthesia, 61, 81, 82, 84, 130 Anal, 10, 28, 131 Analog, 131, 136, 147 Analogous, 36, 131, 140, 161 Anesthesia, 82, 131, 150, 154 Anesthetics, 14, 31, 38, 131, 141 Angina, 131, 154 Angina Pectoris, 131, 154 Animal model, 19, 25, 131 Annealing, 131, 153 Anomalies, 15, 131 Antiarrhythmic, 4, 7, 14, 25, 31, 131, 148 Antibacterial, 131, 136, 158 Antibiotic, 131, 141, 147, 158

Antibodies, 131, 144, 145, 149 Antibody, 130, 131, 134, 137, 141, 144, 145, 149, 158 Anticoagulant, 131, 154 Anticonvulsant, 131, 148 Antigen, 130, 131, 137, 145 Anus, 131, 132 Anxiety, 132, 154 Apnea, 27, 132 Aponeurosis, 132, 143 Arginine, 12, 132 Arrhythmogenic, 6, 15, 18, 50, 59, 67, 70, 77, 132 Arterial, 27, 132, 145, 155, 160 Arteries, 132, 133, 138, 148, 150 Arterioles, 132, 133, 162 Artery, 22, 48, 132, 133, 138, 155, 162 Assay, 20, 26, 132 Asymptomatic, 16, 128, 132, 142 Atrial, 40, 41, 47, 56, 71, 132, 142, 157 Atrial Fibrillation, 132, 157 Atrioventricular, 40, 41, 44, 73, 132, 157 Atrium, 132, 157, 162 Atropine, 48, 132, 133 Attenuated, 16, 132 Auditory, 27, 88, 132, 162 Autoimmune disease, 132, 149 Autonomic, 15, 16, 27, 28, 129, 132, 133, 151, 158, 159 Autonomic Nervous System, 16, 27, 132, 133, 158, 159 Autoradiography, 33, 132 Axons, 34, 132, 151, 156 B Bacteria, 131, 132, 133, 136, 144, 148, 153, 155, 158 Bacterial Physiology, 129, 133 Bacteriostatic, 133, 141 Baroreflex, 27, 133 Basal Ganglia, 133, 143 Belladonna, 132, 133 Benign, 133, 143 Bile, 133, 148 Biochemical, 5, 30, 31, 133, 144, 147 Biogenesis, 12, 24, 31, 133 Biophysics, 10, 22, 36, 133 Biosynthesis, 32, 133, 154 Biotechnology, 38, 102, 113, 133

166

Long QT Syndrome

Bladder, 133, 137, 149 Blood Coagulation, 133, 134, 160 Blood pressure, 133, 135, 145, 149, 158 Blood transfusion, 84, 133 Blood vessel, 27, 129, 133, 135, 136, 141, 147, 157, 159, 160, 162 Blot, 28, 134, 145 Blotting, Western, 134, 145 Body Fluids, 134, 157 Body Mass Index, 134, 151 Bone Marrow, 134, 143 Bowel, 131, 134 Bradycardia, 42, 52, 62, 66, 134, 157 Bronchi, 134, 141, 147, 161 Bronchodilator, 134, 147 Buffers, 133, 134, 158 Bupivacaine, 134, 147 C Calcium, 5, 20, 33, 134, 137, 156 Calmodulin, 5, 20, 134 Carbohydrate, 134, 144 Carboxy, 24, 134 Carcinogenic, 134, 146, 154 Cardiac arrest, 22, 42, 134, 159 Cardiac Output, 133, 134 Cardiomyopathy, 11, 27, 50, 59, 75, 135 Cardioselective, 135, 154 Cardiotonic, 135, 152 Cardiovascular disease, 26, 135 Cardioversion, 135, 157 Carotene, 135, 156 Case report, 52, 70, 71, 135, 136 Case series, 38, 135, 136 Catecholamine, 42, 135, 139 Cause of Death, 6, 135 Cell Death, 135, 150 Cell Division, 133, 135, 153, 154, 157 Cell membrane, 135, 139, 146, 153, 158, 163 Cell Physiology, 34, 135 Cellular Structures, 135, 149 Central Nervous System, 129, 132, 133, 135, 143, 148, 149, 151, 153 Cerebral, 133, 135, 141, 142, 144, 159 Cerebrovascular, 135, 136 Cervical, 136, 144, 158 Chaperonins, 136, 149 Chimeras, 5, 136 Chin, 136, 148 Choroid, 136, 156 Chromosomal, 136, 153 Chromosome, 64, 67, 136, 147, 157

Chronic, 8, 27, 136, 157, 159 Circadian, 53, 136 CIS, 136, 156 Clamp, 6, 8, 14, 19, 22, 29, 30, 33, 136 Clindamycin, 82, 136 Clinical study, 9, 33, 36, 136 Clinical trial, 3, 113, 136, 155 Clone, 8, 18, 136 Cloning, 20, 32, 133, 136 Cofactor, 136, 155, 160 Coitus, 136, 138 Collagen, 130, 137 Complement, 137, 143, 147 Complementary and alternative medicine, 87, 91, 137 Complementary medicine, 87, 137 Compliance, 37, 137 Computational Biology, 113, 137 Conception, 137, 142 Conduction, 15, 19, 31, 37, 40, 41, 44, 55, 62, 63, 137, 150 Cones, 138, 156 Congestive heart failure, 16, 138 Consciousness, 94, 138, 139, 159 Constriction, 138, 147, 162 Contraindications, ii, 138 Contralateral, 130, 138 Coordination, 16, 21, 138, 149 Copulation, 16, 138 Coronary, 15, 22, 27, 48, 131, 135, 138, 148, 150 Coronary heart disease, 135, 138 Coronary Thrombosis, 138, 148, 150 Cortical, 138, 157 Crossing-over, 138, 155 Cues, 16, 138 Curative, 138, 160 Cyclic, 68, 134, 138 Cysteine, 31, 138, 141, 159 Cystine, 138 Cytoplasm, 135, 138, 150, 156 Cytoskeletal Proteins, 138, 140 D Data Collection, 37, 138 De novo, 42, 139 Decongestant, 139, 152 Deletion, 17, 24, 139 Denaturation, 139, 153 Dendrites, 139, 150 Dendritic, 139, 156 Density, 26, 134, 139, 151, 158 Depolarization, 4, 15, 37, 139

167

Dermis, 139, 156 Diagnostic procedure, 93, 102, 139 Dialyzer, 139, 144 Diffusion, 139, 146 Digestion, 130, 133, 134, 139, 148, 159 Dilated cardiomyopathy, 11, 139 Direct, iii, 10, 18, 105, 135, 139, 148, 154, 155, 159 Dissociation, 130, 139 Distal, 12, 139, 140 Dopamine, 37, 139, 150 Dorsum, 140, 143 Drive, ii, vi, 83, 140, 147 Drug Design, 14, 36, 140 Drug Interactions, 9, 106, 107, 140 Dyes, 15, 140 Dysplasia, 50, 140 Dystrophin, 11, 140 Dystrophy, 140 E Echocardiography, 78, 80, 140 Effector, 129, 137, 140 Efficacy, 37, 47, 140 Electrocardiogram, 29, 30, 94, 95, 140 Electrode, 6, 15, 140 Electrolyte, 61, 130, 140, 153, 158 Electrons, 140, 147, 151, 155 Electrophysiological, 5, 12, 15, 18, 24, 25, 28, 33, 36, 37, 43, 44, 79, 140 Empirical, 6, 140 Emulsion, 132, 141 Endemic, 141, 158 Endocardium, 13, 15, 141 Endogenous, 129, 139, 141, 161 Endopeptidases, 141, 154 Endothelial cell, 141, 160 Environmental Health, 112, 114, 141 Enzymatic, 130, 134, 135, 137, 141, 153, 156 Enzyme, 129, 140, 141, 143, 153, 154, 159, 160, 161, 162, 163 Epidemic, 141, 158 Epinephrine, 50, 59, 129, 139, 141, 147, 150, 161 Epitope, 5, 141 Erythromycin, 94, 106, 141 Ether, 10, 12, 24, 28, 30, 35, 36, 59, 78, 141 Eukaryotic Cells, 138, 141, 146, 161 Excitability, 7, 10, 14, 17, 18, 28, 37, 142 Excitation, 6, 8, 17, 29, 142, 150 Exercise Test, 59, 142 Exon, 94, 96, 142 Extracellular, 10, 20, 142, 157

Extrapyramidal, 139, 142 F Facial, 130, 142, 158 Facial Paralysis, 130, 142 Family Planning, 113, 142 Fat, 134, 135, 138, 142, 147, 149, 151 Fatigue, 142, 144 Feasibility Studies, 79, 142 Fetus, 52, 70, 142, 154 Fibrillation, 25, 94, 142, 157 Flecainide, 67, 142 Fluorescence, 8, 142 Fold, 18, 31, 142 G Ganglia, 129, 142, 150, 158, 159 Ganglion, 34, 143, 156, 158 Gastrin, 143, 145 Gastrointestinal, 141, 143, 158, 159 Gene Expression, 143 Gene Therapy, 14, 79, 143 Genetic Code, 143, 151 Genetic Engineering, 133, 136, 143 Genetic Screening, 26, 74, 143 Genetic testing, 10, 51, 76, 143, 153 Genetics, 7, 10, 25, 27, 28, 33, 36, 42, 54, 56, 61, 64, 65, 66, 67, 68, 76, 79, 80, 119, 143, 149 Genital, 143, 163 Genomics, 6, 54, 143 Genotype, 8, 21, 27, 34, 50, 55, 60, 64, 69, 79, 143, 152 Germ Cells, 143, 151 Gland, 118, 129, 143, 145, 152, 157, 158, 160 Glucose, 49, 144, 146 Glycine, 130, 144, 150 Glycoproteins, 144, 146, 153, 158 Glycosylation, 13, 144 Gonad, 144 Gonadal, 89, 144 Governing Board, 144, 154 H Haptens, 130, 144 Health Services, 9, 144 Heart attack, 135, 144 Heart failure, 27, 29, 144 Heartbeat, 144, 159, 162 Heat-Shock Proteins, 144, 149 Heat-Shock Proteins 90, 144, 149 Hemiplegia, 130, 144 Hemodialysis, 63, 139, 144 Hemoglobinopathies, 143, 144

168

Long QT Syndrome

Hereditary, 4, 22, 26, 31, 32, 33, 45, 55, 56, 64, 68, 80, 94, 144 Heredity, 143, 144 Heterogeneity, 7, 13, 19, 21, 56, 67, 130, 144 Homogeneous, 13, 145 Homologous, 4, 32, 138, 143, 145, 157 Hormone, 8, 130, 141, 143, 145, 146, 148, 160 Hybrid, 20, 23, 24, 136, 145 Hydrogen, 129, 134, 139, 145, 149, 151 Hydrogen Bonding, 145, 151 Hydrolysis, 145, 147, 153 Hydroxyproline, 130, 137, 145 Hypertension, 135, 145, 154 Hyperthyroidism, 145, 154 Hypertrophic cardiomyopathy, 65, 74, 145 Hypertrophy, 65, 145 Hypothalamus, 132, 145 I Idiopathic, 14, 18, 25, 33, 37, 40, 47, 57, 58, 65, 67, 71, 72, 82, 88, 145 Immersion, 51, 145, 150 Immunoblotting, 23, 33, 145 Immunohistochemistry, 34, 145 Immunology, 41, 130, 145 Impairment, 145, 152 In situ, 18, 145 In Situ Hybridization, 18, 146 In vitro, 9, 10, 18, 25, 52, 79, 143, 146, 153, 160 In vivo, 4, 10, 24, 25, 36, 52, 79, 143, 146 Incision, 146 Infarction, 146 Inflammation, 146, 153, 158 Infusion, 81, 146, 161 Initiation, 5, 7, 19, 146, 161 Innervation, 49, 51, 146 Inotropic, 139, 146 Insight, 7, 8, 11, 17, 38, 66, 146 Insulator, 146, 149 Insulin, 49, 146 Insulin-dependent diabetes mellitus, 146 Interindividual, 15, 146 Intracellular, 5, 8, 10, 12, 20, 29, 33, 34, 45, 56, 60, 146, 148, 153 Intracellular Membranes, 146, 148 Intravenous, 36, 146 Intrinsic, 14, 130, 146 Invasive, 34, 67, 146 Involuntary, 142, 146, 150, 155

Ion Channels, 6, 7, 10, 11, 12, 13, 15, 17, 18, 19, 22, 26, 27, 28, 32, 34, 146 Ion Transport, 32, 146 Ions, 134, 139, 140, 145, 146, 147, 153, 156, 158 Ischemia, 4, 131, 147 Isoproterenol, 47, 147 K Karyotypes, 143, 147 Kb, 112, 147 Kinetic, 7, 147, 152 L Labyrinth, 147, 162 Latent, 147, 154 Lectin, 147, 148 Lesion, 130, 147, 148 Lethal, 9, 16, 27, 35, 94, 147 Leukemia, 143, 147 Lidocaine, 4, 81, 147, 148 Ligaments, 138, 147 Ligands, 14, 147 Limbic, 18, 147 Lincomycin, 136, 147 Linkage, 4, 20, 61, 67, 147 Lipid, 146, 147, 149 Liver, 73, 133, 141, 147 Localization, 11, 20, 145, 148 Localized, 18, 140, 144, 148, 152 Loop, 17, 31, 42, 43, 148 M Malignant, 11, 14, 21, 45, 63, 148 Manifest, 21, 34, 94, 144, 148 Mediate, 23, 139, 148 MEDLINE, 113, 148 Membrane Proteins, 4, 12, 148, 158 Menopause, 148, 154 Mental, iv, 3, 27, 74, 112, 114, 136, 139, 142, 148, 155 Mental Health, iv, 3, 112, 114, 148, 155 Methionine, 10, 148, 159 Methoxamine, 35, 148 Mexiletine, 44, 148 MI, 8, 49, 56, 128, 148 Microbiology, 129, 148 Microorganism, 136, 148, 162 Modeling, 140, 148, 155 Modification, 9, 38, 130, 143, 148 Modulator, 7, 148 Molecular Chaperones, 30, 32, 136, 144, 148 Molecular Probes, 38, 149

169

Molecule, 131, 137, 139, 140, 141, 142, 144, 145, 147, 149, 151, 153, 155, 162 Monitor, 16, 22, 60, 149, 151 Monoclonal, 145, 149 Monoclonal antibodies, 145, 149 Mucinous, 143, 149 Multiple sclerosis, 34, 149 Muscle Contraction, 140, 149, 156 Muscle Relaxation, 149, 150 Muscular Diseases, 31, 142, 149 Musculature, 16, 149 Mutagenesis, 6, 20, 23, 31, 33, 36, 149, 154 Mutagens, 149 Mydriatic, 149, 152 Myelin, 149 Myocardial infarction, 8, 27, 33, 69, 138, 148, 149, 154 Myocardium, 7, 13, 131, 148, 149, 150 Myofibrils, 140, 150 N Natural selection, 133, 150 Near Drowning, 80, 150 Necrosis, 146, 148, 149, 150 Neonatal, 44, 45, 150 Nervous System, 10, 16, 19, 34, 37, 132, 135, 144, 150, 152, 159 Neural, 27, 71, 150, 158 Neuromuscular, 82, 129, 142, 150 Neuromuscular Blockade, 82, 150 Neuromuscular Junction, 129, 150 Neurons, 16, 37, 139, 142, 150, 159 Neurophysiology, 139, 150 Neurotoxic, 150 Neurotoxins, 37, 150 Neurotransmitter, 129, 130, 139, 144, 146, 150, 151, 159 Norepinephrine, 129, 139, 150 Nuclear, 51, 130, 133, 140, 141, 143, 150, 151, 156 Nuclei, 140, 142, 143, 151 Nucleic acid, 26, 143, 146, 149, 151 Nucleic Acid Hybridization, 26, 151 Nucleus, 138, 141, 151, 154, 158, 159 O Oocytes, 7, 20, 24, 25, 31, 151 Opacity, 139, 151 Opsin, 151, 156 Optic Nerve, 151, 156 Organ Culture, 151, 160 Overweight, 48, 84, 151 Oxidation, 10, 129, 138, 151 Oxygen Consumption, 142, 151, 156

P Pacemaker, 4, 20, 70, 151 Palliative, 151, 160 Palsy, 130, 152 Pancreas, 146, 152 Paradoxical, 50, 152 Paralyses, 37, 152 Paroxysmal, 131, 152 Patch, 6, 19, 22, 30, 33, 152 Pathogenesis, 7, 23, 24, 152 Pathologic, 138, 152, 162 Pathophysiology, 16, 28, 152 Patient Education, 39, 122, 124, 128, 152 Peptide, 12, 23, 37, 130, 141, 152, 153, 154, 155 Pharmacokinetics, 140, 152 Pharmacologic, 4, 33, 34, 36, 37, 95, 131, 152, 161 Phenotype, 8, 13, 18, 21, 25, 37, 45, 56, 60, 66, 69, 79, 152 Phenylephrine, 48, 152 Phosphorus, 134, 152 Phosphorylation, 37, 152 Physiologic, 20, 34, 130, 133, 152, 155 Physiology, 7, 14, 22, 23, 30, 31, 33, 41, 50, 51, 57, 68, 76, 135, 140, 150, 152 Pigments, 135, 152, 156 Pilot study, 37, 152 Plants, 130, 132, 133, 144, 147, 150, 151, 152, 161 Plasma, 11, 12, 30, 32, 131, 135, 140, 153, 156 Plasmid, 79, 153, 162 Platinum, 148, 153 Pneumonia, 138, 153 Point Mutation, 26, 153 Polymerase, 26, 153 Polymerase Chain Reaction, 26, 153 Polymorphic, 13, 15, 27, 71, 89, 153 Polymorphism, 23, 26, 77, 153 Polypeptide, 130, 137, 153, 163 Pons, 130, 142, 153 Posterior, 131, 136, 140, 152, 153 Postoperative, 56, 153 Potassium Channels, 28, 31, 32, 153 Practicability, 142, 153 Practice Guidelines, 114, 154 Precursor, 139, 140, 141, 150, 154, 161 Predisposition, 8, 154 Prenatal, 40, 52, 70, 71, 143, 154 Pressoreceptors, 133, 154 Prevalence, 39, 48, 71, 154

170

Long QT Syndrome

Probe, 13, 14, 32, 38, 154 Procaine, 147, 154 Progression, 27, 131, 154 Promoter, 17, 28, 154 Prone, 5, 18, 154 Prophase, 151, 154 Propofol, 77, 154 Propranolol, 44, 154 Protease, 31, 154 Protease Inhibitors, 31, 154 Protein C, 10, 12, 33, 130, 154, 158 Protein Engineering, 14, 154 Protein S, 11, 133, 141, 143, 155 Protocol, 29, 37, 155 Psychic, 148, 155, 157 Public Health, 35, 114, 155 Public Policy, 113, 155 Pulmonary, 133, 142, 155, 162 Pulse, 23, 33, 149, 155 R Radiation, 131, 132, 142, 155 Radioactive, 132, 145, 149, 151, 155 Randomized, 140, 155 Reactive Oxygen Species, 10, 155 Receptor, 14, 19, 37, 69, 129, 131, 139, 155 Recombinant, 18, 19, 155, 162 Recombination, 28, 143, 155 Reentry, 7, 82, 155 Refer, 1, 137, 148, 155 Reflex, 16, 27, 155 Refraction, 155, 158 Regimen, 140, 155 Respiration, 132, 149, 156 Restitution, 27, 156 Reticular, 29, 156 Retina, 34, 136, 138, 151, 156, 162 Retinal, 34, 151, 156 Retinal Ganglion Cells, 34, 151, 156 Retinol, 156 Retrospective, 21, 156 Retroviral vector, 143, 156 Rhodopsin, 151, 156 Risk factor, 27, 60, 156 Rod, 136, 156 S Saccule, 156, 162 Sarcolemma, 11, 156 Sarcomere, 11, 156 Sarcoplasmic Reticulum, 5, 8, 156 Sclerosis, 149, 156 Screening, 26, 46, 62, 65, 75, 78, 80, 96, 136, 143, 156

Secretion, 40, 49, 146, 156 Segregation, 155, 157 Seizures, 16, 18, 80, 94, 95, 152, 157 Semisynthetic, 136, 157 Sensibility, 130, 157 Sensor, 26, 157 Sequence Homology, 4, 157 Sequencing, 18, 26, 94, 153, 157 Serum, 15, 36, 95, 137, 157 Shock, 136, 157 Sick Sinus Syndrome, 20, 157 Side effect, 105, 129, 157, 160 Sinoatrial Node, 157 Skeletal, 20, 23, 31, 37, 136, 147, 149, 150, 156, 157 Skeleton, 129, 157 Small intestine, 145, 157 Smooth muscle, 134, 149, 157, 159 Sodium, 4, 19, 25, 33, 34, 37, 39, 40, 45, 48, 50, 63, 76, 130, 157, 158 Sodium Channels, 4, 19, 25, 37, 158 Solitary Nucleus, 132, 158 Sound wave, 137, 158 Specialist, 119, 158 Species, 28, 133, 138, 141, 145, 147, 149, 155, 157, 158, 159, 162, 163 Specificity, 17, 24, 37, 130, 141, 158 Spectrin, 140, 158 Spectrum, 21, 158 Sperm, 16, 136, 138, 158 Spinal cord, 135, 143, 144, 150, 155, 158, 159 Sporadic, 23, 61, 158 Steel, 136, 158 Stellate, 28, 48, 158 Stellate Ganglion, 48, 158 Steroids, 89, 158 Stimulant, 147, 158 Stimulus, 140, 142, 146, 155, 158, 160 Stomach, 143, 145, 157, 159 Strand, 28, 153, 159 Stress, 27, 49, 74, 76, 88, 127, 132, 135, 136, 154, 159 Stroke, 112, 134, 135, 159 Subacute, 84, 159 Subclinical, 157, 159 Subspecies, 158, 159 Substance P, 141, 157, 159 Substrate, 13, 14, 15, 16, 25, 26, 159 Sudden cardiac death, 5, 6, 7, 11, 15, 18, 22, 24, 28, 32, 42, 51, 159

171

Sudden death, 6, 7, 11, 13, 15, 19, 21, 23, 24, 26, 27, 30, 33, 35, 42, 53, 63, 89, 94, 95, 159 Sulfur, 148, 159 Suppression, 74, 159 Sympathetic Nervous System, 40, 132, 159 Sympathomimetic, 139, 141, 147, 151, 159 Symptomatic, 16, 22, 75, 142, 159 Synapse, 129, 150, 159, 161 Syncope, 5, 15, 21, 27, 42, 59, 62, 73, 77, 78, 88, 89, 94, 95, 127, 159 Systemic, 9, 19, 106, 133, 141, 160, 162 Systolic, 15, 145, 160 T Tachyarrhythmia, 52, 160 Tachycardia, 15, 25, 27, 52, 73, 76, 77, 82, 88, 89, 160 Tendon, 143, 160 Therapeutics, 6, 9, 57, 107, 160 Thermal, 139, 144, 153, 160 Thoracic, 158, 160, 163 Threshold, 37, 142, 145, 160 Thrombin, 154, 160 Thrombomodulin, 154, 160 Thrombosis, 155, 159, 160 Thyroid, 8, 145, 160, 161 Tissue Culture, 30, 160 Tone, 28, 160 Tonic, 55, 135, 160 Tonus, 160 Tooth Preparation, 129, 160 Torsades de Pointes, 25, 36, 47, 59, 70, 160 Toxic, iv, 132, 150, 152, 160, 161 Toxicity, 140, 161 Toxicology, 60, 114, 161 Toxins, 14, 38, 131, 149, 161, 162 Trachea, 134, 160, 161 Traction, 136, 161 Transcription Factors, 17, 161 Transfection, 6, 133, 143, 161 Transferases, 144, 161 Transfusion, 161 Translation, 130, 141, 161 Translational, 27, 161 Translocation, 141, 161

Transmitter, 129, 139, 146, 151, 161 Triage, 32, 161 Tumour, 143, 161 Tyrosine, 139, 161 U Ubiquitin, 32, 161 Unconscious, 131, 161 V Vagal, 22, 161 Vagina, 161, 163 Vaginal, 161, 163 Vagus Nerve, 158, 161 Vascular, 133, 136, 139, 146, 154, 162 Vascular Resistance, 133, 162 Vasoconstriction, 141, 148, 162 Vasodilator, 139, 162 Vector, 79, 162 Vein, 146, 151, 162 Venoms, 150, 162 Venous, 155, 162 Ventricle, 132, 145, 155, 157, 160, 162 Ventricular Dysfunction, 11, 162 Ventricular fibrillation, 14, 25, 33, 37, 82, 90, 94, 95, 160, 162 Venules, 133, 162 Vestibule, 14, 156, 162 Veterinary Medicine, 113, 162 Virulence, 132, 161, 162 Visceral, 132, 162 Visceral Afferents, 132, 162 Vitreous, 156, 162 Vitreous Body, 156, 162 Vitro, 25, 35, 162 Vivo, 10, 35, 36, 163 Voltage-gated, 4, 10, 14, 16, 17, 19, 23, 36, 37, 163 Vulva, 16, 163 W Windpipe, 160, 163 X Xenograft, 131, 163 Y Yeasts, 152, 163 Z Zymogen, 154, 163

172

Long QT Syndrome