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

ARRHYTHMIAS 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., 1960Arrhythmias: 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: 0-497-00088-1 1. Arrhythmias-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 arrhythmias. 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 ARRHYTHMIAS .......................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Arrhythmias................................................................................ 10 E-Journals: PubMed Central ....................................................................................................... 67 The National Library of Medicine: PubMed ................................................................................ 70 CHAPTER 2. NUTRITION AND ARRHYTHMIAS .............................................................................. 117 Overview.................................................................................................................................... 117 Finding Nutrition Studies on Arrhythmias............................................................................... 117 Federal Resources on Nutrition ................................................................................................. 122 Additional Web Resources ......................................................................................................... 123 CHAPTER 3. ALTERNATIVE MEDICINE AND ARRHYTHMIAS........................................................ 125 Overview.................................................................................................................................... 125 National Center for Complementary and Alternative Medicine................................................ 125 Additional Web Resources ......................................................................................................... 132 General References ..................................................................................................................... 136 CHAPTER 4. DISSERTATIONS ON ARRHYTHMIAS ......................................................................... 137 Overview.................................................................................................................................... 137 Dissertations on Arrhythmias ................................................................................................... 137 Keeping Current ........................................................................................................................ 138 CHAPTER 5. PATENTS ON ARRHYTHMIAS .................................................................................... 139 Overview.................................................................................................................................... 139 Patents on Arrhythmias............................................................................................................. 139 Patent Applications on Arrhythmias ......................................................................................... 160 Keeping Current ........................................................................................................................ 182 CHAPTER 6. BOOKS ON ARRHYTHMIAS ........................................................................................ 183 Overview.................................................................................................................................... 183 Book Summaries: Federal Agencies............................................................................................ 183 Book Summaries: Online Booksellers......................................................................................... 185 Chapters on Arrhythmias........................................................................................................... 188 CHAPTER 7. PERIODICALS AND NEWS ON ARRHYTHMIAS .......................................................... 189 Overview.................................................................................................................................... 189 News Services and Press Releases.............................................................................................. 189 Newsletter Articles .................................................................................................................... 191 Academic Periodicals covering Arrhythmias ............................................................................. 192 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 193 Overview.................................................................................................................................... 193 U.S. Pharmacopeia..................................................................................................................... 193 Commercial Databases ............................................................................................................... 194 Researching Orphan Drugs ....................................................................................................... 195 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 199 Overview.................................................................................................................................... 199 NIH Guidelines.......................................................................................................................... 199 NIH Databases........................................................................................................................... 201 Other Commercial Databases..................................................................................................... 203 APPENDIX B. PATIENT RESOURCES ............................................................................................... 205 Overview.................................................................................................................................... 205 Patient Guideline Sources.......................................................................................................... 205 Associations and Arrhythmias................................................................................................... 212 Finding Associations.................................................................................................................. 214

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APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 217 Overview.................................................................................................................................... 217 Preparation................................................................................................................................. 217 Finding a Local Medical Library................................................................................................ 217 Medical Libraries in the U.S. and Canada ................................................................................. 217 ONLINE GLOSSARIES................................................................................................................ 223 Online Dictionary Directories ................................................................................................... 226 ARRHYTHMIAS DICTIONARY................................................................................................ 227 INDEX .............................................................................................................................................. 299

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

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and arrhythmias, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “arrhythmias” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Dialysate Potassium Source: Seminars in Dialysis. 4(1): 46-51. January-March 1991. Summary: Dialysis assumes a major role in potassium homeostasis in patients with endstage renal disease (ESRD). This review examines the role of dialysate potassium in maintaining potassium balance in hemodialysis patients. Topics include potassium balance in ESRD, hyperkalemia in ESRD, blood transfusion and potassium, potassium removal during hemodialysis, potassium and base interaction during hemodialysis, arrhythmias and dialysate potassium, and hypokalemia and hemodialysis. 36 references.

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Perioperative Care of the Renal Patient Source: Archives of Internal Medicine. Volume 154: 1674-1687. August 8, 1994. Summary: Due to the hormonal and hemodynamic alterations inherent in the surgical experience, acute renal failure (ARF) is common during the perioperative period. In this article, the author focuses on perioperative care of the renal patient and other patients who are at greater risk of ARF. The author notes that patients with chronic renal insufficiency, elderly patients, jaundiced patients, patients with diabetes, and those undergoing cardiac or aortic surgery are at greatest risk for perioperative ARF. Patients with severe chronic renal failure of end-stage renal disease (ESRD) are at significant risk for development of complications during the perioperative period, due both to renal and nonrenal reasons. Hyperkalemia, infections, arrhythmias, and bleeding commonly occur in these patients during the perioperative period. The author concludes that this population has a reasonable surgical mortality for both general and cardiac surgery, but the extremely high morbidity warrants careful perioperative monitoring and care. 2 figures. 10 tables. 121 references. (AA-M).

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Contraindications to Vasoconstrictors in Dentistry: Part I Source: Oral Surgery, Oral Medicine, Oral Pathology. 74(5): 679-686. November 1992. Summary: Epinephrine and levonordefrin (Neo-Cobefrin) are the main vasoconstrictors used today in dental medicine. This article reviews the main contraindications of these vasoconstrictors in cardiac patients, notably unstable angina, recent myocardial infarction, recent coronary artery bypass surgery, refractory arrhythmias, untreated or uncontrolled hypertension, and untreated or uncontrolled congestive heart failure. The authors completed an extensive survey of the literature; they give specific guidelines and recommendations for the rational use of vasoconstrictors in this category of medically compromised patients. 2 tables. 87 references. (AA-M).

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Easing the Pain of Esophageal Surgery Source: RN. Registered Nurse. 58(8): 26-31. August 1995. Summary: In this article, the author provides information about managing patients who have undergone esophageal surgery. Topics include the current treatments for gastroesophageal reflux disease (GERD) and esophageal cancer; the plan of care for a patient undergoing esophageal surgery; and assessing patients for the complications associated with this surgery, including motility problems, arrhythmias, mediastinitis, fever, difficulty breathing, and spleen injury. The article concludes with a brief description of patient education and discharge planning. The article also includes a posttest with which patients can obtain continuing medical education credits. 2 figures. 10 references. (AA-M).

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Hemodialysis and the Heart Source: American Journal of the Medical Sciences. 309(2): 110-121. February 1995. Contact: Available from J.B. Lippincott Company. 12107 Insurance Way, Suite 114, Hagerstown, MD 21740. (800) 638-3030 or (301) 714-2300 in Maryland. Summary: In this review article, the authors discuss cardiac considerations of adults with end-stage renal disease (ESRD) who are treated with chronic hemodialysis. Systemic hypertension is discussed primarily in reference to its cardiac complications. Topics include left ventricular hypertrophy; cardiac performance; refractory congestive

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heart failure; dialysis hypotension; ischemic heart disease; valvular disease and infective endocarditis; pericardial disease; cardiac arrhythmias; cardiac surgery; and cardiovascular drugs. The authors emphasize the application of research information to everyday clinical situations involving hemodialysis patients. 2 tables. 166 references. •

Ischemic Bowel Disease in the Elderly Source: Gastroenterology Clinics of North America. 30(2): 445-473. June 2001. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32821-9816. (800) 654-2452. Summary: Ischemic bowel diseases are caused by acute or chronic insufficiency of blood flow to all or part of the gastrointestinal (GI) tract and include acute and chronic mesenteric ischemia and colonic ischemia. Reduction in blood flow to the intestine may reflect inadequate systemic perfusion (the spread of blood through the body), as in cardiogenic shock, or local structural or functional changes in the mesenteric vascular bed. This article, from a special issue on GI disorders in the elderly, addresses the ischemic bowel diseases, a heterogeneous group of disorders usually seen in elderly individuals. They represent ischemic damage to different portions of the bowel and, therefore, produce a variety of clinical syndromes and outcomes. Colonic ischemia is the most common of these disorders and has a favorable prognosis in most cases. In contrast, acute mesenteric ischemia, most commonly caused by a superior mesenteric artery embolus (clot, piece of tissue, or air bubble), is a disease with a very poor prognosis. Acute mesenteric ischemia typically is seen in elderly patients and often is seen in association with other common disorders of the aged, including congestive heart failure, cardiac arrhythmias, myocardial infarction, and hypotension. Proper diagnosis and management of patients with ischemic bowel diseases require vigilance on the part of the physician and a willingness to embark on an aggressive plan of diagnosis and management in the appropriate setting. 14 figures. 1 table. 73 references.

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Uremic Cardiomyopathy: Reducing the Cardiac Burden in End-Stage Renal Disease Source: Journal of Critical Illness. 13(10): 613-615, 619-623. October 1998. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Greenwich, CT 06831-0010. (203) 661-0600. Summary: Left ventricular (LV) hypertrophy and dilatation and systolic dysfunction are common in patients receiving hemodialysis and are associated with significantly decreased survival and increased morbidity. In this article, the authors discuss abnormalities of LV structure and function. They cover the diagnosis of uremic cardiomyopathy, review data on the prevalence and outcomes of LV dysfunction, and explore interventions relevant to the management of these patients. Echocardiography is the standard diagnostic tool for cardiomyopathy in patients with end-stage renal disease (ESRD). The use of echocardiography to differentiate diastolic from systolic dysfunction can help guide patient management. With few controlled clinical trials specifically examining cardiomyopathy in uremic patients, management generally follows guidelines from studies in the general population. Aims of therapy are to improve quality of life by controlling symptoms of heart failure, ischemic heart disease, cardiac arrhythmias, and dialysis-associated hypotension; and to correct modifiable risk factors, such as hypertension, anemia, uremia, malnutrition, and aortic stenosis. Drug therapy requires great caution in this patient population, and should be begun only after careful consideration of risk and benefit. 1 figure. 6 tables. 38 references. (AA-M).

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Magnesium Deficiency and Diabetes Source: Diabetes Educator. 18(1): 17-19. January-February 1992. Summary: Magnesium plays a key role in many enzyme systems in the body and is required for all enzymatic reactions involving the nucleotide adenosine triphosphate. This article discusses magnesium deficiency and diabetes. The authors report that magnesium deficiency is seen in as much as 25 percent of the diabetes population. The authors discuss magnesium loss and diabetes-associated complications, including hypertension, retinopathy, dyslipidemia, focal seizures, and reduced release of insulin. In addition, they note that magnesium deficiency may influence the binding of insulin to peripheral tissue and has been associated with ventricular arrhythmias and sudden cardiac death. Two final sections cover hypomagnesemia with hypokalemia and magnesium repletion. 1 figure. 25 references.

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Periodontal Management of Patients with Cardiovascular Diseases Source: Journal of Periodontology. 67(6): 627-635. June 1996. Summary: Periodontists are often called upon to provide periodontal therapy for patients with a variety of cardiovascular diseases. This article discusses the more common cardiovascular disorders and the dental management considerations appropriate for each. The authors note that safe and effective periodontal treatment requires a general understanding of the underlying cardiovascular diseases, their medical management, and necessary modifications to dental or periodontal therapy. Disorders discussed include congestive heart failure, cardiac arrhythmias, coronary artery disease (angina pectoris, myocardial infarction), hypertrophic cardiomyopathy, valvular heart disease, patients on anticoagulant drugs, hypertension, and heart transplantation. 4 tables. 94 references. (AA-M).

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HIV Topic Update: Protease Inhibitor Therapy and Oral Health Care Source: Oral Diseases. 4(3): 159-163. September 1998. Contact: Available from Stockton Press. Marketing Department, Houndmills, Basingstoke, Hampshire RG21 6XS, United Kingdom. (800) 747-3187. Summary: This article discusses protease inhibitors which have been a major advance in the management of HIV disease and have reduced the frequency and severity of many complications, including some oral lesions. They may also be of value in the management of occupational exposures to the virus. However, protease inhibitor therapy may produce adverse effects including oral symptoms such as paraesthesia (abnormal sensations), taste disturbances, and xerostomia (dry mouth). Protease inhibitors may also interact with a number of drugs used in oral health care; one of the most dangerous interactions is with astemizole and terfenadine which may result in cardiac arrhythmias Many of the other interactions result from protease inhibitors altering the blood level of other drugs, which may result in toxicity. 4 tables. 55 references. (AA-M).

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Drugs Used to Manage Cardiovascular Disease: Part I-Diuretics Source: Access. 15(2): 30-32. February 2001. Contact: Available from American Dental Hygienists' Association. 444 North Michigan Avenue, Chicago, IL 60611.

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Summary: This article familiarizes dental hygienists with the drugs that may be used to manage cardiovascular disease; this first entry in an ongoing series focuses on diuretics. The series addresses the classes of medications used to manage a variety of cardiac conditions, including hypertension (HTN), angina, myocardial infarction, arrhythmias, heart murmurs, and stroke. Drug interactions, oral side effects, and general side effects of these cardiac medications are discussed, along with recommendations for client management and risk assessment strategies. In this article, the author focuses on HTN and the role of diuretics. Currently, use of a diuretic with a beta blocker is the standard first line approach to treating HTN. Diuretics act upon the kidney to increase sodium and water excretion in the urine, thereby lowering blood volume; decreasing blood volume lowers blood pressure. Diuretics are given at low doses, and are safe and effective in preventing myocardial infarction, heart failure, stroke, and mortality from heart disease. The author covers thiazides, loop diuretics, potassium sparing diuretics, and combination therapies. Research suggests that the thiazide diuretics reduce the risk of stroke better than beta blockers, ACE inhibitors, and calcium channel blockers, and should be considered the best choice of treatment for managing HTN. 3 tables. 7 references. •

Drugs Used to Manage Cardiovascular Disease: Part V-Calcium Channel Blockers Source: Access. 15(7): 38-40. August 2001. Contact: Available from American Dental Hygienists' Association. 444 North Michigan Avenue, Chicago, IL 60611. Summary: This article in one in a series that familiarizes dental hygienists with the drugs that may be use to manage cardiovascular disease; this fifth entry in the ongoing series focuses on calcium channel blockers. The series addresses the classes of medications used to manage a variety of cardiac conditions, including hypertension (HTN), angina, myocardial infarction, arrhythmias, heart murmurs, and stroke. Drug interactions, oral side effects, and general side effects of these cardiac medications are discussed, along with recommendations for client management and risk assessment strategies. In this article, the author focuses on calcium channel blockers (CCBs), which are divided into three main chemical classes: benzothiazepines, including diltiazem (Cardizem, Dilacor); diphenylalkylamines, notably verapamil (Calan); and dihydropyridines, including nifedipine (Procardia, Adalat), amlodipine (Norvasc), felodipine (Plendil), isradipine (DynaCirc), nicardipine (Cardene), and nisoldipine (Sular). Two additional drugs are discussed: bepridil (Vascor) and nimodipine (Nimotop). Gingival hyperplasia (gum overgrowth) occurs with some of these CCBs, including nifedipine, diltiazem, verapamil, and amlodipine. Good oral hygiene may help to limit the degree of severity of overgrowth; however, plaque control will not prevent overgrowth from occurring. One chart summarizes drug interactions with calcium channel blockers. 2 tables. 16 references.

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Drugs Used to Manage Cardiovascular Disease: Part IV-Nitrates and Other Antianginals Source: Access. 15(5): 64, 66, 68-69. May-June 2001. Contact: Available from American Dental Hygienists' Association. 444 North Michigan Avenue, Chicago, IL 60611. Summary: This article is one in a series that familiarizes dental hygienists with the drugs that may be use to manage cardiovascular disease; this fourth entry in the ongoing series focuses on nitrates and other antianginals. The series addresses the classes of

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medications used to manage a variety of cardiac conditions, including hypertension (HTN), angina, myocardial infarction, arrhythmias, heart murmurs, and stroke. Drug interactions, oral side effects, and general side effects of these cardiac medications are discussed, along with recommendations for client management and risk assessment strategies. In this article, the author focuses on nitrates, which are used for both the prevention and treatment of angina pectoris (chest pain), a common symptoms of ischemic (lack of blood flow) heart disease. Nitrates relieve the symptoms of angina by relaxing vascular smooth muscle, which vasodilates the large veins and causes pooling of blood on the venous side of the systemic circulation. This effect reduces the amount of blood that is returned to the heart, which in turn reduces the work of the heart. In addition, nitrates produce vasodilation of the coronary arteries, which improves blood flow to the myocardium. Other drugs discussed in this article are beta blockers, calcium channel blockers, and antithrombin and antiplatelet drugs. 5 tables. 9 references. •

Detecting Hereditary Hemochromatosis Source: Nurse Practitioner. 25(7): 64, 69, 73-74, 76. July 2000. Contact: Available from Nurse Practitioner. Circulation Department, P.O. Box 5053, Brentwood, TN 37024-5053. (800) 490-6580. Fax (615) 377-0525. Summary: This article reviews the diagnosis of hereditary hemochromatosis (HH), the most commonly inherited autosomal recessive disorder. Hemochromatosis is a current or potential progression of abnormally high accumulations of iron in the liver. If left untreated, the condition can lead to chronic or irreversible hepatic (liver) fibrosis, cirrhosis (scarring), hepatocellular carcinoma (liver cancer), arthritis, and organ failure. Common signs and symptoms seen in the primary care setting include fatigue, weakness, abdominal pain, palpitations, skin pigmentation (coloring) changes, and arthropathy, but any symptom associated with organ damage may be reported. Because prompt intervention can cease or reverse the debilitating effects of iron overload, prompt disease diagnosis and treatments are imperative. The author notes that often an HH diagnosis is delayed in asymptomatic patients or patients with vague complaints of fatigue and arthropathy. The goal is to identify patients prior to symptom onset and organ damage; recent gene typing studies have made this a possibility. Early manifestations of HH include vague symptoms of weakness, fatigue, weight loss, skin pigmentation changes, abdominal pain, loss of libido, and diabetes mellitus symptoms. Advanced physical signs include liver and spleen enlargement, skin pigmentation changes, spider angiomas, arthropathy, ascites, cardiac arrhythmias, heart failure, testicular atrophy, and jaundice. Because HH is an inherited disorder, the family history should be specific and complete. Routine assays are the most commonly used testing. A definitive diagnosis is made via liver biopsy. Patients with HH should be instructed to increase their dietary protein, as hemoglobin is 96 percent protein; folic acid of 1 mg daily will assist in hemoglobin formation. Vitamin or mineral supplements that contain iron should be avoided. And because alcohol is a hepatotoxin and wine contains iron, alcohol should be avoided. 1 figure. 31 references.

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Practical Ethical Issues of Dialysis in the Elderly Source: Seminars in Nephrology. 16(4): 339-352. July 1996. Contact: Available from W.B. Saunders Company, Periodicals Department, 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Summary: This article reviews the medical and ethical issues raised by dialysis for the elderly, which have important implications for health care policies regarding the

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application of all other life-sustaining treatments in the elderly. The main underlying diseases leading to end-stage renal disease (ESRD) in the elderly are hypertension and diabetes, but in many patients, the cause of renal disease is unknown. The elderly on hemodialysis have a higher rate of access morbidity, and, in this population, the most common hemodialysis-related complications are hypotension, arrhythmias, and gastrointestinal bleeding. Incidence of malnutrition increases significantly with age; the quality of life of these patients varies according to different investigators, who described results that are lower, similar, or better than those in younger patients. The authors address ethical issues, including the high cost of long-term therapy, conflicts over treatment futility and rationing, the financial restrictions on dialysis resources, and the withholding or withdrawing of treatment from older patients. 155 references. •

Diabetic Autonomic Neuropathy. Part 1: Early Detection Source: Practical Diabetology. 20(1): 7-8, 10-12, 14. March 2001. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (212) 989-0200 or (773) 777-6801. Summary: This article, the first of two parts, focuses on the diagnosis of diabetic autonomic neuropathy (DAN). This dysfunction of the autonomic nerve system (ANS) is one of the most prevalent and debilitating complications of diabetes, affecting more than 25 percent of patient with diabetes. The ANS is the part of the peripheral nervous system that is responsible for maintaining homeostasis. ANS dysfunction can affect any and every organ in the body. Autonomic neuropathy is more subtle than the sensory or motor neuropathies, so patients experience it only indirectly through its effects on the organs that the ANS influences. When ANS dysfunction is detected in one organ, there is generally dysfunction throughout the body. Autonomic neuropathy progresses slowly and often causes damage for years before the development of obvious symptoms. Some of the most common and severe conditions associated with DAN include silent myocardial infarction, cardiac arrhythmias, ulceration, gangrene, amputation, nephropathy, impotence, and hypoglycemic unawareness. DAN first appears in the longer nerves and later progresses to the shorter nerves. Early detection of DAN is important because it identifies patients with early, asymptomatic disease, thus allowing changes in treatment to produce better clinical outcomes. The most sensitive, repeatable, and practical measure of DAN is the heart rate variability test in response to provocative stimuli. The three most common provocative stimuli used for enhancing heart rate are deep breathing, Valsalva maneuver, and standing from the supine position. The article provides guidelines on selecting the proper test and interpreting test results. 1 figure. 1 table. 18 references.

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Giant Cell Myocarditis: Most Fatal of Autoimmune Diseases Source: Seminars in Arthritis and Rheumatism. 30(1): 1-16. August 2000. Summary: This journal article provides health professionals with information on the pathogenesis and treatment of giant cell myocarditis (GCM). The article reviews relevant publications from the literature in English on GCM. This rare, frequently fatal inflammatory disorder of cardiac muscle has no known cause. It typically affects young to middle aged adults and is characterized by widespread degeneration and necrosis of myocardial fibers. Congestive heart failure and ventricular tachycardia are common clinical manifestations. GCM occurs primarily in previously healthy adults, although it is frequently associated with various systemic diseases, primarily of autoimmune origin. The inflammatory infiltrate is characterized by the presence of multinucleated giant cells

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and is distinct from cardiac sarcoidosis. Animal models of GCM are similar to models of other autoimmune disorders such as rheumatoid arthritis. The major distinction to be made, and probably the most difficult, is between GCM and sarcoidosis, a systemic disease defined by the presence of epithelioid granulomas in multiple organs. Initial therapy should be directed toward controlling heart failure, preventing thrombosis, and controlling arrhythmias. The specific therapeutic approach to human myocarditis is inconsistent, in part because of uncertainty as to the severity of the disease, the underlying pathologic process, and the need to tailor therapies accordingly. Nonsteroidal antiinflammatory drugs have been frequently used, but without any observable benefit beyond their analgesic effect. The use of immunosuppressive therapy has not been adequately substantiated in human disease and remains controversial. The poor prognosis improves with cardiac transplantation. The article concludes that the clinical and immunopathogenetic similarities with classical rheumatologic diseases, the differential diagnosis with sarcoidosis and other inflammatory conditions, and the use of standard immunosuppressive medications make GCM a disease process that should be added to the rheumatologist's expertise. 2 figures, 4 tables, and 119 references. (AAM). •

Drug-Induced Liver Disease Source: Current Opinion in Gastroenterology. 12(3): 246-251. May 1996. Contact: Available from Rapid Science Publishers. 400 Market Street, Suite 700, Philadelphia, PA 19106. (215) 574-2266. Fax (215) 574-2292. Summary: This review article discusses recent developments with several important drug groups associated with drug-induced hepatotoxicity. The latest data indicate that nonsteroidal anti-inflammatory agents differ in the character, mechanism, incidence, and clinical importance of the hepatic injury that they may provoke. Reports of hepatotoxicity with flucloxacillin and amoxicillin-clavulanic acid continue despite publicity about risk factors. Concerns continue about adverse reactions to amiodarone, which should be prescribed only for serious cardiac arrhythmias. It is becoming quite clear that the threshold dose for hepatotoxicity from acetaminophen can be considerably lower than normal in regular users of alcohol. Evidence has also emerged that the mechanism of acetaminophen hepatotoxicity may involve release of cytotoxic mediators by hepatic macrophages in addition to the well-accepted mechanism of direct toxicity of an acetaminophen metabolite. The authors also discuss further developments in hepatotoxicity due to histamine H2-receptor antagonists, immunosuppressants, and steroid hormones. 2 tables. 58 references (19 annotated). (AA-M).

Federally Funded Research on Arrhythmias The U.S. Government supports a variety of research studies relating to arrhythmias. 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.

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

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

Project Title: A NOVEL HIGH THROUGHPUT ASSAY FOR ION CHANNEL MODULATORS Principal Investigator & Institution: Wible, Barbara A.; Assistant Professor; Chanxpress, Inc. 14656 Neo Pky Cleveland, Oh 44128 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JUL-2004 Summary: (provided by applicant): Ion channels comprise 10-20 percent of known drug targets for diseases including cardiac arrhythmias, stroke, hypertension, heart failure, asthma, cystic fibrosis, epilepsy, migraine, mental disorders, muscular dystrophy, and cancer. While ion channels provide important therapeutic targets, they are often the focal point of unwanted drug interactions leading to potentially serious side effects. The cardiac potassium channel hERG is an example of frequent unwanted drug interactions; block of hERG can predispose individuals to cardiac arrhythmias. Given the dual nature of ion channel targets, there is a need for high throughput assays that address the therapeutic potential as well as the drug safety issue. ChanTest, an ion channel company dedicated to providing technology services to the biopharmaceutical industry for drug safety testing and drug discovery involving ion channels, is developing novel high throughput screens that can address both needs. These proprietary assays monitor the level of expression of ion channels using an antibody-based chemiluminescent reaction. The goals of this proposal are to develop assays using the hERG potassium channel for two purposes: 1) HTXpress: high throughput screening of diverse chemical libraries for compounds which either increase or decrease hERG expression without affecting the kinetic properties of the channel, and 2) hERG-Lite: high throughput drug safety screening to identify drugs which block hERG using increased surface expression of mutant hERG channels as a biosensor for block. For HTXpress, the specific aim of this proposal is to optimize the assay by screening a structurally diverse chemical library of over 800 compounds. The identification of ion channel expression modulators, i.e. novel agonists and antagonists, is an untapped area of drug development and can be easily applied to channels other than hERG. With respect to hERG-Lite, the goal is to validate the use of this assay as a rapid safety test for hERG block. Eighty drugs (half known hERG blockers and half nonblockers) will be assayed for their behavior in the expression assay. Their potencies and rank order will be compared to hERG block assayed by standard electrophysiological measurements. The goal is to introduce hERG-Lite to the pharmaceutical industry as a rapid, inexpensive, and sensitive screen for hERG safety testing early in drug development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ALCOHOL MODULATION OF CARDIAC CALCIUM CHANNELS Principal Investigator & Institution: Aistrup, Gary L.; Mol Pharm & Biol Chemistry; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004

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Summary: Alcohol exerts a variety of actions on the cardiovascular system, the nervous system, and other organs. Clinical studies, have linked alcohol consumption with a number of asymptomatic and overt cardiovascular abnormalities, including cardiomyopathy, hypertension, arrhythmias, heart failure, and stroke. The mechanisms responsible for these various problems are not well understood. In the nervous system, voltage activated calcium channels and certain ligand-gated channels arc particularly sensitive targets of alcohol. These channels are suspected of being instrumental in acute intoxication and withdrawal. In cardiac tissues, calcium channels play a key role in rhythmicity, conduction, and excitation-contraction coupling. These channels are a major site of control by endogenous hormones and transmitters, and by therapeutic drugs. Calcium channels have been directly linked to a number of the actions of ethanol on the heart. Ethanol interferes with contractility in a variety of models, and it reduces electrically-stimulated calcium transients in ventricular myocytes. Our preliminary data with rat myocytes, and results from other laboratories, have confirmed that ethanol blocks L-type calcium channels in isolated cardiac cells. Defining how alcohol affects the physiology and regulation of these channels is essential in explaining immediate consequences of alcohol ingestion, as well as events that occur during prolonged periods of alcohol ethanol abuse. The overall objective of the proposed studies is to use whole-cell patch clamp techniques to analyze ethanol modulation of cardiac calcium channels. Ventricular myocytes will be dissociated from cardiac tissues of adult rats, and subjected to acute alcohol exposure. Biophysical and pharmacological experiments will evaluate calcium channel function under these conditions, and impossible mechanisms of channel modulation. Certain second messenger systems are known to exert regulatory control over calcium channel function in heart cells. Among these, the betaadrenergic/cAMP/PKA pathway is a critical mechanism for enhancing L-type calcium channels and stimulating cardiac contractility. We will therefore test the hypothesis that ethanol alters regulation of channels through this signal transduction system. Our preliminary data have shown that ethanol not only blocks currents stimulated via the beta-adrenergic system, but it also inhibits desensitization of the coupling process. We have also just completed exciting new preliminary studies demonstrating that ethanol is capable of reversing or occluding nifedipine-induced channel block. This novel action may have major implications, given the widespread clinical use of dihydropyridines and other calcium channel antagonists. Drug interactions of this type will be an important focus of the project. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANDROGENS PATHOPHYSIOLOGY

&

SLEEP:

APNEA

EPIDEMIOLOGY

&

Principal Investigator & Institution: Fogel, Robert B.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: (Adapted from the applicant's abstract) Obstructive sleep apnea (OSA) is a common disorder with important consequences for afflicted individuals. This disorder is characterized by recurrent pharyngeal collapse during sleep with subsequent repetitive arousals, along with substantial hypoxia and hypercapnia. Associated consequences include daytime somnolence, decreased performance on cognitive and vigilance testing and decreased quality of life. In addition, there is also increasing evidence that OSA may lead to adverse cardiovascular outcomes such as hypertension, arrhythmias, myocardial infarction and stroke. The pathophysiology of sleep apnea is dependent upon a complex interaction between upper airway anatomy, pharyngeal

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dilator muscle function and ventilatory control mechanisms, and the effects of state related changes in these variables. Substantial literature indicates that this disorder is much more common in men than in women, and that androgens in both men and women can exacerbate the disorder. However, neither the true extent of the effect of androgens on sleep apnea incidence and severity, nor the mechanisms by which androgens predispose to apnea have been well delineated to this point. With the proposed Mentored Patient-Oriented Research Career Development Award, the applicant will build upon his prior experiences investigating the role of androgens in the pathophysiology of sleep apnea. Based upon very positive experiences in the laboratory to date, the applicant is firmly committed to a career in academic pulmonary and critical care medicine, focused primarily on clinical research. The laboratory of Dr. David P. White at the Brigham and Women's Hospital will provide a rich intellectual environment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ARRHYTHMIA MECHANISMS OF THE METABOLIC SENSOR AMP KINASE Principal Investigator & Institution: Patel, Vickas V.; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): This proposal describes a 5-year training program to develop an academic career in molecular cardiac electrophysiology. The principal investigator has extensive training in clinical cardiac electrophysiology, basic electrophysiology, biophysics, and electrical engineering and will expand his scientific skills through a unique integration of interdisciplinary resources. This program will promote the command of molecular developmental biology, as applied to the development of cardiac arrhythmias and conduction disorders. Dr. Michael Parmacek will mentor the principal investigator's scientific development. He is a recognized leader in the field of molecular cardiac development and has trained numerous postdoctoral fellows and graduate students. To enhance the training, an advisory committee of highly regarded medical scientists will provide scientific and career guidance. The research will focus on mechanisms of arrhythmogenesis produced by mutations in the metabolic sensor AMP-activated protein kinase. Recent work has shown that mutations in AMP kinase produce familial Wolff-Parkinson-White syndrome in humans, and mice engineered with inhibitory mutations in their hearts die suddenly. The proposed experiments will use a combination of in vivo and in vitro electrophysiologic studies, biochemical and molecular techniques, and in situ localization analysis. We will study mice engineered with constitutively activating and inhibitory mutations in AMP kinase to elucidate the arrhythmogenic mechanisms of AMP kinase in the whole heart to the molecular level. The specific aims include: 1) determining the effect of mutations in AMP kinase upon cardiac arrhythmia inducibility, 2) determining if mutations in AMP kinase alter ion channel function, 3) determining if ion channel distribution is affected by mutations in AMP kinase that contribute to arrhythmogenesis. This will be the first functional analysis of how AMP kinase produces electrophysiologic disorders and may provide insight into novel mechanisms of arrhythmogenesis. The Cardiovascular Division of the University of Pennsylvania provides an ideal setting for training physician-scientists by incorporating expertise from diverse resources into customized training programs. Such an environment maximizes the potential for the principal investigator to establish scientific expertise from which to launch an independent academic career.

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

Project Title: BIOLOGY OF ARRHYTHMIA SUSCEPTIBILITY Principal Investigator & Institution: Roden, Dan M.; Professor; Medicine; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-AUG-1992; Project End 31-JUL-2007 Summary: (provided by applicant): Cardiac arrhythmias extract a huge public health cost in morbidity and mortality, they are becoming more prevalent as the population ages, and available drug therapies are only partially effective and cause serious adverse effects, including proarrhythmia. The last decade has seen a quantum increase in our understanding of the molecular mechanisms underlying cardiac arrhythmias, due in large part to identification of the genes whose expression results in pore-forming ion channel subunits. However, as our understanding of arrhythmia mechanisms has advanced, it is becoming clear that electrical activity in the heart is driven not by ion channels alone, but by the complex biologic context in which these channels are expressed. Cloning of human and mouse genomes offers an new opportunity to determine the way in which this context - including components such transcription, protein-protein interactions, and post-translational modification by activation of intracellular signaling - can be disrupted to cause arrhythmias. In this Program, a highly interactive group of scientists propose 5 Projects to test a series of specific hypotheses relating arrhythmia susceptibility to dysfunction of myocyte biology. Themes that cross Projects include studies of decreased channel availability, channel interactions with known and new subunits, and altered channel function by activation of intracellular signaling. Scientific tasks common to multiple Projects will be supported in two Cores: a cellular and mouse surgical Core and a microarray Core. This Program, by applying a new, genomic/systems approach to arrhythmias, will improve available therapies through identification of new targets for risk stratification and for antiarrhythmic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOMAGNETIC SIGNALS OF INTESTINAL ISCHEMIA Principal Investigator & Institution: Richards, William O.; Surgery; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-JAN-2006 Summary: (Provided by Applicant): Intestinal ischemia whether resulting from emboli, thrombosis or strangulation obstruction continues to be a serious and potentially fatal condition. We have pioneered the use of Superconducting Quantum Interference Device (SQUID) magnetometers for biomagnetic recordings of gastrointestinal smooth muscle activity in vitro, and in both animal and human subjects. This non-invasive, non-contact measurement of biomagnetic currents in smooth muscle demonstrates the feasibility of using SQUIDs to investigate human intestinal smooth muscle physiology. SQUIDs have unique fundamental advantages over cutaneous electrode recordings of intestinal electrical activity because magnetic fields readily penetrate layers of fat while electrical fields do not and cutaneous electrode recordings of human small bowel can not be routinely obtained. SQUIDs represent a striking new diagnostic device that has no equivalent except for invasive surgery and placement of electrodes onto the bowel surface. Hypothesis 1: Mesenteric ischemia causes uncoupling and arrhythmias of intestinal smooth muscle detectable in externally recorded magnetic fields. We will develop models to explain the arrhythmias, uncoupling and the effects of intervening

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tissue on the externally recording magnetic fields. Advanced analysis techniques to discriminate ischemic bowel from normal signals will be developed base upon our knowledge of smooth muscle behavior during ischemia. We will characterize for the fist time the magnetic currents in recordings taken during and after surgical exploration. Hypothesis w: Mesenteric ischemia causes sustained polarization of affected smooth muscle cells resulting in injury currents detectable in the externally recorded magnetic fields. Injury currents have been previously demonstrated to occur and be detectable magnetically in cardiac animal and human studies to detect this phenomenon. The new multichanel SQUID specifically designed for study of human intestinal magnetic fields developed and built as part of a SBIR grant will be available for use and will give us an extraordinary opportunity for the first time to explore smooth muscle pathophysiology during intestinal ischemia-one of the most deadly diseases known to man. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CALCIUM SIGNALING AND CARDIAC ARRHYTHMIAS Principal Investigator & Institution: Lederer, W Jonathan.; Professor; 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: Cardiac arrhythmias are a leading cause of death in humans and occur in diverse conditions. The proposed research seeks to identify and characterize fundamental mechanisms that underlie fatal cardiac arrhythmias. Specific cellular and molecular events that trigger arrhythmias will be examined to test the hypothesis that changes in subcellular calcium signaling contribute to arrhythmogenesis. Animal models of altered electrical activity in the heart will be studied at the single cells level using whole patch clamp methods and confocal calcium imaging. Isolated cardiac myocytes from control and transgenic animals and cells expressing specific constructs will be used in the planned work. Preliminary results have demonstrated calciumdependent links between altered electrical behavior and the expression of specific cellular proteins that are being examined in Project 1 (Russo), Project 2 (Marks) and Project 3 (Kass). The proteins of particular interest include beta1AR, beta2AR, RyR2, FKB12, FKBP12.6, SCN5A and mutations of these proteins. The proposed work examines how expression of the target proteins affects intracellular [Ca2+]i and also Ca2+-dependent membrane currents. This examination will explore the importance of the action potential shape and duration on [Ca2+]i signaling in the proposed experimental models. Additionally the relationship between SR Ca2+ content and Ca2+ release (as measured by Ca2+ sparks and the global (Ca2+) transient) will be examined with these molecular models. The experiments carried out in this project should thus provide fundamental new information on the arrhythmogenic roles played by the betaAR signaling system, sarcolemmal ion channels and the intracellular Ca2+ release channels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CALMODULIN CARDIOMYOPATHY

KINASE

AND

ARRHYTHMIAS

IN

Principal Investigator & Institution: Anderson, Mark E.; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Arrhythmias cause 50% of deaths in patients with cardiomyopathy and heart failure. Recent findings have highlighted the importance of

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Ca2+-activated kinases and phosphatases in activating gene programs driving morphological and functional changes in cardiomyopathy. One focus of our previous studies has been the arrhythmogenic potential of Ca2+/calmodulin-activated protein kinase (CaMK) II in normal cardiomyocytes with drug-induced action potential prolongation. More recently, we have developed evidence for an arrhythmogenic phenotype in cardiomyopathy that consists of increased CaMKII expression and activity, action potential and QT interval prolongation, disordered intracellular Ca2+ homeostasis, and arrhythmias or sudden death. The goal of this Project is to test the hypothesis that CaMKII is a molecular link between functional and morphological phenotypes, and thus a contributor to arrhythmia susceptibility in cardiomyopathy. To accomplish this goal, two distinct and well-characterized mouse models with cardiomyopathy, increased CaMKII activity, and arrhythmias will be interbred with mice that we have developed with cardiac-specific expression of a CaMKII inhibitory protein, or an inactive control. Using these tools, we will determine the effect of chronic CaMKII inhibition on the arrhythmogenic and the morphological and functional phenotypes in cardiomyopathy. To further understand the mechanisms underlying the salutary effects of CaMKII inhibition, we will determine the effect of chronic, cardiactargeted CaMKII inhibition on potential downstream signaling pathways. These experiments will target an arrhythmogenic molecular mechanism and build from single molecule assays to biochemical, histological, and functional studies in the whole heart. Delineation of the role of CaMKII in arrhythmogenesis will be an important step in developing new antiarrhythmic therapies in patients with heart failure. 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 2003; Project Start 01-FEB-1993; Project End 31-JAN-2008 Summary: (provided by applicant): 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 our understanding of mechanisms that underlie cardiac excitation and arrhythmias, and of principles behind interventions that lead to arrhythmia termination and prevention. It is our premise that understanding of mechanisms is imperative to the development of better treatment of arrhythmia and prevention of sudden death. As in the previous period of support, our approach is to study these phenomena through the use of theoretical, computer models in close conjunction with experimental observations. Specific aims are: (1) To continue the development of 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 caused by gene mutations and by abnormal calcium cycling. (3) To study the cellular electrophysiologic changes and single-cell arrhythmogenic behavior caused by ion-channel remodeling during myocardial infarction (MI). (4) To integrate the single cell behavior from (2) and (3) above into a multicellular model of cardiac tissue, and to study the mechanisms of arrhythmias associated with ion-channel mutation and with MI remodeling in the heterogeneous and anisotropic myocardium.

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

Project Title: SYMPOSIUM

CARDIAC

PACEMAKING

AND

CONDUCTION

SYSTEM

Principal Investigator & Institution: Gourdie, Robert G.; Associate Professor; Cell Biology and Anatomy; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2005 Summary: (provided by applicant): Partial support is requested for one year for a research symposium entitled the "Choreography of the Heart Beat: The Cardiac Pacemaking and Conduction System" to be held as a meeting-within-a-meeting over two days at the Experimental Biology Conference 2004 in Washington, D.C. between April 17-21, 2004. The cardiac pacemaking and conduction system (PCS) is vital for generating and synchronizing the heartbeat. Dysfunction of this vital system can be a direct cause of cardiac conduction disturbance, arrhythmias and sudden cardiac death. There have been recent notable advances in our understanding of the pacemaker system biology - particularly with respect to its development, cellular organization and electrophysiology. An opportunity and need exists to bring together basic scientists, clinicians and biomedical engineers working in disparate aspects of the PCS who would otherwise not typically find themselves at the same meeting venue (e.g. developmental biologists and electrophysiologists). The primary goals of our meeting are thus to; (1) bring investigators of the adult and embryonic heart together to share information on the PCS, (2) facilitate cross-disciplinary discussion and collaboration, and (3) bring young investigators to the meeting and encourage their ongoing participation in this burgeoning field. Topics to be covered will include the developmental biology, molecular and cell biology, morphology, electrophysiology and pathology of the developing and mature PCS. In addition to enabling us to support travel costs of the speakers, support by NIH/NHLBI will allow us to increase interactions between the participants and enhance accessibility of this meeting to students and junior faculty by decreasing travel costs. The meeting proceedings will be published in the form of fulllength articles in a peer-reviewed journal. A website on the "cardiac pacemaking and conduction system" will be established at Medical University of South Carolina with content arising from work presented and published from the meeting. 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

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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: CARDIOVASCULAR CELL AND GENE THERAPY CONFERENCE Principal Investigator & Institution: Hajjar, Roger J.; Associate Professor of Medicine; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2005 Summary: (provided by applicant): Cardiovascular disease is a major cause of morbidity and mortality in the United States. New treatments are being formulated based on a better understanding of the signaling pathways involved in the pathogenesis of cardiovascular diseases. Furthermore cell replacement therapy has recently emerged as a novel way of correcting contractile and vascular deficiencies in cardiovascular diseases. The focus of this yearly symposium will be on the use of somatic gene transfer and cell therapy in cardiovascular diseases. Targeting genes to the heart through somatic gene transfer or transplanting stem cells have the potential to alter our approach to patients with cardiovascular diseases. Gene and cell therapy allow us to test hypotheses about mechanisms of disease, and, it is hoped, tailor therapy accordingly. This symposium will bring together scientists from industry, clinicians and basic scientists. It will be a multidisciplinary meeting that should bring together people who are beginning to have regular dialogues but whose traditions have been somewhat separate Through this combination of investigators with multidisciplinary backgrounds, diverse scientific perspectives will be brought into focus on gene and cell therapy. The conference will consist of cover nine separate sessions over two and a half days. The topics of the sessions are 1) Viral vectors, 2) Delivery approaches, 3) Lessons from development, 4) Cell therapy, 5) Targeting Ischemic Heart Disease, 6) Targeting hypertrophy and growth, 7) Targeting heart failure and arrhythmias, 8) Targeting vascular disease, and 9) NIH programs and regulatory issues.The conference will be organized on a yearly basis in April. All the logistics of the first conference along with speaker commitments have been completed and the assigned date of the first conference is April 8-20, 2002. The convergence of investigators from different fields which are typically separate will hopefully foster greater collaborative efforts in gene and cell therapy and provide better understanding and treatment modalities for cardiovascular diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CELLULAR MECHANISMS OF DRUG TRANSPORT IN CHOROID PLEXUS Principal Investigator & Institution: Giacomini, Kathleen M.; Professor of Pharmacy; Biopharmaceutical Sciences; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-JAN-1991; Project End 31-DEC-2003 Summary: Nucleosides (e.g., adenosine) and synthetic nucleoside analogs (e.g., cytosine arabinoside (Ara-C) and 2',3'-dideoxyinosine (ddI)) are being used in the treatment of a

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wide array of disease states including cancer, viral infections, and cardiac arrhythmias. The overall goal of studies proposed in this competitive renewal application is to identify the structure, function and biological roles of Na+-dependent nucleoside transporters with particular emphasis on the specific transporters in the choroid plexus that are vital in the central nervous system (CNS) disposition and targeting of nucleosides and nucleoside drugs. In recent exciting studies, the first Na+-dependent nucleoside transporters were cloned from rat (rPUR and rPYR) and human (hPUR (cloned in this laboratory) and hPYR) tissues. hPYR and rPYR are pyrimidine-selective whereas hPUR and rPUR are purine- selective. Initial studies suggest that these cloned transporters are present in choroid plexus epithelium and play a role in the CNS targeting of nucleosides and nucleoside analogs. Novel studies performed in this laboratory with chimeric transporters have identified, for the first time, the gross structural domains responsible for the purine and pyrimidine selectivity of rPUR and rPYR. The specific aims of the proposed studies are: (1) To determine the functional characteristics hPUR and hPYR in heterologous expression systems. Particularly, we will investigate the mechanisms of interactions of synthetic nucleoside analogs which are important in the treatment of cancer and viral infections; (2) To determine the functional domains and critical amino acids responsible for purine and pyrimidine substrate recognition in PUR and PYR; and (3) To localize rPUR and rPYR to the brush border or basolateral membrane of the choroid plexus. Briefly, we will perform functional studies in a mammalian expression system. Site-directed mutagenesis, construction of chimeric transporters together with molecular modeling will be used to determine the critical amino acids responsible for substrate selectivity in the transporters. Studies with antibodies will localize the transporters in choroid plexus epithelium. These studies will greatly advance our understanding of the molecular mechanisms involved in nucleoside transport and the structural elements of nucleoside transporters critical in purine and pyrimidine discrimination. The information gained is important in drug design and targeting to the CNS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHRONIC MONITORING OF ISCHEMIC MODELS OF SUDDEN DEATH Principal Investigator & Institution: Smith, William M.; Professor; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: Most sudden cardiac death (SCD) is associated with coronary artery disease, but little is known about the exact sequence of events that leads up to it and the mechanisms responsible for it. There is a complex interplay between old myocardial infarcts, acute ischemia, the status of the autonomic system, mechanical viability, and electrophysiology that leads to SCD and influences whether tachycardia or bardycardia is the final rhythm. In this project, it is proposed to combine a unique set of technological and physiological resources to study the events surrounding sudden death. An animal model of infarct/ischemia leading to spontaneous SCD has been developing and will be studied in two complementary ways. One set of animals will be instrumented with a custom-developed telemetry system to acquire electrophysiologic and functional data during the conscious, ambulatory state, eliminating the confounding effects of thoracotomy and anesthesia and anesthesia on the incidence and nature of sudden death. Another set of animals will be studied with high resolution, three dimensional mapping to elucidate the mechanisms of the spontaneous arrhythmias that lead to SCD. It is hypothesized that the balance between the vagal and

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sympathetic arms of the autonomic system and that changes in repolarization properties of the myocardium are predictors of which animals die suddenly and spontaneously and spontaneously as well as the mode of death. It is also hypothesized that spontaneous tachycardia/fibrillation is initially reentrant and that the old infarct is involved in the arrhythmia maintenance. Further, it is hypothesized that bradycardia is associated with pump failure rather than a vagal reflex leading to hypotension. It is proposed to use the data from this research to develop, implement and validate measures that predict imminent SCD on the time scale of seconds to minutes. Because of the continuous nature of data acquisition over several days when no sustained arrhythmias are observed, it will be possible to determine the specificity as well as the sensitivity of derived predictors. Innovations in telemetry capability, cardiac mapping, and new animal models of spontaneous sudden cardiac death will provide information about the context and mechanisms of sudden death that has not been available before. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLONING/CHARACTERIZATING A MYOTONIC DYSTROPHY LOCUS Principal Investigator & Institution: Ranum, Laura P.; Professor; Neurology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-JUN-1997; Project End 31-MAY-2005 Summary: Myotonic dystrophy (DM) is a multisystem disease and the most common form of muscular dystrophy in adults. In 1992, one form of DM was shown to be caused by an expanded CTG repeat in the 3' untranslated region of the myotonin protein kinase gene (DMPK) on chromosome 19. Although multiple theories attempt to explain how the CTG expansion causes the broad spectrum of clinical features in DM, there is no consensus about how this mutation, which does not alter the protein coding region of a gene, affects cellular function. We have identified a five-generation family (MN1) with a genetically distinct form of myotonic dystrophy. Affected members have the characteristic features of DM (myotonia, proximal and distal limb weakness, frontal balding, cataracts, and cardiac arrhythmias) but do not have the chromosome 19 mutation. We have mapped the disease locus (DM2) for the MN1 family to a small region of chromosome 3 (Nature Genetics 19:196- 198). This proposal outlines a strategy to identify and characterize the DM2 locus. Understanding what is common to chromosome 19 DM (now designated DM1 by the DM consortium) and DM2 at the molecular level should shed light on the mechanisms responsible for the broad constellation of clinical features present in both diseases. Our specific aims are: 1) to develop a high-resolution map of the DM2 region (0.5-1.0 cM) using haplotype and linkage disequilibrium analysis of 29 DM2/PROMM families from Minnesota and Germany; 2) to identify the expressed genes and repeat motifs in the region and prioritize candidates based on homology and expression patterns; 3) to identify the DM2 mutation; 4) to characterize the DM2 gene and investigate whether or not the pathogenic molecular changes found in DM2 are part of a common pathway also affected in DM1; 5) to determine whether molecular changes affecting RNA splicing, CUG binding proteins, and apamin receptors are similar to those found in DM1. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CNS AUTONOMIC REGULATION BY ELECTROACUPUNCTURE Principal Investigator & Institution: Longhurst, John C.; Professor; Medicine; University of California Irvine Irvine, Ca 926977600

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Timing: Fiscal Year 2002; Project Start 20-SEP-2000; Project End 31-DEC-2003 Summary: (Adapted from Applicant's Abstract): Acupuncture is an effective therapeutic modality in Eastern cultures, but has not achieved widespread recognition as a useful therapeutic option in Western medicine. In addition to its use in pain and anesthesia, electro-acupuncture (EA) has been used in hypertension, hypotension, angina and cardiac arrhythmias. Recently, the Pl's laboratory has begun to explore the physiological basis of EA. An initial study demonstrated that low frequency EA ameliorates myocardial ischemia by reducing myocardial oxygen demand in a feline model of reversible ischemia. In this model, stimulation of gallbladder chemosensitive afferent nerve endings reflexly increased arterial blood pressure, and augmented myocardial oxygen demand, which outstripped coronary blood supply following partial coronary ligation. Concurrent stimulation of the median nerves underlying the Neiguan acupoints reduced myocardial ischemia, measured as a reduction in regional wall thickening. A second study employing EA suggests a role of the endogenous opiate system in the rostral ventral lateral medulla (rVLM). Preliminary data from the Pl's laboratory indicate that the rVLM and periaqueductal gray (PAG) mediate the interaction between visceral (gallbladder) and somatic (EA) afferent nerve stimulation, and suggest a role for mu- and delta-opioid receptors. Also, the Pl has demonstrated in preliminary studies the ability to identify cells in the rVLM that receive convergent input from the greater splanchnic nerve (supplying the gallbladder) and the median nerve. Five hypotheses are now proposed: 1 ) The order of potency for the blood pressure-lowering effect of EA will be mu-equal to or greater than delta-greater than kappa-opioid receptors; 2) Non-NMDA excitatory amino acid receptors are responsible for stimulation of its neuronal subpopulation; 3) EA of Neiguan produces post-synaptic inhibition of an excitatory input to these neurons; 4) The ventrolateral PAG participates in EA modulation of reflex autonomic responses through an opioid mechanism and by influencing sympathoexcitatory rVLM neurons; and 5) Deep but not superficial somatic nerves underlying specific acupoints provide convergent input into rVLM and PAG neurons, and, through an opioid mechanism, modulate neuronal activity. Studies will be conducted in anesthetized cats whose rVLM and PAG are approached stereotaxically for extracellular recording and to deliver pharmacologic antagonists and agonists. Collaboration with both US and Chinese authorities on central neural electrophysiological and acupuncture research will significantly contribute to the ability to accomplish this investigation. By demonstrating the central neural mechanisms underlying this clinically beneficial modification of a cardiovascular reflex response by EA, scientists and clinicians will have a better understanding that will likely aid in acceptance and use of this alternative therapy. The Pl indicates that this project has important clinical implications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONNEXIN43 EXPRESSION AND FUNCTION IN THE HEART Principal Investigator & Institution: Fishman, Glenn I.; William Goldring Professor; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2002 Summary: Cardiac arrhythmias associated with structural heart disease are a major cause of morbidity and mortality in the United States and lead to as many as several hundred thousand sudden cardiac deaths each year. Several converging lines of investigation suggest that dysregulation of gap junction mediated intercellular communication, or gap junctional remodeling, contributes to the substrate for cardiac

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arrhythmias. Myopathic hearts, however, invariably show a multitude of structural and functional perturbations, thus, the unique contribution of gap junctional remodeling to the substrate for cardiac arrhythmias has been difficult to study in isolation from these other contributory factors. The long-term goal of the studies described in this proposal are to determine the specific contribution of dysregulated gap junction mediated intercellular coupling to the formation of the arrhythmogenic substrate and to understand the molecular mechanisms resulting in gap junctional remodeling. Toward this end, we have established several conditional gene-targeted murine models to elucidate the role of the remodeling process in formation of the arrhythmogenic substrate. We have also begun to elucidate mechanisms controlling gap junctional expression and remodeling and discovered that the Wnt signaling cascade acting through a beta-catenin signaling pathway is an important regulatory circuit controlling Cx43 expression in cardiomyocytes. Our specific aims are to establish a direct, causal relationship between gap junctional remodeling, conduction abnormalities and arrhythmogenesis, to determine the role of beta-catenin mediated signaling and its relationship with other signaling pathways in the regulation of Cx43 expression in normal and remodeled murine and canine hearts, and to characterize the role of Wnt signaling in the context of the adult mouse myocardium. Elucidation of the mechanisms regulating gap junctional remodeling and its role in the arrhythmogenic substrate have significant implications for novel pharmacotherapy of lethal cardiac arrhythmias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--GENETIC MODELS AND MOLECULAR SIGNALING Principal Investigator & Institution: D'armiento, Jeanine M.; Associate Professor; 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: This program Project Grant (PPG) proposal comprises four Projects and two Cores. The focus of the projects is identification of molecular signaling that initiate fatal cardiac arrhythmias (Sudden Cardiac Death SCD). A central hypotheses is that adrenergic modulation of ion channels perturbs intracellular Ca signaling leading to triggers of SCD. We propose that perturbations of intracellular calcium homeostasis, primarily due to defective regulation of the ion channels including potassium, sodium, calcium channels as well as the ryanodine receptor/calcium release channel on the cardiac sarcoplasmic reticulum, initiate, initiate triggers of fatal cardiac arrythmias. Each of the proposed projects requires extensive work with animal models which will be supported by the following core. The present core will provide support for the projects in four major areas: (a) the preparation and maintenance of transgenic and knockout mice and (b) Characterization of transgenic and knock-out mice including preparation and analysis of tissue specimens from animals (c) Physiological measurements on transgenic and knockout mice including drug testing and (d) Characterizing B adrenergic receptor signaling in the normal and transgenic mouse hearts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--MICROARRAY SUPPORT Principal Investigator & Institution: Levy, Shawn E.; Research Assistant Professor and Directo; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Vanderbilt University has established a state-of-theart microarray facility that is presently supported by the Vanderbilt-Ingram Cancer

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Center, the Diabetes Center and the Vanderbilt NIDDK Biotechnology Center. This facility provides high quality microarray production, hybridization and data analysis for members of these research centers. Core B will enable Program investigators access to the full spectrum of advanced technologies offered by this resource. Projects 0010, 0011 and 0013 will utilize Core B for proposed experiments aimed at revealing changes in gene expression associated with arrhythmia susceptibility. In Project 0010, experiments have been outlined to compare gene expression patterns between mice expressing a CaM Kinase II inhibitory peptide or control peptide in heart in experimental cardiomyopathies. These experiments seek knowledge of the role of CaMKII and its upstream and downstream regulators on molecular pathways leading to cardiac failure and arrhythmias. Project 0011 will utilize microarray experiments to study an in vitro cell culture system for examining electrical remodeling in atrial myocytes subjected to rapid pacing, with the goal of identifying early molecular changes contributing to an atrial fibrillation-susceptible phenotype. Project 0013 has developed a novel molecular resource, a canine expressed sequence tag (EST) collection from heart, that will be used to develop gene arrays to be applied initially to dog models of susceptibility to arrhythmias closely resembling human disease. Core B consists of two main critical elements: (1) microarray production and hybridization; and (2) data acquisition and analysis. Both elements operate with state-of-the-art technological and computational tools that guarantee superior quality and reliability in microarray experiments. The Core will support the salaries of key personnel needed for operating the core, equipment and other infrastructure costs that enable expansion of existing services, and support for expertise in analysis of the data that emerge from microarray experiments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CROSS-MODULATION OF EXCITABILITY/CA IN HEART FAILURE Principal Investigator & Institution: O'rourke, Brian D.; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: Heart failure currently affects more than two million Americans and its economic and human tool will continue to increase as the population ages. Strictly defined, heart failure is an inability to match cardiac output to physiological demand; however, roughly half of the early deaths following diagnosis are thoroughly cataclysmic arrhythmic events, or Sudden Cardiac Death (SCD). SCD is presumed to result from a set of primary cellular alterations that predispose the failing heart to a fatal electrical event. A leading hypothesis has been that prolongation of the cardiac action potential resulting from slowed repolarization shifts the cell into a vulnerable state. Two important changes with heart failure that could influence repolarization are a reduction in repolarizing K/+ currents and a slowed rat of removal of intracellular Ca/2+. The former involves a selective reduction in the transient outward K+ current (I/to/1) and the inward rectifier K+ current (I/k1) while the latter results from a decrease in the sarcoplasmic reticulum Ca/2+ ATPase (SERCA2a) and a increase in sarcolemmal Na/+/Ca/2+ exchange in the sarcoplasmic reticulum Ca/2+ ATPase (SERCA2a) and a increase in sarcolemmal Na/+/Ca/2+ exchange (NCX). The full scope of cellular alterations in heart failure can only be understood when all of the changes are considered together; changes in the action potential waveform will govern the triggered release of Ca/2+ from the sarcoplasmic reticulum and conversely, intracellular Ca/2+ will reshape the action potential. At present, little is known about the relative importance of each of these factors on the contour of the action potential and the intracellular Ca/2+ transient in normal or failing heart cells. The goal of the present

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application is to examine how varying each these factors (e.g., I/to, I/k1, SERCA2a, and NCX) affects the cellular action potential and Ca/2+ transient of each change to the integrated cell response. This effort will be aided by the parallel development of a comprehensive computer model of action potentials and Ca/2+ handling. Special attention will be paid to how the alterations contribute to the susceptibility of the cardiac cell to arrhythmias. The ultimate objective is to understand which changes associated with heart failure contribute most to the pathology of the disease, so as to precisely target therapy to the site(s) that correct both the electrophysiological and mechanical alterations of heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CX43 IN A GENETIC MODEL OF ALTERED MYOCARDIAL CONDUCTION Principal Investigator & Institution: Saffitz, Jeffrey E.; Professor of Pathology & Immunology; Pathology and Immunology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAY-2005 Summary: The goal of the proposed research is to define the functional role of Cx43 in normal cardiac conduction and to delineate the role of altered coupling at gap junctions in the pathogenesis of conduction disturbances and arrhythmias. Proposed experiments will be performed using mice that are heterozygous for a null allele for the gene encoding the major cardiac gap junction protein, Cx43 (Cx43 plus/minus mice). These mice produce 50 percent of the wildtype level of Cx43 and have significant reduction in the number of gap junction interconnecting ventricular myocytes. The functional consequence of reduced Cx43 expression in adult mice is a 25-30 percent slowing of ventricular conduction velocity. Whereas the electrophysiological phenotype in Cx43 plus/minus mice is subtle under physiological conditions, a more dramatic phenotype can be elicited under pathophysiological condition. In response to acute regional ischemia, Cx43 plus/minus mice exhibit accelerated onset and increased incidence, frequency and duration of ventricular arrhythmias. The proposed research is focused on defining mechanisms by which reduced coupling promotes arrhythmias in accute and chronic ischemic heart disease. Studies in Specific Aim 1 will elucidate the mechanistic relationship between the rate and extent of electrical uncoupling at gap junctions and development of ventricular tachyarrhythmias induced by acute ischemia. Studies in Specific Aim 2 will define arrhythmia mechanisms in Cx43 plus/minus following acute coronary occlusion and delineate the roles of Cx43 and altered cell-to- cell coupling in electrical triggering events and sustained conduction abnormalities that underlie initiation and maintenance of ventricular arrhythmias in the setting of acute myocardial ischemia. In Specific Aim 3, the role of gap junction remodeling in the pathogenesis of arrhythmias in chronic ischemic heart disease will be elucidated by comparing arrhythmogenesis in Cx43 plus/minus and wildtype mice with healed myocardial infarcts. And in Specific Aim 4, molecular and structural determinants of conduction will be delineated using neonatal mouse ventricular myocytes grown in patterned arrays of defined structure and packing geometry, and analyzed by high resolution optical mapping. The results of the proposed research will define mechanisms by which reduced coupling promotes ventricular tachyarrhythmias in mouse models of acute and chronic ischemic heart disease in patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEFIBRILLATION ARRHYTHMIAS

MECHANISMS

DURING

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Principal Investigator & Institution: Walcott, Gregory P.; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: Sudden cardiac death is a major cause of mortality in the United States. In an effort to attach this problem, the concept of a Chain of Survival has been presented as a way to characterized the tasks necessary for successful resuscitation. It is clear that early defibrillation is central to improved survival rates following out-of-hospital cardiac arrest. 1) successful defibrillation of the arrhythmia of the arrhythmia, 2) recurrence if arrhythmias following defibrillation, and 3) poor cardiac function following defibrillation This project will address the first two problems. Very little is known about defibrillation efficacy of spontaneous arrhythmias in the presence of acute ischemia. A much larger shock is needed to halt ventricular fibrillation that occurs spontaneously in the presence of acute is ischemia than to halt electrically induced ventricular fibrillation in the non-ischemic heart. We will study the activation patter following successful and failed defibrillation shocks with the heart in four conditions designed to model different aspects of ischemic ventricular fibrillation shocks the heart in four conditions designed to model different aspects of ischemic ventricular fibrillation: (1) acute regional ischemia causing spontaneous ventricular fibrillation, (2) acute regional ischemia followed by electrically induced ventricular fibrillation, (3) acute regional ischemia causing spontaneous ventricular fibrillation which in turn causes prolonged global ischemia, and (4) acute regional ischemia causing spontaneous ventricular fibrillation in the setting of prolonged global ischemia, and (4) acute regional ischemia causing spontaneous ventricular fibrillation in the setting of an old myocardial infarction. We will test the hypothesis that, in the setting of an ischemically induced spontaneous arrhythmia, a defibrillation shock must do three things: (1) stop all fibrillation wavefronts, (2) not restart fibrillation, and (3) stop the trigger of the original arrhythmia. We will test the hypothesis that a major determinant of whether or not a spontaneous arrhythmia, a defibrillation shock must do three things: (1) stop all fibrillation wavefronts, (2)m not restart fibrillation and (3) stop the trigger of the original. We will test the hypothesis that a major determinant f whether or not a spontaneous arrhythmia caused by acute ischemia can be easily defibrillated depends upon the mechanism of initiation of the arrhythmia and duration of the arrhythmia. We will also test the hypothesis that arrhythmias that occur following the initial fibrillation episode are initiated by focal rather than reentrant mechanisms and will be harder to defibrillate than the initial arrhythmia. To test these hypothesis, we will induce acute ischemia by creating a thrombus in a coronary artery and use electrical mapping techniques to map the initiation of ventricular arrhythmias, and the first few post-shock activations following delivery of a defibrillation shock. By developing an understanding of how a defibrillation shock succeeds or fails under these conditions, we will be in a better position to develop new defibrillation techniques that increase survival rates of patients suffering an episode of sudden cardiac death. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEPRESSION AND CARDIOVASCULAR PATHOLOGY

HEART

FAILURE

ASSOCIATED

Principal Investigator & Institution: Johnson, Alan K.; Associate Professor; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2003; Project Start 21-JAN-2003; Project End 31-DEC-2007

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Summary: Depression is both a debilitating psychological disorder and a condition that affects an individual's physical well-being. Depression is a recognized risk factor for heart disease. Research has demonstrated that depression predisposes an individual to myocardial infarction, sudden death, atherosclerosis, thrombosis and arrhythmias. While the behavioral and cognitive aspects of depression have been studied extensively, there has been much less research investigating the mechanisms responsible for the physiological consequences of mood disorders. Exposure of rodents to a series of chronic mild stressors (CMS) generates key behavioral characteristics of human depression that are observable and quantifiable. The CMS model of experimentallyinduced depression (ID) mimics the reduced responsiveness to pleasurable stimuli (anhedonia)which is a pivotal diagnostic criterion seen in depression. In the CMSdD model, anhedonia is induced by presenting mild unpredictable stressors (e.g., paired housing, stroboscopic illumination, white noise) of varying durations. In rats,anhedonia is operationally defined as a decrease in responding for a previously demonstrated reinforcer (reward). Recently, we have begun to characterize cardiovascular function in rats with CMS-ID. We have found that rats exposed to CMS for 4 weeks showed anhedonia along with cardiovascular alterations. Similar to patients with depression and with heart failure,CMSgD rats had elevated resting heart rates and reduced heart rate variability. In addition, rats exposed to CMS have increased susceptibility to experimentally-induced premature ventricular contractions. In other studies investigating the behavioral consequences of heart failure, we have found evidence of anhedonia (i.e., experimental depression) in rats with experimental myocardial infarction. The proposed research program will extend our characterization of the cardiovascular changes that accompany experimentally-induced depression and investigate the role of brain serotonergic mechanisms that are hypothesized to be common in the mediation of cardiovascular alterations that accompany both experimental depression and experimental heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEVELOPING PREDICTIVE METHODS FOR SUDDEN CARDIAC DEATH Principal Investigator & Institution: Chon, Ki H.; Biomedical Engineering; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2004 Summary: (Adapted from the applicant's abstract): Physiological systems are characterized by their dynamics nature. These dynamics arise from instabilities in regulatory systems, from nonlinear interactions between different regulatory systems, and from external perturbations. As a consequence, many physiological systems display complex spatio-temporal phenomena like oscillations, bifurcation, chaos, and spiral waves. Indeed, recent reports have shown that noninvasively-measured cardiac rhythms exhibit characteristics of nonlinear dynamics, including deterministic chaos, and that chaos theory may have diagnostic and prognostic significance in screening patients susceptible to lethal arrhythmias. However, current methods for detecting deterministic chaos require long, stationary, and relatively noise- free data records. This limits the utility of these methods in most experimental and clinical settings. To improve upon the limitations of current techniques. The investigators first specific aim is to develop a new iterative n-step-ahead stochastic nonlinear autoregressive algorithm that can be applied to clinical cardiac arrhythmia data to obtain the most accurate diagnostic and prognostic information as to whether or not a patient will be susceptible to sudden cardiac death. To perform quantitative evaluation of the algorithm, the second specific

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aim is to systematically determine the accuracy and limitations of the method by testing with short data records against well-known chaotic systems under noisy conditions. To validate and extend the algorithm, the third specific aim is to test the accuracy of the algorithm against electrophysiologic "gold standard" techniques using noninvasively measured heart rate data obtained from healthy subjects and patients with various forms of malignant cardiac arrythmias. In the fourth specific aim, the investigators aim to disseminate the developed algorithm to the general biomedical community via the internet so that the algorithm can be further tested with other researchers' own databases. It is intended that the algorithm will be applicable to other physiological systems and may become a widely accepted noninvasive clinical alternative. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISCOVERY AND CHARACTERIZATION OF ION CHANNEL MODULATORS Principal Investigator & Institution: Minor, Daniel L.; Cancer Research Institute; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 31-MAY-2008 Summary: (provided by applicant): The long-term goals of this project are to develop general, high-throughput methods to identify, evolve, and characterize small molecule and protein inhibitors and activators of ion channel function. Ion channels are coveted drug targets. As membrane proteins, they are readily accessible to applied extracellular compounds and their modulation brings about rapid changes in the signaling properties of excitable cells in the heart and brain. However, as membrane proteins, they also reside beyond many of the well-established approaches for inhibitor and activator development that require purified material. Consequently, many lack any significant pharmacologies. This problem leads to a large gap in our ability to connect ion channel genes with in vivo function. Unraveling the physiological and biophysical functions of ion channels demands new tools that allow the manipulation of a given type of channel's action in a variety of settings. To address this issue, we are using novel genetic selection approaches to develop activators and inhibitors of two classes of potassium channels that lack robust pharmacologies, inwardly rectifying and Two-P potassium channels. These channels are thought to play central roles in neurotransmitter regulation of neuronal and cardiac excitability but precise delineation of their functions awaits reagents that can specifically activate or block their function. We are pursuing genetic selections for both small molecule and peptides. Our approach is multidisciplinary and includes genetics, biochemistry, electrophysiology, and structural biology to dissect and characterize the modes of action of selected modulators. Because of their important roles in human physiology, ion channels are the targets for drugs to treat a wide range of diseases including epilepsy, cardiac arrhythmias, stroke, hypertension, diabetes, and memory loss. In addition to being intended drug targets, a number of ion channels, particularly cardiac ion channels, are unusually susceptible to unwanted crossreactivity. This issue impedes the progress of many drug development trials. Thus, developing an understanding of how small molecules act on ion channel function as well as developing high-throughput methods for assaying compounds that lead to ion channel block should not only provide powerful tools for dissecting channel mechanism and function but should aid in the development of new therapeutic agents for a range of human diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECTS OF CHRONIC HYPOXIA ON A NONMAMMALIAN VERTEBRATE Principal Investigator & Institution: Burleson, Mark L.; Biology; University of Texas Arlington 301 South Center Street Arlington, Tx 76019 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2007 Summary: (provided by applicant): A number of human health problems stem from dysfunctional cardiovascular and ventilatory control processes which have been altered by chronic and/or intermittent hypoxia. These include SIDS, developmental effects in the fetus and neonate, periodic breathing, hypertension, increased risk for stroke, arrhythmias and the long-term effects of various cardio-pulmonary diseases. Some of the physiological responses of mammals to hypoxia are adaptive for sojourn to high altitudes. However, the consequences of some of the responses lead to pathologies. While there has been significant progress towards understanding the effects of chronic and intermittent hypoxia, the neural mechanisms responsible for many of the changes in cardiovascular and ventilatory control remain elusive. Also, significant changes occur in the effect of chronic hypoxia as a mammal matures from a fetus through neonate to adult. An investigation of animals that have the ability to routinely cope with large chronic and intermittent changes in O2 availability may lead the way to a better understanding of human diseases and perhaps novel treatment strategies. The overall objective of this proposal is to use standard physiological measurements and confocal laser microscopy to investigate changes in central and peripheral neural mechanisms responsible for altering cardiovascular and ventilatory control in response to chronic and intermittent hypoxia in the water-breathing channel catfish (Ictalurus punctatus). This study will fill a critical gap in our knowledge of O2 chemoreception. Strategic repetitions of some mammalian studies will allow a the beginning of a comparative/phylogenetic analysis of O2 chemoreception in vertebrates. Other experiments utilizing this novel animal model and the determination of central and peripheral neurotransmitter identities and levels may provide insight into the evolution of O2 chemoreception. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ELECTRICAL CONTROL OF GASTRIC MOTILITY Principal Investigator & Institution: Sanders, Kenton M.; Professor & Chairman; Physiology and Cell Biology; University of Nevada Reno 204 Ross Hall Mailstop 325 Reno, Nv 89557 Timing: Fiscal Year 2004; Project Start 01-AUG-1988; Project End 31-DEC-2008 Summary: (provided by applicant): Electrical pacemaker activity serves a critical function in gastric motility. Recent studies have determined that interstitial cells of Cajal (ICC), located in the myenteric region of the tunica muscularis of the corpus and antrum, are the primary pacemaker cells in mammalian gastric muscles. Pacemaker events, originating near the greater curvature of the corpus, spread around and down the stomach to the pyloric sphincter. This activity, known as electrical stow waves, times the occurrence of gastric peristaltic contractions. Proper spread of slow waves depends upon a proximal-to-distal gradient in the intrinsic frequency of pacemaker activity. Loss of pacemaker activity, emergence of ectopic pacemakers, or defects in slow wave propagation can lead to functional motility disorders of the stomach. This project will seek to understand the pacemaker mechanisms in gastric ICC. Studies will be performed on isolated ICC from the corpus and antrum to determine the conductance(s) responsible for pacemaker currents and the intracellular events leading to activation of

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pacemaker currents. We have found that the gastric pacemaker frequency gradient is encoded in ICC from the corpus and antrum, and further experiments will carefully attempt to dissect the differences in pacemaker activity of the ICC from these regions to understand the basis for the pacemaker frequency gradient. We will also determine whether the mechanisms responsible for generation of pacemaker current are required for regeneration of slow waves, and experiments will be performed to understand how electrical pacing from an external current source can affect generation and propagation of slow waves. Experiments to determine the factors involved in regulation of pacemaker frequency in ICC and to determine the mechanisms by which various biogenic chemicals affect the timing of pacemaker events will be performed. This information may provide new insights into the causes (and perhaps cures) for gastric arrhythmias. Basic information about generation, propagation and regulation of pacemaker frequency will be used in studies of intact muscles to explore the nature of the gastric frequency gradient and how changes in pacemaker frequency affect the spread of slow waves (i.e. functional coupling) between the corpus and antrum. New animal models of gastric arrhythmias will be studied to determine how pacemaker abnormalities affect functional coupling. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GAP JUNCTION CHANNEL PERMEABILITY: A MUTAGENIC APPROACH Principal Investigator & Institution: Brink, Peter R.; Professor and Chair; Physiology and Biophysics; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2002; Project Start 01-MAY-1997; Project End 31-JUL-2006 Summary: (provided by applicant): We hypothesize that there are specific charge groups that preferentially influence the permeation of molecules in the size and charge range of second messengers while having little influence on monovalent cation selectivity. We hypothesize that there are multiple sites able to affect the permselectivity of gap junction channels. The specific aims are: Aim la) Transfect mouse N2A cells or rat insulinoma cells (RIN) with mutant versions of Cx43, Cx40, and Cx37 cDNA and determine expression via Western and Northern blot analysis. We will also use the GFP tag strategy to determine cellular distribution. We have chosen Cx43 and Cx40 because of their ubiquity in the SA an AV nodes of the heart and hence their potential to affect cardiac arrhythmias. Cx37 is the major connexin of endothelium. Aim ib) Monitor single channel conductance in homotypic mutants in KC 1, CsCI, NaCI and TEACI to assess changes in cation/anion selectivity using dual whole cell patch clamp. Aim 2) Monitor single channel conductance in which one hemichannel is composed of a mutant connexin (muCx43 or muCx4O) and the other is composed of a wild type connexin of Cx43 or Cx40 in Kcl, CsCI, NaCl and TEAC1 to assess changes in cation/anion selectivity. We will use cysteine scanning mutation to determine if a mutated site lines the poor wall. Aim 3) Simultaneously determine junctional conductance and junctional permeability to charged fluorescent probes for wild type and mutant connexins (homotypic and heterotypic forms). This will allow the determination of the permeation rates of charged probes in the 0.8-1.2 nm size range relative to K+/Cs+. Inert probes (Lucifer Yellow, DAPI, carboxyfluorescein) are probes of choice because they are not rapidly removed from the cytosol, as is the case for lP3 (Tau less than 60s). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETICS STUDIES OF FAMILIAL DILATED CARDIOMYOPATHY Principal Investigator & Institution: Mcnally, Elizabeth M.; Associate Professor; Medicine; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: Many etiologies lead to the development of dilated cardiomyopathy. Idiopathic dilated cardiomyopathy arises from intrinsic muscle disease in the presence of normal coronary arteries and the absence of a clear toxic or immunologic insult. Approximately 30 percent of idiopathic dilated cardiomyopathy patients have first degree relatives that also show evidence of cardiac dilatation with or without symptoms of congestive heart failure. Supporting this, genetic loci have been significantly associated with familial dilated cardiomyopathy (FDC). Positional cloning efforts are underway to increase our understanding of the molecular mechanisms that underlie familial dilated cardiomyopathy. Through genetic linkage analysis, we have identified a region of chromosome 6q23 that is associated with dilated cardiomyopathy, conduction system disease that produces progressive atrio-ventricular block and a mild, adult onset, slowly progressive muscular dystrophy. We have constructed a physical map of this region of chromosome 6 and evaluation of candidate genes is underway. We have also discovered a second region, chromosome 2q22, that is associated with dilated cardiomyopathy and ventricular arrhythmias. We propose to refine the genetic interval, identify candidate genes and, through mutation analysis, identify the gene responsible for chromosome 2-associated FDC. The FDC-gene product will be studied for expression patterns in both normal and diseased tissue. The murine homolog of the FDC-gene will be determined. We will also establish a clinical and DNA database of dilated cardiomyopathy patients. This database will be used to determine the role of certain mutations in the development of the cardiomyopathic process. While genetic heterogeneity is present in FDC, the study of genes responsible for this disorder will reveal whether multiple cellular mechanism lead to cardiomyopathy. Additionally, in families with dilated cardiomyopathy, we find a prodrome of arrhythmias prior to the onset of cardiac dilatation and congestive heart failure. By developing genetic markers, we will identify those at risk for arrhythmia and most like to benefit from pacemaker and/or implantable defibrillator treatment. 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

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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 •

Project Title: HIGH INTENSITY ULTRASOUND FOR NON-INVASIVE SURGERY Principal Investigator & Institution: Cain, Charles A.; Chair; Bioengineering; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: (Adapted from Applicant's Abstract): Check thisWays to make acoustic cavitation predictable, and thus practical as a mechanism for noninvasive surgery, will be explored in this research. Novel ways to accurately place therapy beams and verifying that surgical lesions have been formed will also be explored. With the use of large aperture phased array systems, and aberration correction techniques, it is possible to form high quality ultrasound beams around and through obstructions like ribs, or the skull, with the attractive possibility of noninvasive brain surgery or cardiac ablation for treatment of life threatening arrhythmias. With the loss of energy in propagating around and through such obstructions, thermal ablation, without heating the complex intervening tissue, is a difficult proposition. However, cavitation, particularly from arrays operating at lower ultrasound frequencies, becomes an exciting tissue ablation mechanism for further study. Of particular interest is the potential use of stabilized microbubbles, often used as ultrasound imaging contrast agents, to act as cavitation nuclei lowering cavitation thresholds and making spatial localization predictable. Cavitation has been intentionally avoided in the past because reproducible localization of ablation zones (or surgical lesions) has been difficult mostly due to large unpredictable spatial variations in cavitation thresholds in living tissues. Preliminary experiments with phased array systems suggest that surgical lesion size and shape become more predictable with prior administration of contrast agents. The applicants proposed to systematically explore the role of contrast agents on cavitation thresholds, surgical lesion size and histology, predictability of shape and spatial localization of necrotic zones, and role of contrast agent concentration. Such systems will allow highly predictable beams to be formed non-invasively, for example, around the ribs onto a moving target, e.g. the heart. Contrast agents will also be explored as means for targeting therapy beams and as a way to verify that surgical lesions have been formed in the desired treatment volume. This application is based on their experimental observation that microbubbles can be "collapsed" by low intensity ultrasound causing "darker" areas in the image, thus allowing sub-lesion forming intensities to be used for beam localization prior to application of surgical intensities. Since cavitationally induced lesions will likely destroy the local vasculature, a surgically necrosed volume will not reperfuse with contrast agent indicating lesion extent. The applicants will explore use of contrast agents as means to guide, enhance, and verify surgical lesion formation with high intensity ultrasound. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IGF-1 & RAS IN DEVELOPMENT /REGRESSION OF HYPERTROPHY Principal Investigator & Institution: Haddad, Georges E.; Assistant Professor; Howard University Washington, Dc 20059 Timing: Fiscal Year 2002; Project Start 01-JUN-1977; Project End 31-JUL-2006 Summary: Cardiac hypertrophy is a pathological state that can lead to heart failure. More than the quarter of US adult American population lives , whereby more than half of these cases are associated with cardiac hypertrophy. A universal electrophysiological finding in ventricular cells of hypertrophied heart is prolonged on the action potential duration (APD), which facilitates the propagation of re-entry arrhythmias and heart failure. The role of different ionic currents responsible for this APD lengthening is still debatable; mainly due to the fact and electrophysiological alterations are dependent on the etiology stage and model of hypertrophy and species. On the other hand, the reninangiotensin system plays an important role in the regulation of cardiovascular tone and hypertrophy through its vasoactive component, angiotensin II (ANG II) mainly via its non-tyrosine kinase G-protein AT1 receptors. However, it is more evident that ANG II mitogenic effects are mediated essentially by the tyrosine kinase IGF-1 receptors through a cross talk with activated AT1 receptors. This proposal is intended to elucidate the modulation by ANG II and IGF-1 of potassium (IK1 and IK-ATP) and calcium (Ica,L) channels during the development and regression phases by (angiotensin-converting enzyme inhibitor (ACE-I) or AT1-antagonist treatment) of cardiac hypertrophy in the adult rat. The patch-clamp technique will be used to study channel activity, while the intracellular imaging technique with Fura-II will be used to monitor changes in intracellular calcium handling in isolated ventricular myocytes. Changes at the membrane level will be correlated to ANG II- and IGF-1-induced changes at 2nd messenger level (PKA, PKC, PI-3 kinase, and downstream tyrosine kinase and MAP kinase) during cardiac hypertrophy and after its regression by ACE-I or AT1-antagonist. The mitogenic effects of ANG II and its cross talk with IGF-1 signal transduction will be evaluated in association with the electrophysiological changes during both phases. Therefore, the effects of ANG II on Ica, L and [Ca2+]i as well as potassium currents (IK1 and IK-ATP) will be compared in the presence of varying IGF-1 concentrations. Thus, this project will identify and evaluate the signal transduction pathways mediating both ANG II and IGF-1 effects and the importance of the cross talk during the development and regression of cardiac hypertrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INTERACTIONS OF MYOTONIC DYSTROPHY PROTEIN KINASE Principal Investigator & Institution: Epstein, Henry F.; Professor; Neurology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-MAY-1996; Project End 31-MAY-2005 Summary: (adapted from applicant's abstract): Myotonic Dystrophy Protein Kinase (DMPK) is encoded by the Myotonic Dystrophy 1 (DM1) locus. Studies on human tissues and cultured cells suggest that haploinsufficiency affecting DMPK expression is a significant consequence affecting DMPK expression is a significant consequence of the dCTG repeat expansion mutations that cause DM1. These mutations may affect other genes as well by several mechanisms. Studies of the DMPK knockout and transgenic mice have reported skeletal and cardiac myopathy, cardiac arrhythmias, and in our preliminary results, altered synaptic plasticity in the central nervous system. Knockout of the neighboring gene, Six5 or DMAHP (DM associated homeodomain protein) leads to cataracts. The CUG expansion in mRNA may sequester proteins required for splicing

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of the RNAs of multiple genes. On the other hand, loss-of-function mutations in other serine-threonine protein kinases can also lead to autosomal dominant traits with variable expressivity and pleiotropy such as in Coffin-Lowry and Peutz-Jeghers Syndromes. These results support continued study of DMPK with respect to understanding the pathogenesis of DM1. DMPK is also representative of a new group of serine-threonine protein kinases active in cell-cycle control, cell differentiation, and cytoskeleton organization. At least two other human protein kinases are also members. Preliminary studies in our laboratory suggest that DMPK may serve as a nexus for cross-talk or convergence between distinct signaling networks. DMPK can interact with two well known proteins that mark distinct signaling pathways: chemically stimulated Raf-1 kinase and the cytoskeleton-linked Rho family GTPase Rac-1. In order to more rigorously establish the biochemical, cellular, and physiological significance of these interactions and further understand the responsible mechanisms, we propose the following Specific Aims: 1) to study the interactions of Rac-1 and Raf-1 kinase with DMPK as purified recombinant proteins as tests for direct functional activation and synergy and their structural basis in the DMPK molecule; 2) to test for cross-talk or convergence of Rac-1 and Raf-1 kinase signaling upon DMPK in cultured myogenic and neurogenic cells in culture and verify its structural basis in the DMPK molecule; and 3) to verify cross-talk in vivo between Rac-1 and Raf-1 kinase upon DMPK in brain and muscle by constructing and studying mutant mouse lines derived from crosses of wildtype controls or DMPK knockouts with dominant negative mutant transgenes expected to alter the activation of DMPK by Rac-1 and/or Raf-1 kinase. Accomplishment of these objectives would suggest that DMPK integrates different signals in its modulation of function in muscle and nerve. These results would clearly provide a foundation for better understanding of the role that DMPK may play in the pathogenesis of DM1 and for a potentially rational design of therapeutics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERCELLULAR COMMUNICATION IN THE HEART Principal Investigator & Institution: Beyer, Eric C.; Professor; Pediatrics; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-JUL-1990; Project End 31-JUL-2004 Summary: Gap junctions contain intercellular channels that are critical for cardiac electrical conduction and cardiovascular cell coupling. Abnormalities of the abundance, distribution, or sequences of subunit gap junction proteins (connexins) within the cardiovascular system have been associated with severe cardiac arrhythmias, developmental abnormalities, or atherosclerosis in humans or in mice. Connexins may have relatively specialized functions within the cardiovascular system, since they have differing patterns of expression, and they form channels with differing conductance and selectivities. Preliminary data suggest that there is a significant prevalence of different polymorphic variants of cardiovascular connexins which may form channels which vary in conductance. The present proposal will address issues that determine the extent of gap junction mediated coupling between cardiovascular cells: (1) regulation of connexin expression (i.e. when and where is a connexin expressed?) and (2) conductance and permeability of connexin channels (i.e. what can go through the channel?). Specifically, we will ask: What determines the limited expression patterns of two specialized cardiovascular connexins (Cx37 and Cx40)? What is the extent of natural variation of cardiovascular connexin sequences; what is the prevalence of different polymorphic variants; are they associated with clinical disease; and, do they exhibit altered channel function? What sequence features determine the molecular permeability of connexin

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channels? We will use a variety of molecular tools to analyze the promoters for Cx37 and Cx40 in vitro and in vivo. We will use PCR amplification of genomic DNA from a population of patients to screen for connexin polymorphisms. We will study the conductance and permeability properties of the wild-type and polymorphic or mutated connexins as expressed in Xenopus oocytes and in transfected cells and as reconstituted in liposomes. This study may have significant implications for the elucidation of cardiovascular disease (including arrhythmias) associated with connexins. 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 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

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Project Title: ION CHANNELS AND THE THERAPY OF VENTRICULAR ARRHYTHMIAS Principal Investigator & Institution: Wit, Andrew L.; Professor; Pharmacology; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-JAN-1984; Project End 31-JUL-2005 Summary: PROPOSED PROGRAM (Adapted from Applicant's Abstract) The objectives of this application, Ion Channels and the Therapy of Ventricular Arrhythmias, are to identify the changes in ion channel function that occur as a consequence of prolonged cardiac ischemia and infraction (ion channel remodeling), some of the molecular mechanisms that cause these changes, how ion channel remodeling causes ventricular arrhythmias and how the remodeled ion channel function can be modified by drugs to provide anti-arrhythmic effects. The Program consists of four highly integrated Projects: 'Remodeling of Gap Junctions in Reentrant Circuits', Dr. Andrew L. Wit, Project Leader, and Molecular the consequences of remodeling of gap junctions and how they lead to slow conduction, block and reentrant excitation. The structural features of gap junctional remodeling will be investigated with immunofluorescent techniques, the electrophysiological alterations with mapping and patch clamp studies of myocyte cell pairs. The molecular mechanisms will be studied in the infarcted canine heart and transgenic murine models. "Ion Channel Function in Myocardial Cells from Infarcts," Dr. Penelope Boyden, Project Leader and "Molecular Targeting of Ca2+ and K+ Channels in Heart," Dr. Robert Kass, Project Leader, focus on sarcolemmal ion channel remodeling. Dr. Boyden's project channels will characterize the electrophysiological changes in Na+, Ca2+ and K+ channels in infarct border zone myocytes, defining the heterogeneity remodeling in different parts of reentrant pathways and how it effects drug action. The last project, Ca2+ and K+ channels expressed in mammalian systems in which subunits can be varied, serve as models to investigate the actions of antiarrhythmic drugs, particularly the molecular basis of action of L-type calcium agonist shown to stop reentrant excitation. The project will also focus on how remodeling of the delayed rectified K+ current alters drug action, particularly the molecular basis of action of an L-type calcium agonist shown to stop reentrant excitation. The project will also focus on how remodeling of the delayed rectified K+ current alters drug action. These Projects are supported by an administrative unit (Core A), an electronics and computer Core, and Core C which provides dissociated remodeled ion channels in causing arrhythmias and provide the necessary remodeled channels and prevent sudden cardiac death. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ISCHEMIA-REPERFUSION INJURY IN CARDIAC SURGERY Principal Investigator & Institution: Holman, William L.; Professor; Surgery; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 05-JUN-2001; Project End 31-MAY-2005 Summary: (Provided by Applicant): The purpose of this study is to develop a new approach to managing severe myocardial ischemic injury that occurs during a cardiac operation. This will be achieved by focusing on one aspect of myocardial ischemiareperfusion (I-R) injury, namely myocyte sodium (Na) influx and consequent loss of ionic homeostasis. Na influx is an early event that putatively leads to myocardial calcium (Ca) influx, contractile dysfunction, mitochondrial injury, and cell death. This lab has found three methods (I-ischemic preconditioning, 2-Na/H exchange inhibition, and 3-reperfusion with a warm cardioplegia solution [controlled reperfusion]) that each

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eliminate myocyte Na content gain due to moderate l-R injury (cardioplegic arrest) in a porcine model. An intriguing pilot study in isolated rat hearts showed that two of these methods (preconditioning and Na/H exchange inhibition) when used simultaneously have additive beneficial effects on post-ischemic contractile function. The proposed study will measure reperfusion arrhythmias, contractile function mitochondrial function, and myocyte ion content in order to define the effects of severe I-R injury in rat and pig hearts. The goal of this study is to determine if three methods, with putatively independent but inter-related mechanisms of action, will work additively to protect the heart from severe I-R injury as defined by biochemical, functional, histologic, and electrophysiologic variables. The specific aims of the proposed study are as follows: Aim 1: Define the mechanisms of three methods for myocardial protection (Na/H exchange inhibition, mitochondrial K+ATP channel opening [pharmacologic preconditioning], and controlled reperfusion) in a clinically relevant, intact porcine heart model of severe regional I-R injury. These data will serve as baseline data for Aim 4. Aim 2: Measure the effects of the three methods for myocardial protection on post-ischemic systolic and diastolic function, coronary vascular resistance, myocyte and mitochondrial ion content, and mitochondrial function in an isolated blood perfused rat heart model of severe global ischemia. Aim 3: Test for the postulated beneficial interactions between pharmacologic preconditioning (diazoxide), NalH exchange inhibition (cariporide), and controlled reperfusion in a blood perfused rat heart model of I-R injury. Aim 4: Determine if the best combination of methods, as defined in aim #3, provides better protection than each method used individually in pig hearts. Better protection will be defined by irnproved myocyte and mitochondrial ion homeostasis, irnproved regional mechanical function, fewer reperfusion arrhythmias, superior protection of mitochondrial function, and smaller infarcts in hearts subjected to severe regional I-R injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ITO IN DOGS WITH INHERITED VENTRICULAR ARRHYTHMIAS Principal Investigator & Institution: Kornreich, Bruce G.; Molecular Medicine; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853 Timing: Fiscal Year 2002; Project Start 15-JUN-2001; Project End 31-MAY-2006 Summary: Abnormalities of ventricular repolarization have been identified in a number of cardiac disease states and may predispose to malignant or fatal ventricular arrhythmias. The transient outward potassium current, I- to, is an important determinant of ventricular repolarization. The potassium channel isoform responsible for I-to varies between species. Kv1.4, Kv1.5, Kv4.2, and Kv4.3 have been identified as contributors to ventricular repolarization in various species, with Kv1.4, Kv4.2, and Kv4.3 representing the most likely contributors to I-to in canine cardiac myocytes. Decreased I-to density has been found in several pathologic states including myocardial hypertrophy, terminal heart failure, and acute Trypanosoma cruzi infection, and prolonged ventricular repolarization may increase the morbidity and mortality of these conditions. Moise and collaborators have previously reported a line of German Shepherd dogs with inherited ventricular arrhythmias and sudden death. Affected dogs have a decreased sympathetic innervation of the left ventricle and decreased left ventricular I-to density. Norepinephrine application rescues I-to in myocytes isolated from affected regions in these dogs, suggesting that the decreased I-to may result from a loss of the trophic influence of the sympathetic nervous system during development. Nerve growth factor and enkephalins have been shown to promote growth and survival of central and peripheral neurons. Using whole cell patch clamp recording ribonuclease

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protection assays, and Western blot techniques, we will address the following questions: (1) Is decreased NGF and ppENK expression responsible for the abnormal peripheral sympathetic innervation in the hearts of affected dogs? (2) Which potassium channels (Kv1.4, Kv1.5, Kv4.2, and Kv4.3) are responsible for I-to in affected dogs? Is the decreased expression of one or a combination of these channel isoforms responsible for deceased I-to in affected dogs? Is the increased expression of one or a combination of these isoforms responsible for NE mediated restoration of I-to in affected dogs?, and (3) Is the restoration of I-to by NE in the hearts of affected dogs mediated by alpha or beta adrenergic receptors and their associated second messenger cascades? The scientific training obtained while performing this research in a vital and supportive intellectual environment will provide valuable theoretical and technical experience for the applicant to expand upon his clinical and basic scientific experience to achieve his goal of a link between the basic scientific study of membrane bound ion channels/receptors and clinical cardiology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LASER TACHYCARDIA

CATHER

FOR

ABLATION

OF

VENTRICULAR

Principal Investigator & Institution: Gowda, Ashok; President; Biotex, Inc. 8018 El Rio St Houston, Tx 770544104 Timing: Fiscal Year 2002; Project Start 28-SEP-1999; Project End 31-JUL-2004 Summary: (provided by applicant): Ventricular Tachycardia (VT) is a life-threatening condition characterized by an abnormally high rate of ventricular contraction. During VT, the ventricles lack sufficient time to fill with blood prior to each contraction often resulting in dizziness, loss of consciousness and sudden cardiac arrest. Catheter ablation has been shown to be an effective means for curing many arrhythmias, but current approaches are not able to coagulate tissue in the midmyocardium or subepicardial regions where foci responsible for VT often originate. We have developed a cooled-tip laser catheter (CTLC) capable of creating large lesions that extend into these regions with little to no thermal damage to the endocardium. In our phase I study we designed, built, and tested prototypes of the CTLC system. The current system is comprised of an 8F deflectable catheter, which houses a fiber optic and a pathway for circulation of saline. We incorporated a low cost pump system and a low-power diode laser to complete the system. Acute and chronic animal studies were performed to test the prototype system and the results were indeed dramatic. Using our CTLC system, we successfully produced large (1 cm in diameter) lesions that began on average 1 mm below the irradiated surface. These lesions were free of char or carbonization and well circumscribed by a distinct border separating the lesion form normal tissue. Additional advantages of our approach include the ability to monitor real-time electrophysiological activity during delivery of laser energy. In Phase II we plan to refine the current CTLC by including functional mapping electrodes and improving maneuverability. Animal studies are designed to characterize in a thorough manner the dose response for our system, compare it against current state of the art ablation technologies, and acquire data necessary for submission of an investigational device exemption from the FDA for clinical trials. PROPOSED COMMERCIAL APPLICATION: This research is specifically targeted towards the development of an improved laser-based catheter for treatment of VT. Cardiac arrhythmias including ventricular tachycardia (VT) and ventricular fibrillation (VF) are responsible for 400,000 cases of sudden death in the U.S. each year. Unlike other therapies, our catheter has potential for providing a curative means for

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patients who suffer from VT, and therefore could become the treatment of choice in such patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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 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

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Project Title: MECHANISM ALDOSTERONE

OF

MECHANORECEPTOR

INHIBITION

BY

Principal Investigator & Institution: Drummond, Heather A.; Physiology and Biophysics; University of Mississippi Medical Center 2500 N State St Jackson, Ms 39216

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Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2006 Summary: (provided by applicant): The long term objective of my lab is to understand the molecular basis of mechanotransduction. This includes the 1) identification of components of mechanosensitive ion channel complexes in sensory neurons and muscle cells, 2) regulation of mechanosensitive channel expression by physical and hormonal factors and 3) involvement in cardiovascular pathophysiology (autonomic dysfunction, hypertension). The current proposal will address a highly novel area of research: aldosterone regulation of mechanosensitive ion channel expression and function. Hypertension and chronic heart failure are characterized by elevations in circulating aldosterone. Aldosterone is known to inhibit baroreceptor function, which may contribute to cardiac arrhythmias frequently associated with these diseases. The molecular mechanism of aldosterone suppression of baroreflex control of the autonomic nervous system is unclear. The hypothesis underlying this proposal is that aldosterone activation of the MAPK signaling pathway, decreases the expression of mechanosensitive channels in baroreceptor neurons by inhibiting transcription and augmenting degradation of ENaC proteins, thus causing baroreceptor dysfunction. This is a novel hypothesis. The goals of this proposal are to determine if 1) aldosterone inhibits DEG/ENaC transcript expression and mechanically gated calcium transients, 2) activation of the MAPK signaling cascade inhibits ENaC expression and mechanically gated calcium transients, and 3) ENaC proteins are required for mechanosensory function in cultured sensory neurons. We will use real time RT-PCR and immunofluorescence to determine the role of aldosterone and MAPK pathway on ENaC expression in cultured sensory neurons. We will use 2 assays to assess mechanosensory function in cultured sensory neurons. The importance of ENaC proteins in mechanotransduction will be determined using interference RNA and overexpression of dominant-negative isoforms. The results from this proposal may help define the molecular mechanism of baroreceptor inhibition by aldosterone and provide a better understanding of the mechanism of autonomic dysfunction in hypertension and chronic heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS AND THERAPY OF ISCHEMIC SUDDEN CARDIAC ARREST Principal Investigator & Institution: Ideker, Raymond E.; Jeanne V. Marks Professor; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: Increasing survival from sudden cardiac arrest caused by ischemia and infarction, an extremely health problem, requires better understanding of the mechanisms both of the arrhythmias causing it and of the problems encountered during resuscitation attempts. This program project application proposes to use electrical and optical and optical mapping techniques in animals to obtain this information. Project 1 (Chronic monitoring of ischemic models of sudden death) will telemeter from chronically instrumented animals and use of electrical mapping to understand how, when, and why sudden death occurs with ischemia and infarction. Project 2 (Mechanism of VF maintenance in ischemia and infarction) will use optical and electrical mapping to quantify the mechanisms maintaining VF. Project 3 (Purkinje-myocardial reentry in ischemia and infraction) will use electrical mapping to investigate the role of Purkinje fibers in initiating arrhythmias. Project 4 (Defibrillation mechanisms during ischemic arrhythmias) will use electrical mapping to determine the mechanisms for the elevated defibrillation and high incidence of refibrillation in ischemia during

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resuscitation. Project 5 (Electrical therapy for pulseless electrical activity) will use electrical and optimal mapping to study how new electrical therapies eradicate pulseless electrical activity during resuscitation. Core A (Administration) will administrate and provide biostatistical and manuscript preparation support for the project. Core B (Instrumentation and Software) will provide and software support. Core C (Animal models and pathology) will insure optimal animal care and pathological examination. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF ACTIVATION OF CARDIAC NOCICEPTORS Principal Investigator & Institution: Pan, Hui-Lin; Professor; Anesthesia; Pennsylvania State Univ Hershey Med Ctr 500 University Drive Hershey, Pa 170332390 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2006 Summary: (provided by the applicant): Patients with myocardial ischemia typically experience angina pectoris. Activation of cardiac sympathetic afferents during ischemia is responsible for conveying cardiac nociception and initiating cardiovascular reflexes, which lead to hemodynamic alterations and arrhythmias. However, the mechanisms of activation of cardiac nociceptors are not fully understood. Endothelin-l (ET-1) and cyclooxygenase-2 products are produced early during myocardial ischemia. but their contributions to activation of cardiac nociceptors during ischemia remain uncertain. Therefore, we propose to test the following novel hypotheses: 1. Myocardial interstitial prostaglandins are increased during ischemia due to stimulation of the cyclooxygenase2 pathway, which plays a significant role in activation of cardiac sympathetic afferents during ischemia. 2. Production of ET-1 in myocardial interstitium is increased during ischemia; an increased cardiac interstitial ET- 1 level elicits generation of prostaglandins through cyclooxygenase-2. 3. ET- 1 selectively stimulates ischemically sensitive cardiac afferents through activation of ETA, but not ETB, receptors; the stimulating effect of ET-l on ischemically sensitive cardiac afferents is mediated by prostaglandins due to activation of cyclooxygenase-2. 4. Endogenously produced ET- 1 during myocardial ischemia contributes to ischemic stimulation of cardiac sympathetic afferents. The techniques of cardiac microdialysis and single-unit recording of cardiac sympathetic afferents will be used to explore the mechanisms of generation of prostaglandins and ET-1 during myocardial ischemia, and to study the role of ET-1 and cyclooxygenase-2 in ischemic stimulation of cardiac sympathetic afferents. These studies are important prerequisites for the understanding of the pathophysiological role of ET-1 and prostaglandins in activation of cardiac nociceptors and elaborating the perception of chest pain in patients with myocardial ischemia. Such information could also suggest alternate interventions designed to treat intractable angina pectoris and to limit potentially detrimental cardiovascular reflexes in patients with coronary artery disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF ARRHYTHMIA SUPPRESSION BY EXERCISE TRAINI* Principal Investigator & Institution: Collins, Heidi L.; Psychiatry & Behav Neuroscis; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (Applicant's abstract) I have a long-standing interest and commitment to developing into an independent biomedical investigator. My research goals are to understand cardiac complications (ventricular arrhythmias and sudden cardiac death) associated with hypertension and to investigate interventions designed to reduce the

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untoward effects of these complications. In this regard, I have been examining the effects of endurance exercise training on the autonomic nervous system in hypertensive rats. From these experiences I have gained valuable skills and training in whole animal integrative physiology. However, I realize that in order to answer many of my scientific questions as well as achieve my goals and launch a career as an independent investigator, I must extend my studies to the cellular and molecular levels. Therefore, I asked Dr. James Marsh to sponsor my proposal. Dr. Marsh has contributed significantly to the field of calcium transport in cardiac myocytes. He is internationally recognized for his work examining factors that influence calcium regulatory proteins. Dr. Marsh has agreed to enhance the development of my research career b providing training opportunities in cellular and molecular cardiology. This is a natural "fit" that can be coupled with my previous training to enhance my abilities to investigate the effects of exercise training on the autonomic nervous system induced changes in molecular cardiology. It is important to incorporate my skills in whole animal integrative physiology with molecular approaches since the formidable task of linking genes to function has now begun. The scientific community is in the midst of a revolution challenging scientists to understand and utilize experimental approaches that link molecular biology and physiology. Therefore, Dr. Marsh and I developed a plan to investigate the influence of exercise training on the ventricular arrhythmia threshold of hypertensive rats and to explore the underlying molecular changes. The proposed studies represent a bold new endeavor linking molecular pathways to functional pathways. This experience will provide for me the research skill to develop into an independent investigator and the scientific foundation to obtain external funds at the national level. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF CARDIOTOXICITY OF ANTIPSYCHOTIC DRUGS Principal Investigator & Institution: Flockhart, David; Chief, Division of Clinical Pharmacology; Medicine; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2001; Project Start 01-AUG-1998; Project End 31-JUL-2004 Summary: (Adapted from the Investigator's Abstract) This proposal involves a series of coordinated, translational studies designed to establish the mechanisms by which important antipsychotic drugs might bring about cardiac arrhythmias and sudden death. While a great deal of research over the past thirty years has resulted in the recent appearance of antipsychotic drugs that have reduced extra-pyramidal side-effects, a number of these novel agents have recently been shown to possess the ability to prolong the electrocardiac QT interval, and cause potentially lethal torsades-de-pointes arrhythmias that are reminiscent of older agents. Using antipsychotic drugs chosen for their wide clinical use, and potential cardiotoxicity the investigator propose to study potential pharmacodynamic and pharmacokinetic mechanisms that might expose vulnerable patients to the risk of these arrhythmias. The present study will have the following specific aims: 1) To test in vitro whether antipsychotic their metabolites or combinations of drug and metabolite modulate cardiac electrophysiology in isolated perfused heart using the characteristics of the action potential (AP), QT interval and early after depolarization (EAD) occurrence. To investigate whether any electrophysiologic changes noted are the result of specific cardiac Na, Ca, or K, channel activity in isolated ventricular cardiomyocytes and Purkinje cells, using currient patch clamp techniques. Since the investigators have preliminary data that indicate that

42

Arrhythmias

haloperidol can slow cardiac repolarization in vitro, the focus of our studies in the first year will be on this widely-used drug and its metabolites. In subsequent years, the investigators will evaluate thioridazine, fluphenazine and loxapine. 2) To probe the cytochrome P450 isoforms responsible for metabolism of antipsychotic drugs or metabolites that the investigators find to be cardiotoxic. This information will allow assessment of pharmacogenetic and pharmacokinetic influences that might increase the concentration of these agents, and the risk of arrhythmia. The investigators will document the cytochrome P450 isoforms responsible for the metabolism of specific drugs using isolated human hepatic, intestinal and cardiac microsomal preparations, isoform-specific inhibitors and antibodies, and recombinant cytochrome P450 isoforms. 3) To determine if antipsychotic agents that are found to be potentially cardiotoxic in vitro have clinical electrocardiac effects at the doses routinely used in healthy volunteers. The investigator will document the relationship between the serum concentrations of these drugs and their electrocardiac pharmacodynamics. The results of these studies should allow physicians and researchers to more confidently predict patients at risk for lethal torsades-de-pointes arrhythmias while taking neuroleptic drugs, and to gain mechanistic insights that will allow the design of safer drugs in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS ARRHYTHMIAS

OF DEFIBRILLATION

& SHOCK-INDUCED

Principal Investigator & Institution: Fast, Vladimir G.; Assistant Professor; Biomedical Engineering; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 10-AUG-2001; Project End 31-JUL-2006 Summary: Defibrillation is routinely used in patients to interrupt ventricular fibrillation, yet there is a need to improve its efficacy and reduce side effects. To achieve these goals, a better understanding of the interaction between defibrillation shocks and cardiac tissue is needed. This application will address two fundamental questions: (1) how electrical field produces changes of transmembrane potential (deltaVm), which are necessary for defibrillation; (2) how strong defibrillation shocks induce arrhythmias, that can cause defibrillation failure. To achieve a deeper mechanistic understanding of these events, we will monitor spatio-temporal dynamics of Vm and Ca 2+ changes during shocks using novel techniques for simultaneous optical imaging of Vm and Cai2+ and ratiometric imaging of Vm. Studies will be performed in two experimental models that offer unique advantages for studying defibrillation mechanisms: patterned growth cell cultures and coronary perfused wedges of pig ventricles. Using 2dimensional cell cultures will allow for precise control of tissue structure, electrical field and cell environment. Using coronary perfused wedges of ventricular myocardium will allow to obtain information on intramural shock-induced changes of Vm. The project will have three Specific Aims. 1) To determine the mechanisms of nonlinear shockinduced deltaVm. Recent optical mapping studies showed that defibrillation shocks induce complex nonlinear deltaVm. The roles of ionic currents and membrane electroporation in nonlinear deltaVm responses will be determined in cell cultures using simultaneous Vm/Cai2+ mapping and ionic channel blockers. 2) To determine the mechanism of arrhythmias induced by strong shocks. Using patterned growth cell cultures we will determine the type of deltaVm causing post-shock arrhythmias, the roles of Cai2+ overload and Vm depolarization, modulation of arrhythmia initiation by tissue structure, hyperkalemia and shock waveform. 3) To determine the distribution and magnitude of intramural deltaVm. Presently, no data are available on deltaVm in

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the intramural layers of myocardium during shocks. We will use optical mapping of Vm to measure the distributions of deltaVm in intramural layers of coronary-perfused wedges of pig ventricles and the effects of deltaVm on the duration of intramural action potentials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF REPOLARIZATION-INDUCED ARRHYTHMIAS 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-AUG-1999; Project End 31-JUL-2004 Summary: Cardiac arrhythmias remain a major cause of morbidity and mortality. Some arrhythmias result from rare congenital conditions, while most are caused by damage to the heart and its electrical system from ischemia, infarction, cardiac surgery, and assorted non-cardiac diseases. All of these conditions show enhanced dispersion of repolarization (DR) and of refractory periods (DRP) and this may be a unifying mechanism, central to the initiation of arrhythmias and the ensuing pathophysiological process. The mechanisms by which prolonged action potential duration (APD) contributes to ventricular tachycardia (VT), fibrillation (VF), and sudden death are not well understood. New insights of arrhythmogenic mechanisms have emerged from patients with the rare congenital long QT syndrome (LQTS) that is caused by mutations that prolong the cardiac APD and produce polymorphic (VT). This proposal seeks to identify how spatial heterogeneity of channel expression in myocardial tissue generates spatial and temporal heterogeneity in repolarization and refractoriness. It will use a combination transgenic mouse models, measurements of spatio-temporal changes in repolarization and computer modeling to elucidate basic mechanisms by which reentrant arrhythmias are initiated, sustained and self-terminated. To clarify the role of K+ channels and K+ currents in health and disease, we have engineered mice with specific K+ channel and K+ current defects. i) A dominant negative transgenic mouse that expresses an N- terminal fragment of Kv1.1 and has a prolonged QT interval, with spontaneous and inducible VT. ii) A dominant negative transgenic that expresses a mutant Kv4.2 alpha subunit and has a prolonged QT and brief inducible VT. iii) A mouse with a targeted mutation of Merg1, the mouse homolog of HERG has a normal QT but is highly susceptible to PVT. Voltage-sensitive dyes and imaging techniques will be used on perfused intact mouse hearts to map spatio-temporal characteristics of Aps, DR and AP restitution kinetics as well as vulnerability to arrhythmia by programmed stimulation. Enhanced DR at the level of the intact heart will be correlated with cellular variations of channel expression and ionic currents (immuno-histochemistry and single cell voltage clamp) to test the underlying mechanism for DR in these mouse models. The specific aims will be to test the following hypotheses: 1) Enhanced DR and/or DRP are required for uni-directional propagation of extra-Aps and initiation of VT. 2) Spatial heterogeneities of cardiac ionic currents are the basis of altered DR. Cells isolated from various regions will be used to correlate repolarization heterogeneities in intact hearts to cellular properties using voltage-clamp. 3) Spatio-temporal modifications of [Ca2+]i transient underlie electrical instabilities, enhanced DR and promote VT. 4) Develop mathematical models of repolarization to predict the measured repolarization abnormalities from genetic alterations in ionic channels. These studies will provide new insights on the molecular basis of spatio-temporal heterogeneities of repolarization and refractoriness and their role in maintaining a normal cardiac rhythm or in producing conditions that provoke arrhythmias.

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Arrhythmias

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

Project Title: MODULATORS OF HERG FUNCTION AND PHARMACOLOGY Principal Investigator & Institution: Balser, Jeffrey R.; Professor; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The Human Ether-a-go-go Related Gene (HERG, KCNH2) encodes the major, pore-forming subunit of the cardiac K+ current IKr. Suppression of IKr, through inherited mutations or pharmacologic blockade, can provoke sudden death from a ventricular arrhythmia (Torsades de Pointes). Like IKr, HERG channels are sensitive to a wide array of therapeutic agents but in practice, the development of cardiac arrhythmias upon exposure to HERG-blocking compounds is unpredictable, suggesting modulating factors critically influence HERG pharmacology. The goal of this proposal is to identify molecular mechanisms that mediate drug interactions with the IKr complex. While HERG block by most pharmacologic agents develops as the membrane is depolarized and channels open, block still develops slowly (over minutes) suggesting that access of drug to its receptor site in the inner pore vestibule (S6) is limited. While the mechanisms that underlie drug interactions with HERG are incompletely understood, our recent studies have identified the HERG Cterminus and a HERGinteracting protein (KCR1) as inhibitors of block. We will test the hypothesis that HERG blockade by therapeutic compounds is modulated by functional interactions involving HERG subdomains and other proteins that compose the IKr complex. Using electrophysiologic and biochemical approaches, Cterminal deletion mutants, and C-terminal peptides, we will determine the mechanism whereby the HERG C-terminus limits drug access to the pore. Using the same approaches, we will elucidate the molecular mechanism whereby human KCR1 inhibits drug block. Finally, to expand our understanding of the IKr complex and the molecular substrates of proarrhythmic risk, we will utilize the enetically tractable organism C. elegans as a model system to identify new HERG-interacting protein candidates, taking advantage of the association among the C. elegans homologue of HERG (UNC-103), methanesulfonanilde drug action, and the rhythmic pattern of pharyngeal pumping in the worm. The improved understanding of drug-channel interactions arising from this research should enable improvements in predicting risk for drug-induced arrhythmias, and the development of improved antiarrhythmic therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR BASIS OF SUDDEN CARDIAC DEATH Principal Investigator & Institution: Marks, Andrew R.; Professor of Molecular Cardiology; Pharmacology; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: This proposal for a Program Project Grant (PPG) in Sudden Cardiac Death is designed to enhance our understanding of SCD by combining genetics with molecular and cellular biology and biophysics. The overall goal of the proposed research is to identify the cellular and molecular triggers that initiate fatal cardiac arrhythmias. A fundamental premise that new understandings regarding the molecular basis of normal and pathological cardiomyocyte electrical excitability will be the foundations upon which genotype-phenotype correlates combined with non-invasive testing will the foundations upon which genotype-phenotype correlations combined with non-invasive

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45

testing will be used to risk stratify patients. Major goals: 1) to elucidate the molecular basis of the triggers that initiate fatal cardiac arrhythmias that cause SCD; and 2) to establish a genotype-phenotype correlations that can be used to identify individuals at high risk for Sudden Cardiac Death who may be candidates for more aggressive therapy. The rationale for this approach is that understanding the molecular basis of the triggers for Sudden Cardiac Death will provide a mechanistic basis for risk stratification and may lead to novel therapeutic approaches. Four projects and two cores (administrative, mouse models) are proposed. Project 1 will identify variant betaadrenergic receptors (betaAR) and ryanodine receptors (RyR) associated with increase risk of Sudden Cardiac Death. Project 2 will examine the role of adrenergic modulation of RyR/intracellular calcium release channels in initiating triggers of fetal calciumdependent cardiac arrhythmias. Project 3 will use identified human mutations of cardiac ion channels and/or signaling molecules linked to the Long Q-T Syndrome and Brugada Syndrome as Paradigms to test the hypothesis that changes in ion channel activity may alter the configuration of the cellular action potential which contributes to changes in calcium homeostasis that, in turn, triggers arrhythmic activity. Project 4 will investigate the role of perturbations of local and global calcium signaling in initiating triggers of fatal cardiac arrhythmias. The hypothesis to be tested is that perturbations of ion channel and adrenergic mediated signaling alter calcium homeostasis in cardiomyocytes, generating triggers for fatal cardiac mediated signaling alter calcium homeostasis in cardiomyocytes, generating triggers for fatal cardiac arrhythmias. A major focus of all four projects is identification of triggers that initiate arrhythmic events. Thus, this work has the potential to determine a mechanistic basis for Sudden Cardiac Death. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR PHARMACOLOGY OF AN INHERITED HEART DISEASE Principal Investigator & Institution: Kass, Robert S.; Professor of Pharmaclogy and Chairman; Pharmacology; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2006 Summary: The overall goal of the research proposed in this application is to understand the molecular basis of cardiac arrhythmias caused, at least in part, by inherited mutations of the SCN5A gene, and to determine novel gene-targeted therapeutic strategies to treat them. The central hypothesis is that one step in the genesis of these arrhythmias is the perturbation of membrane electrical activity caused by alteration in the biophysical properties of the SCN5A gene product, the principal cardiac Na+ channel alpha subunit, by diseased-linked mutations, but that similar functional perturbations may be linked to distinct clinical disorders. Altered ion channel properties may also confer unique pharmacological properties upon the encoded ion channels making them unique targets for therapeutic intervention but, perhaps less effective in unmasking distinct inherited syndromes. We will focus on identified SCN5A mutations linked to the long QT syndrome (LQT-3) and Brudaga's syndrome (BrS) as paradigms to test this hypothesis. Structural analysis of the alpha subunit and site directed mutagenesis will complement the analysis of inherited mutations to provide a structural framework to interpret alteration in channel function. There are two aims of this project. Aim 1 is to test the hypothesis that there can be functional overlap caused by inherited mutations of the SCN5A gene linked either to BrS or LQT-3. Aim 2 is to test the hypothesis that there can be overlap in inherited BrS and LQT-3 SCN5A mutation-

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specific pharmacology due to overlap in mutation induced gating changes of expressed channels. 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 ion channel gating and cardiac action potentials that incorporate our patch clamp data. We hypothesize that information gained from these cellular and molecular experiments can be translated directly to improved therapeutic intervention in humans based on specific properties of mutant gene products, and also shed light on the possible interrelationship of these two inherited disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR PHARMACOLOGY OF CARDIAC ION CHANNELS Principal Investigator & Institution: Li, Ronald A.; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-AUG-1994; Project End 31-JUL-2004 Summary: The pore of the sodium channel binds a variety of clinically-important drugs (local anesthetics, antileptics and antiarrhythmics). The overall goal of this proposal is to define, at a detailed molecular and biophysical level, the determinants of drug binding to voltage-dependent Na channels. Substantial progress has been made during the initial funding period using a combination of mutagenesis, electrophysiology and quantitative modelling. We have discovered major differences in lidocaine sensitivity between cardiac and skeletal muscle sodium channels, defined interactions between local anesthetic block and slow inactivation gating processes, and mapped the crucial determinants for high-affinity tetrodotoxin block in the outer pore. We now propose to continue functional characterization of normal and mutant channels while obtaining hard structural information on the Na channel pore and related drug binding sites. The central goals of the application are the following: 1) to elucidate the origin of the differences in lidocaine sensitivity between cardiac and skeletal muscle Na channels; 2) to define determinants of selectivity, conductance and drug block which lie outside the conventional selectivity filter region; 3) to determine the impact of pore flexibility on gating and drug block; 4) to test a model of the secondary structure in which a pore helix precedes the selectivity filter in each domain; and 5) to solubilize and purify the Na channel alpha subunit and/or a truncated protein containing the critical determinants of Na channel pore function and drug/toxin block. Given the central importance of sodium channels in normal physiology and in diseases of excitability (arrhythmias, epilepsy and myotonic disorders of muscle), this work promises not only to be of intrinsic biological interest but also of practical value in pharmacology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DYSPLASIA

MULTIDISCIPLINARY

STUDY

OF

RIGHT

VENTRICULAR

Principal Investigator & Institution: Marcus, Frank I.; None; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 27-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant): This application is part of a clustered proposal consisting of three components: an application by Dr. Frank Marcus describing the overall scientific program, an application by Dr. Jeffrey Towbin describing the genetic analyses for the study, and a proposal by Dr. Wojciech Zareba describing the organization and operation of the Coordination and Data Center (CDC) for the study.

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The proposed five-year research plan is a multi-disciplinary, multicenter, collaborative study to investigate the cardiac, clinical, and genetic aspects of arrhythmogenic right ventricular dysplasia (ARVD), a progressive disorder that predominantly affects the right side of the heart and causes ventricular arrhythmias. In many patients the disease is familial. ARVD may account for as many as 5% of unexpected sudden deaths under the age of 65 and 3-4% of sudden death during sports. There can be considerable difficulty in diagnosing this disease with certainty, and there is incomplete information on the pathogenesis, natural history, and treatment of the patients and affected members. The overall objective of the Multidisciplinary Study of Right Ventricular Dysplasia is to characterize the genetic and clinical features of arrhythmogenic right ventricular dysplasia (ARVD). The specific aims are: 1) to establish a North American ARVD Registry enrolling ARVD patients and their family members, based on standardized diagnostic test criteria, in a prospective longitudinal follow-up study; 2) to determine the genetic background of ARVD by identifying chromosomal loci and specific gene mutations associated with this disorder; 3) to determine the influence of the genotype on the clinical course of patients with ARVD and explore phenotypegenotype associations that will contribute to improved diagnosis, risk stratification, and therapy; and 4) to develop quantitative methods to assess right ventricular function in order to enhance the specificity and sensitivity of ARVD diagnosis. This integrated research grant proposal offers a substantial prospect of expanding the fund of clinical knowledge regarding ARVD and of localizing the gene(s) responsible for this disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SYSTEMS

MULTISCALE

ANALYSIS

OF

COMPLEX

PHYSIOLOGICAL

Principal Investigator & Institution: Iyengar, Srinivas R.; Professor; Pharmacology/Biological Chem; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): We propose the planning of a pre-NPEBC Center for Multiscale Analysis of Complex Physiological Systems, with the overall goal of understanding specific systems, and mathematical, computational and biological issues involved in scale-up. The knowledge explosion in biomedicine, matched by revolutionary advances in computational technology and mathematical algorithms enable the attack on problems of a complexity that was heretofore beyond reach. A new and genuinely multidisciplinary approach, anchored in research on specific biomedical problems, will be required to realize the potential of these developments. The Center will be planned to develop such an approach. The Development Projects focus on neuronal functions at the molecular and cellular levels ( Modeling interactions and networks in the cell), as well as at the multicellular and tissue level ( Modeling the function of neural circuits), and on analysis at the integrated organ level ( Modeling physiology and pathophysiology in the cardiovascular system). The biological and computational issues involve scale-up to progressively more complex levels in order to understand physiological processes and diseases. One example is development of adaptation and tolerance in higher order neuronal functions underlying the addictive state, with insights expected about 1)- how such tolerance can be attributed to specific cellular components and molecular processes in complex cell and multi-cell systems responsible for integrated functions, and 2)- how pharmacological challenges, e.g., from medication or drugs of abuse, modulate integrated functions. Multi-scale analysis should reveal how external stimuli can reset systems behavior so that repeated external

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stimulus (e.g. drug use) is needed to maintain homeostasis of systems behaviors, including in the addicted state. New methods for quantitative analysis and modeling of the heart will be developed to understand pathophysiology (sudden cardiac death and malignant ventricular arrhythmias) in terms of molecular components and processes. Insights from simulations of stimuli in the heart from medication and drug abuse could parallel those done for neuronal systems, enabling cross-reference and validation between neuronal and cardiac systems. New computational tools, including for imaging will be fostered in the Center's Tools Core that will serve as well in dissemination and curation. Educational programs for faculty and students (including MS and PhD degrees) will be developed in an Education Core to sustain and disseminate the multidisciplinary science of the Center. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NERVE AND REPOLARIZATION IMAGING IN SUDDEN CARDIAC DEATH Principal Investigator & Institution: Dae, Michael W.; Professor; Radiology; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2004 Summary: We recently demonstrated heterogeneous myocardial sympathetic innervation in a colony of German shepherd dogs with ventricular arrhythmia and sudden cardiac death. The proposed research will apply scintigraphic methods to study the development of sympathetic nerves in these arrhythmic animals, and determine the effects of altered nerve development on adrenergic receptors, gap junctions, and repolarization responses. In Aim 1, we will study the postnatal development of myocardial innervation and perfusion and compare the results to the postnatal development of ventricular arrhythmias. The hypothesis to be tested is that postnatal maturation of sympathetic innervation is delayed in this colony of animals, and this delayed maturation is a primary determinant of ventricular arrhythmia. In Aim 2, we will study the effects of modulation of sympathetic nerve growth on the expression of ventricular arrhythmias. We will test the hypothesis that modulation of sympathetic nerve growth, or induced homogeneity of innervation will decrease the frequency and severity of arrhythmias. In Aim 3, we will study effects of regional denervation on the distribution of sympathetic nerve histology, myocyte gap junctions, and alpha and beta adrenergic receptor density and affinity. We will test the hypothsosis that heterogeneous spatial gradients of sympathic innervation result in associated gradients in adrenergic receptors and gap junctions. Aim 4 will study the developmental effects of sympathetic innervation on local myocardial repolarization. The hypothesis to be tested is that heterogeneous innervation results in local abnormalities of myocardial repolarization during the basal state and during sympathetic stimulation. The unique opportunity to investigate the development of cardiac sympathetic innervation and compare functional abnormalities of the sympathetic nerves to myocardial perfusion, signal transduction, intercellular communication and cardiacarrhythmia. These studies may provide a more comprehensive understanding of the interaction of the sympathetic nervous system and arrhythmogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NERVOUS SYSTEM CHANNELOPATHIES: PATHOGENESIS & TREATMENT Principal Investigator & Institution: Griggs, Robert C.; Professor and Chair; Neurology; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627

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Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): This application responds to RFA RR-03-008, Rare Diseases Clinical Research Network and proposes the investigation of 3 rare neurological channelopathies: periodic paralysis, non-dystrophic myotonic disorders and episodic ataxia. The research plan will exploit the strengths of 7 collaborating centers to link molecular scientists studying these disorders with clinical investigators with established expertise in the development of new treatments for neurological disease. It will extend a prototype NIH training program in experimental therapeutics to train a cadre of patient-oriented-researchers committed to rare disorders. Study investigators have strong links with the patient advocacy organizations focused on these rare disorders: the Periodic Paralysis Association, the National Ataxia Foundation and the Muscular Dystrophy Association. A particular strength of the collaborating institutions is an established nationwide infrastructure, including GCRCs and a biostatistician, for the implementation of multicenter clinical trials that will facilitate investigation of the efficacy of putative new treatments for rare diseases. Currentlysupported studies of the pathophysiology of the 3 specific target diseases will provide resources for molecular characterization of subjects and make it possible to: (1) begin the characterization of the phenotype/natural history of each; (2) devise outcome measures for treatment trials; (3) assess quality of life -- all in preparation for pilot clinical trials of novel treatments. The focus of investigation is on: (1) Andersen's syndrome, a periodic paralysis with associated life-threatening cardiac arrhythmias for which no treatment has been identified; (2) the nondystrophic myotonias caused by sodium and chloride channel mutations for which there is no established treatment and there have been no well-designed clinical trials; (3) the episodic ataxias EA1 and EA2 for which treatment is not yet defined. Both cellular model systems and animal models, funded separately, are (or soon will be) available for each of these disorders and can provide pre- clinical data necessary for proposed phase 1 and 2 trials of novel treatments. These 3 disorders are prototypes for the development of treatment strategies for over 50 other rare neurological channelopathies. They may also offer a window for understanding common disorders likely to be caused by CNS channel mutations/dysfunction such as migraine and epilepsy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROTRANSMITTER CONTROL OF IONIC CHANNELS Principal Investigator & Institution: Bean, Bruce P.; Professor; Neurobiology; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-APR-1985; Project End 31-JUL-2004 Summary: Voltage-dependent calcium channels are present in all nerve and muscle cells. In heart muscle, calcium entry through voltage- dependent calcium channels triggers contraction. In neurons, calcium entry through presynaptic calcium channels plays multiple roles, including triggering release of neurotransmitter. Calcium channels in cardiac muscle and neurons can be modulated by the action of neurotransmitters and hormones. The proposed work will investigate mechanisms by which neurotransmitters modulate voltage- dependent calcium channels in cardiac myocytes and in hippocampal neurons. Patch clamp techniques will be used to study the control of calcium channels in cardiac myocytes by beta-adrenergic stimulation, using coordinated measurements of whole cell current, gating current, and single channel current. Cloned calcium channels in heterologous expression systems will be used to explore in detail how voltagedependent gating steps are controlled by phosphorylation of the channel. The control of calcium channels by beta-adrenergic stimulation will be also studied in hippocampal

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Arrhythmias

CA3 and granule neurons. The types of calcium channels subject to beta- adrenergic modulation will be identified using selective toxins. The alteration of voltage-dependent gating properties of the channels will be characterized, and the consequences for control of the firing properties of the neurons will be explored. Using cardiac muscle, hippocampal neurons, and cloned channels, the mechanisms underlying potentiated channel activity induced by strong depolarizations will be studied. The physiological significance of this potentiation during action potentials in cardiac muscle and neurons will be evaluated. Neurotransmitter control of calcium channels is a basic process for the normal operation of the heart and the brain. Understanding the mechanisms involved will help understand pathological states such as cardiac arrhythmias, cardiac failure, stroke, and epilepsy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEW DRUGS FOR TREATMENT OF ATRIAL FIBRILLATION Principal Investigator & Institution: Lacerda, Antonio E.; Chantest, Inc. 14656 Neo Pky Cleveland, Oh 44128 Timing: Fiscal Year 2003; Project Start 07-AUG-2001; Project End 31-MAY-2005 Summary: (provided by applicant): Atrial fibrillation (AF) is the most common cause of arrhythmias in the elderly; it has an incidence of more than 5 percent in people > 69 years of age. At present, there is no satisfactory treatment of this disease. The ChanTest Phase I SBIR was directed towards the discovery of novel drugs for this disease and in these experiments, the investigators identified a substituted piperidine compound that promises to be an effective antiarrhythmic agent. They found that this drug blocks the hERG/IKr current at low nanomolar concentrations, yet does not prolong the action potential duration in canine Purkinje fibers at micromolar concentrations as might be expected. The investigators hypothesized that the drug also blocked cardiac Na and Ca currents at nanomolar concentrations and, as a result, the hERG/IKr block was offset and there was no change in action potential duration. The drug had another useful characteristic, namely the forward use-dependence of a drug that is most effective at faster heart rates. This drug was in clinical trials in the late 1970s as an antidepressant and although it was safe, did not have the desired efficacy. It is now in clinical trials as a treatment for substance abuse. In neither of these trials were proarrhythmic tendencies noted and the ECGs in both sets of trials were unaffected. Because its properties are so favorable, ChanTest has filed a use patent on the drug for treatment of cardiac arrhythmias in general, and AF in particular. Given its very high affinity for hERG, a radioactive derivative can be used in high throughput displacement studies to test for non-cardiac drugs that may bind to hERG. Identifications of such drugs are of considerable importance for safety pharmacology. The specific aims of this proposal are to: 1) complete in vitro tests of the effects of the drug on other cardiac membrane currents ITo, IKs and IK1; 2) test the drug's efficacy in animal models of AF; 3) test the drug's safety in the cardiac muscle wedge preparation that is presently the best predictor of the potentially lethal ventricular arrhythmia torsade de pointes (TdP); and 4) characterize the drug congeners as tools for HTS displacement studies of drugs that bind hERG. After the drug passes the hurdles of the specific aims, ChanTest will file a 355(b)(2) NDA application with the FDA to go forward with the Phase II and III clinical trials. ChanTest believes that this drug will offer great relief to the many people who are debilitated by atrial fibrillation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies

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Project Title: HYPOTHESIS

NON-REENTRANT

ARRHYTHMIAS:

ECTOPIC

51

NEXUS

Principal Investigator & Institution: Sarvazyan, Narine; Physiology; Texas Tech University Health Scis Center Health Sciences Center Lubbock, Tx 79430 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Cardiac arrhythmias arise from abnormalities of either impulse propagation (reentry-based) or impulse initiation (focal or ectopic). The development of reentry arrhythmias, which involves rotation of an excitation wave around an anatomical or functional block, was observed both in vitro and in vivo and conceptually is well understood. In contrast, our comprehension of ectopic (nonreentrant) arrhythmias has a major gap. To gain initial insights into this process we propose to use a range of available models of cardiac tissue (both experimental and theoretical) in which infarct-like area will be created. Our preliminary studies have revealed that development of ectopic arrhythmias proceeds via an essential step, which we named an ectopic nexus (EN) It refers to a functional state of an injured cardiac tissue in which multiple poorly-coupled ectopic sources form a transient "breeding" microenvironment in which ectopic activity develops from individual cells into slowly propagating ectopic waves confined to the area of injury. The waves of excitation from surrounding healthy tissue fail to invade the EN, allowing slow ectopic waves to coexist side-by-side with normal propagation pattern. Subsequent relief of EN conditions results in an escape of the ectopic waves leading to an arrhythmia. The EN is a novel concept, which, if it does occur in vivo, has important implications for both understanding and clinical treatment of arrhythmias and ventricular fibrillation. However, experimental and theoretical models employed in our previous studies had several limitations and the relevance of the EN concept to in vivo arrhythmias needs to be further established. Specifically, one needs to know whether EN is limited to 2D cultures of cardiac cells or to a specific set of experimental conditions, how electrical activity match data obtained using calcium transients, whether the EN occurs in a 3D environment, and many other questions. The goal of this application is to provide answers to these questions in order to establish a pathophysiological significance of EN. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ORGANIZATION OF CENTRAL SYMPATHETIC PATHWAYS Principal Investigator & Institution: Guyenet, Patrice G.; Professor of Pharmacology; Pharmacology; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 01-APR-1989; Project End 31-MAR-2004 Summary: Arterial pressure (AP) and regional blood flows are finely tuned by the central nervous system CNS) via the sympathetic system. This neural control is essential to match circulation with respiration and behavior. It is also critical to the maintenance of a stable level of AP. Most of the work will be focused on a region of the brain (rostral ventrolateral medulla, RVLM) that plays a critical role in regulating sympathetic tone and AP. RVLM also deserves intensive study because it is the main site of action of numerous drugs that have actions either beneficial or detrimental to circulation. RVLM controls sympathetic tone via a small group of neurons (BS neurons) that project to the spinal cord. A key to understanding how RVLM controls AP is to find how BS neurons are in turn regulated and what type of transmitters they release. A third of the work proposed is to analyze with state of the art patch-clamp recording methods the local neuronal circuitry that regulates the activity of BS neurons. We will first identify the

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major synaptic inputs of these neurons. We will then examine in detail how catecholamines regulate their excitatory inputs since our preliminary data suggests that the antihypertensive clonidine and its new imidazoline congeners may work by mimicking the effect of noradrenaline at this level. Next we will study the presynaptic regulation of the synaptic inputs of BS neurons by other substances of pharmacological or toxicological interest like neuropeptides, nicotine and opiates. We will then determine whether RVLM contains interneurons that regulate the discharges of the BS neurons and we will identify the transmitters used by these interneurons. A second major aspect of the work will be to analyze the structure of various subclasses of BS neurons and to identify the type of transmitters that they release. This will be done with a new method that permits to localize an enzyme or an mRNA within a single neuron physiologically characterized "in vivo". In the last part of the work we will examine the possibility that sympathetic tone could also be regulated by GABAergic inhibitory inputs that originate from the brainstem and, in particular, from the nucleus of the solitary tract. The research will contribute to the basic physiological knowledge needed to understand how sympathetic tone is regulated in health and in diseases such as arrhythmias, hypertension and dysautonomias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PARTICULATE MECHANISMS

MATTER

EXPOSURE:

CARDIOVASCULAR

Principal Investigator & Institution: Chen, Chao-Yin; Med Pharmacology & Toxicology; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 956165200 Timing: Fiscal Year 2004; Project Start 01-MAY-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Epidemiological studies show significant associations between exposure to particulate matter with particles of aerodynamic diameter of <_2.5 fm (PM2.5) and cardiovascular-related morbidity including ventricular arrhythmias and sudden cardiac death. While there appears to be little doubt that PM2.5 exposure poses a significant cardiovascular health risk, the underlying causes are poorly understood. The decreased heart rate variability (HRV) associated with PM2.5 exposure is particularly important since decreased HRV has been shown to be an index of cardiac vagal regulation and is associated with increased susceptibility to ventricular arrhythmias and risk for cardiovascular-related sudden death. Even less understood is the mechanism(s) mediating the reduced HRV and hence the cardiovascular-related morbidity. Using the mouse we propose to use state-of-the-art inhalation facilities to deliver environmentally relevant particulate pollutants (iron/soot) from a true combustion source that captures the carbon-based particles and a transition metal ubiquitous in the environment to test the Hypothesis that short-term (3-day) exposure to PM2.5 results in a reduced HRV due to decreases in the intrinsic membrane properties and/or synaptic excitability of anatomically- and functionallyidentified CNS cardiac vagal neurons in the nucleus ambiguous (NA) that regulate HRV. We will test the hypothesis in mice exposed to two concentrations of iron/soot particles and filtered air (FA) as a control by the following Specific Aims. 1. To determine whether short-term (3-day) exposure to PM2.5 in the form of iron/soot particles produces the phenotype of a reduced cardiac vagal regulation of heart rate, by quantifying overall 24-h HRV, diurnal changes in HRV, and heart rate recovery following an acute stressor (exercise). 2. To determine whether the PM2.5 exposureinduced decrease in HRV is mediated by decreased intrinsic excitability of the NA cardiac vagal neurons by measuring resting membrane potential, membrane

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conductance and spiking responses to depolarizing current injections. 3. To determine whether the PM2.5 exposure-induced decreased intrinsic excitability of NA cardiac vagal neurons is mediated by increased potassium currents, left shift in activation kinetics, and/or right shift in inactivation kinetics of three major potassium channels present in NA neurons. 4. To determine whether the PM2.5 exposure-induced decrease in HRV is mediated by decreased synaptic excitability by enhanced inhibitory;?aminobutyric acid (GABA) mechanisms at the NA cardiac vagal neurons, by measuring the frequency and amplitude of tonic GABA-mediated inhibitory postsynaptic currents (GABA IPSCs). 5. To determine whether the PM2.5 exposure-induced decrease in HRV is mediated by decreased synaptic excitability by depressed glutamatergic (GLU) excitatory mechanisms at the NA cardiac vagal neurons, by measuring the frequency and amplitude of tonic excitatory postsynaptic currents (GLU EPSCs) and the amplitude of evoked GLU EPSCs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POTASSIUM CHANNEL GATING Principal Investigator & Institution: Mackinnon, Roderick; Associate Professor; Lab/Mol Neurobiology/Biophysic; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2003; Project Start 01-APR-1990; Project End 31-JUL-2007 Summary: (provided by applicant): The long-term objective of this project is to understand the mechanisms of K + channel gating, that is, how the opening of K + channels is regulated in living cells. Potassium channels play a central role in many different cellular processes including the production of electrical impulses in the nervous system, the control of heart rate, blood pressure, and the secretion of hormones such as insulin. For these reasons, a deeper understanding of how K+ channels open and close - based on their chemistry and structure -will eventually enhance our ability to treat many illnesses that afflict humans, including seizure disorders, cardiac arrhythmias, hypertension, and asthma. A wide range of techniques will be applied to the study of K + channel gating, including molecular biology, protein biochemistry, electrophysiology, and X-ray crystallography. Three fundamentally different gating mechanisms will be studied: channel opening induced by Ca 2+ binding, by G-protein binding, and by membrane voltage. The first of these mechanisms underlies muscle contraction and signal processing in the nervous system, the second mechanism controls heart rate and neurotransmitter responses, and the third is responsible for generating electrical impulses known as action potentials in both nervous and non-nervous cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: PRACTICAL CHEMICAL SYNTHESIS OF COMPLEX ALKALOIDS Principal Investigator & Institution: Overman, Larry E.; Professor; Chemistry; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2002; Project Start 01-JUL-1980; Project End 31-MAR-2005 Summary: (Principal Investigator's) The objective of this research program is to invent and/or discover efficient chemical synthesis methods that will allow structurally complex nitrogen-containing molecules to be prepared in a practical way from commercially-available building blocks. Our ultimate goal i to develop sufficiently versatile and efficient synthesis tools so that any desired molecule could be synthesized in a commercially viable manner. In this endeavor we target structurally novel, complex chemical structures for which there is no existing road map, or obvious strategy, for their synthesis. Our intent is not just to make the target compounds, but to evolve new

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synthesis strategies and to learn about the chemical peculiarities of novel chemical structures. In the long term, the availability of these new organic synthesis tools will facilitate the future development of new chemical agents for treating cardiovascular and other diseases. Many of our current natural produc synthesis targets exhibit promising medicinal properties, yet are not sufficiently accessible for in vivo evaluation. In these areas, our proposed investigations could have immediate practical application by making these compounds, and analogs, available for biomedical investigation. A variety of complex guanidine and polyamine alkaloids have been selected for investigation. These structures are targeted for two reasons: (1) guanidine an polyamine functional group arrays are found in a high percentage of recently-isolated, pharmacologicallyactive, natural products, and (2) methods for chemical synthesis of compounds containing many nitrogen atoms are less developed than other organic synthesis tools. Among our synthesis targets are (a) the crambescidin alkaloids, for which a variety of pharmacological activities have been reported, most significantly in vitro anticancer activity inhibition of calcium channels, inhibition of Na(+), K(+) and Ca(2+)-ATPases, (b) the batzelladine alkaloids, which inhibit protein-protein interactions tha are important for immunological responses, (c) palau'amine, a relatively non-toxic immunomodulator, (d) styloguanidine, a chitinase inhibitor, and (e) aloperine, an active component of traditional Chinese medicines used for treating heart arrhythmias and inflammatory disorders. The proposed investigations are founded on discoveries made during the current project period of new strategies for preparing complex guanidine alkaloids by cyclocondensation and cycloaddition reactions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROGNOSTIC SIGNIFICANCE OF T WAVE VARIABILITY Principal Investigator & Institution: Rashba, Eric J.; Medicine; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2006 Summary: (provided by applicant): The overall objective of this application is to support the principal investigator's development in a career focused on patient-oriented research. To accomplish this objective, the proposed program has both training and scientific components. The training component will consist of didactic coursework and preparation of a written thesis, culminating in a Master of Science degree in Clinical Investigation. This innovative degree program is offered by the Department of Epidemiology and Preventive Medicine at the University of Maryland. The coursework will provide training in clinical research methods including biostatistics, responsible research conduct, clinical epidemiology, and design and implementation of research studies. The scientific component of the proposal is focused on the primary prevention of sudden cardiac death. Sudden cardiac death remains a common clinical problem in the United States, with over 350,000 deaths annually. Patients with left ventricular systolic dysfunction are at particularly high risk for the ventricular arrhythmias that precipitate sudden cardiac death. The goal of this research is to develop a new method to identify those patients with systolic dysfunction who are most likely to suffer malignant ventricular arrhythmias. If a high-risk subgroup can be identified, these patients are likely to benefit from prophylactic treatment with an implantable cardioverter-defibrillator (ICD). This proposal is focused on the development of two novel risk stratification techniques that independently quantify dynamic changes in ventricular repolarization: T wave variability and T wave alternans. The scientific program will test the following hypotheses: 1) T wave variability and T wave alternans are both predictors of arrhythmic events among patients with ischemic cardiomyopathy.

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2) Patients with increased T wave variability derive a greater mortality benefit from prophylactic ICD implantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INFARCTION

PURKINJE-MYOCARDIAL

REENTRY

IN

ISCHEMIA

AND

Principal Investigator & Institution: Pollard, Andrew E.; Associate Professor; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: The contribution of the heart's specialized conduction system to arrhythmia initiation is not completely understood. While Purkinje fibers are considered a potent source for the initiating extrasystoles in focal and reentrant ventricular arrhythmias, recent suggests a contribution of Purkinje-myocardial reentry to polymorphic tachycardia that can precede fibrillation and sudden death. Our main objective is to investigate how reentrant circuits distribute between the peripheral conduction system and overlying myocardium during early cycles of sub-endocardially- induced ventricular arrhythmias. We believe those circuits circumscribe functional centers that are primarily located on the peripheral conduction system-myocardial interface, where the two components are weakly coupled via the system of discrete Purkinje-ventricular junctions (PVJs). We hypothesize this arrangement establishes peripheral conduction system and myocardial wavefronts that are out of phase with one another, which places critical importance about the ability of premature action potentials to propagate from peripheral conduction system to myocardium, i.e. antegrade PVJ conduction, for reentry maintenance. Antegrade PVJ conduction is inherent discontinuous because the myocardium imposes a large electrical load on peripheral conduction system. Experiments to test this hypothesis will use 1056-channel electrical mapping from perfused rabbit right ventricular free wall surfaces. Companion stimulations will incorporate membrane equations for ionic currents into detailed grids replicating the interface. The project has two aims. The first aim is to establish the relationship between antegrade PVJ PVJ conduction and subendocardially induced ventricular arrhythmias in macroscopically normal hearts. The second aim is to correlate regional acute ischemia and healing myocardial infarction with peripheral conduction system participation during subendocardially induced ventricular tachycardia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF CARDIAC ION CHANNEL EXPRESSION Principal Investigator & Institution: Levitan, Edwin S.; Associate Professor; Pharmacology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-AUG-1996; Project End 31-JUL-2005 Summary: (the applicant's description verbatim): The function of electrically excitable cells depends on expressing appropriate levels of a variety of voltage-gated ion channels. This is particularly important in the heart because aberrant ion channel activity can promote the incidence of arrhythmias and sudden death. In the current funding period, we showed that hormones and renovascular hypertension, which is associated with hypertrophy, regulate cardiac voltage-gated potassium (Kv) channel gene expression. Furthermore, we discovered two post-translational effects that control expression of Kv channels. Here we will continue to study these mechanisms that affect expression of cardiac Kv channels. First, we have discovered that native Kvb2 subunits

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that were previously shown to interact with the N-terminus of Kv1 family channels are associated with Kv4.3 channels. This association requires the C-terminal region of Kv4.3 and enhances protein expression and activity of these transient outward current channels. Aim 1 will determine the molecular basis of the novel interaction, and elucidate how the auxiliary subunit increases channel expression. Second, we have identified a three amino acid motif near the C-terminus of Kv1 channels that governs cell surface expression. Deletion of the motif, which occurs in some genetic diseases, inhibits complete glycosylation and localization of channels in the plasma membrane. Furthermore, natural variations in the motif account for many differences among wild type Kv1 family members. Aim 2 will explore how the VXXSL motif governs processing and surface expression of Kv1 channels. Third, we have found that the hypertrophy inducers phenylephrine and Angiotensin II downregulate Kv4.3 mRNA and protein in cultured cardiomyocytes. Although both of these agents activate Gq-coupled receptors, it appears that they use distinct mechanisms to change the expression of the channel. Aim 3 will determine the molecular and signaling mechanisms used by phenylephrine and Angiotensin II to reduce K4.3 gene transcription and mRNA stability. These studies will identify and elucidate novel mechanisms that control Kv channel expression. The understanding of such mechanisms may aid in the development of drugs to regulate channel expression with the goal of reducing the incidence of arrhythmias and sudden death. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF INTERCELLULAR COUPLING IN THE HEART Principal Investigator & Institution: Lerner, Deborah L.; Pediatrics; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): The heart has a remarkable ability to change the extent to which myocytes are electrically coupled by remodeling gap junctions in response to changing physiologic and pathophysiologic conditions. Regulation of the formation and function of gap junction channels is, therefore, of critical importance in myocardial function during health and disease. To gain mechanistic insights into the regulation of intercellular coupling in the cardiac hypertrophic response, an in vitro model of pulsatile mechanical stretch of cultured myocytes was designed to simulate overload in the heart in vivo. Only one hour of stretch leads to a 2-fold increase in Cx43 expression and a 30% increase in impulse propagation velocity. This experimental system will be exploited to elucidate cellular mechanisms and signaling pathways regulating intercellular coupling during the hypertrophic response. We propose that stretch induces upregulation of Cx43 through multiple signaling pathways that have different time courses of action and work through different cellular mechanisms. The early response to stretch occurs within 15 minutes and induces upregulation of Cx43 expression by alterations in Cx43 trafficking and degradation mediated by vascular endothelial growth factor signaling. The later response to stretch (>1-2 hours) is mediated by angiotensin II signaling and contributes to the upregulation of Cx43 expression by increasing Cx43 synthesis. In Specific Aim 1, the time course of stretchinduced upregulation of Cx43 will be defined and the relative contributions of alterations in Cx43 trafficking, synthesis and degradation will be delineated. In Specific Aim 2, the temporal relationships of stretch-activated signaling pathways initiated by vascular endothelial growth factor and angiotensin II in regulating changes in Cx43 trafficking, synthesis and degradation will be determined. In Specific Aim 3, the role of alterations in Cx43 phosphorylation at specific tyrosine residues in stretch-induced

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upregulation of Cx43 expression will be defined. Elucidation of mechanisms enhancing intercellular coupling will provide the potential for novel therapeutic strategies for the treatment of heart failure and prevention of arrhythmias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION MYOCARDIUM

OF

LIPID

METABOLISM

IN

DIABETIC

Principal Investigator & Institution: Gross, Richard W.; Professor; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: The cardiac sequelae of diabetes represents the largest cause of morbidity and mortality in the diabetic population. In both Type I and Type II diabetes, an increased reliance on fatty acid substrate is present which leads to the development of an intrinsic cardiomyopathy and an increased susceptibility of diabetic myocardium to the effects of ischemia/hypoxia. During the current grant interval, we have defined the complete genomic organization and protein sequence of a novel calcium- independent phospholipase A2 (iPA2gamma), which we propose modulates energy storage (lipid accumulation) and dissipation (FA removal through heat production) in the cardiac myocyte. Accordingly, in Specific Aim 1 we will first purify iPA2gamma to homogeneity, determine its substrate specificity and ability to transacylate salient lipids in the peroxisomal compartment. In Specific Aim 2, the biochemical and pathophysiologic sequelae of alterations in myocardial iPLA2gamma activity will be examined both by characterizing mice over-expressing iPA2gamma in a cardiac myocyte specific fashion and by generating mice null for the iPA2gamma gene. The effects of both Type I and Type II diabetes on transgenic mice over-expressing and null for iPLA2gamma will be examined by focusing on the transgene-dependent alterations in hemodynamic function and lipid flux manifest in the diabetic state. Remarkably, the gene encoding iPLA2gamma cosegregates to a locus identified by positional cloning as one of the multigenic determinants of Type II diabetes in the Pima Indian population. Accordingly, we will first identify common allelic variants of the iPLA2ganma gene in the Pima Indian population and express those allelic variants in Sf9 cells to identify their biochemical sequelae. Finally, we have demonstrated that mice over-expressing iPLA2beta in a cardiac myocyte specific fashion have ischemia-induce malignant ventricular arrhythmias. Accordingly, in Specific Aim 4 we will examine the functional sequelae of iPLA2beta over-expression in both Type I and Type II models of diabetes through detailed hemodynamic electrophysiologic and biochemical characterization of these transgene mice. Covalent alterations in iPLA2beta induced by the diabetic state will be identified and characterized. Collectively, Project 1 represents a multidisciplinary, highly synergistic, targeted proposal to identify the importance of alterations in cardiac myocyte lipid storage and utilization as a primary determinant of the excessive cardiovascular mortality and morbidity present in the diabetic patient. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF SYMPATHETIC FUNCTION BY INFARCTION Principal Investigator & Institution: Habecker, Beth A.; Physiology and Pharmacology; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-MAY-2005 Summary: Provided by applicant): The long term goal of the proposed research is to understand the molecular basis for the depletion of norepinephrine (NE) and loss of NE

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uptake in the peri-infarct sympathetic innervation following myocardial infarction (MI). Myocardial infarction can lead to ventricular arrhythmias and heart failure, and is a leading cause of mortality and morbidity in the United States. Changes in the cardiac innervation following Ml play a crucial role in the development of arrhythmias and heart failure, but the mechanisms that underlie the depletion of NE and loss of NE uptake in the peri-infarct innervation remain unknown. Several lines of evidence suggest a completely novel hypothesis that can account for these changes in the periinfarct innervation. First, infarction is accompanied by the elevation of inflammatory cytokines, and interleukin-6 (IL-6) in particular. Sympathetic neurons have receptors for IL-6, and other cytokines in the IL-6 family suppress NE synthesis and reuptake in sympathetic neurons while inducing the production of peptides including vasoactive intestinal peptide (VIP). IL-6 shares common receptors and signaling pathways with these related cytokines. and our preliminary data indicate that IL-6 suppresses NE uptake and induces VIP in cultured sympathetic neurons. Therefore, we hypothesize that IL-6 released in the heart after infarction causes the depletion of neuronal NE and loss of NE uptake observed in the peri-infarct cardiac innervation. To test this hypothesis we will determine if: 1) IL-6 suppresses NE and NE synthetic enzymes in sympathetic neurons, 2) IL-6 suppresses NE uptake and the NE transporter in sympathetic neurons, 3) IL-6 suppresses neunopeptide Y and induces other neuropeptides in sympathetic neurons, and 4) suppression of inflammatony cytokines or the absence of IL-6 during and after infarction prevents the depletion of NE and loss of NE uptake in the peri-infarct cardiac innervation. A variety of molecular, biochemical, and histological approaches will be used to carry out these experiments both in vitro and in vivo. These studies will determine if IL-6 is a key player in the pathological changes in the cardiac innervation following infarction, and will identify the sites at which IL-6 regulates sympathetic function. This work tests a novel hypothesis that would provide a mechanistic explanation for the depletion of neuronal NE and NE uptake following infarction, and will provide the scientific basis for the development of new therapies These studies will also provide new and important information about the expression of vasoactive peptides in the heart following infarction. Similar changes in IL-6 and NE uptake occur during heart failure as well, indicating that these studies will have implications beyond the treatment of myocardial infarction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RGS PROTEIN FUNCTION IN CARDIAC PHYSIOLOGY Principal Investigator & Institution: Muslin, Anthony J.; Professor of Internal Medicine, Cell Bio; Barnes-Jewish Hospital Ms 90-94-212 St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 15-AUG-2000; Project End 31-MAR-2003 Summary: Postnatal mammalian cardiomyocytes respond to mechanical stress, growth factor and hormonal action, and metabolic abnormalities by enlarging, but these cells are unable to proliferate for reasons that are not understood. The clinical consequences of human cardiac hypertrophy are very significant and include the development of serious cardiac arrhythmias, of diastolic dysfunction that can result in pulmonary edema and fluid overload, and of congestive heart failure. Intracellular signaling cascades play a major role in the development of cardiac hypertrophy. Several lines of evidence support the role of G proteins in the development of cardiac hypertrophy. RGS (regulator of G protein signaling) proteins were recently found to be GTPase activating proteins (GAPs) for heterotrimeric G proteins. In this proposal, we will outline experiments to test the hypothesis that RGS proteins determine the responsiveness of cardiomyocytes to extracellular stimuli, and that RGS gene expression can be increased

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as an adaptive mechanism to limit G- protein-mediated signal transduction. We will examine the expression pattern of RGS family members in animal models of cardiac hypertrophy and congestive heart failure. We will determine the relative ability of RGS family members to block cardiomyocyte signal transduction and hypertrophic growth. We will determine whether RGS4 inhibits cardiac hypertrophy in a transgenic mouse model in response to provocative stimuli. Finally, we will determine whether dominant negative mutant forms of RGS2 and RGS4 promote cardiomyocyte signal transduction and hypertrophic growth. These experiments will help to establish the role of RGS proteins in the pathophysiology of cardiac hypertrophy and may have an impact on future treatment of patients with this disorder and those in whom hypertrophy has progressed to heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF PMNL, PAF AND KCNK3 IN CARDIAC ARRHYTHMIAS Principal Investigator & Institution: Feinmark, Steven J.; Research Scientist; Pharmacology; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-JAN-2007 Summary: (provided by applicant): Polymorphonuclear leukocytes (PMNL) accumulate rapidly in the heart after ischemia/reperfusion and play a critical role in the ensuing tissue damage and generation of arrhythmias. We have focused on the role of the inflammatory phospholipid, platelet-activating factor (PAF) in this process. PAF causes arrhythmias in isolated ventricular myocytes, and affects the rhythm of infarcted hearts perfused ex vivo. The goal of this application is to determine the mechanisms by which PAF-induced arrhythmias occur and thus, identify novel targets for antiarrhythmic therapy. Aim 1: What are the ionic and signaling mechanisms by which PAF induces arrhythmias? We propose that PAF-induced arrhythmias are caused by a protein kinase C-epsilon (PKC-epsilon) block of the two-pore domain K+ channel, Kcnk3 (first known as cTBAK-1 or TASK-1). Using a combination of biochemical and electrophysiological methods in murine ventricular myocytes or CHO cells expressing murine Kcnk3, we will determine if the Kcnk3 channel is the target for phosphorylation by PKC-epsilon or a downstream kinase and if so, we will determine the phosphorylation site(s) and prepare site-directed and truncation mutants. The functional properties of the expressed channels will be characterized. We further propose that the intracellular signaling pathway by which anandamide, the putative lipid ligand of the cannabinoid receptors, blocks Kcnk3 overlaps with the PAF pathway and mimics the arrhythmogenic effects of PAF. We hypothesize that there is a biochemical relationship between PAF and anandamide. Aim 2: Is PAF arrhythmogenic in intact heart and does ischemia alter the responsiveness of heart to PAF? PAF receptor (PAFR) antagonists are beneficial in animal models of infarction. We suggest that the sensitivity of infarcted heart to PAFinduced arrhythmias is greater than normal heart. Using whole animals, or intact hearts from PAFR knockout and transgenic mice that overexpress the PAFR in a Langendorff perfusion set-up and isolated myocytes incubated with PMNL or cytokines, we will determine the mechanism by which the sensitivity of the heart is modulated. We will compare the ability of PAF and anandamide to induce arrhythmias in control heart or after ischemia/reperfusion. We hypothesize that conditions that activate myocytes will upregulate PAFR expression and sensitize the heart to arrhythmias. We will measure electrophysiological parameters and quantify the ability of PMNL to bind to isolated myocytes and induce arrhythmias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Arrhythmias

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: SPECIALIZED CENTER OF RESEARCH IN ISCHEMIC HEART DISEASE Principal Investigator & Institution: Mendelsohn, Michael E.; Professor; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2005 Summary: This proposal describes a Specialized Center for Research (SCOR) in Ischemic Heart Disease that tests the hypothesis that the genetics, expression and function of cardiovascular estrogen receptors (ER) and estrogen-regulated target genes mediate protection against ischemic diseases and their sequelae, including vascular dysfunction, post- myocardial infarction remodeling, and arrhythmias. The program is based on widely noted gender differences in ischemic disease, beneficial effects of estrogen on cardiovascular diseases in women, and recent data demonstrating: 1) the presence of functional ER in cardiovascular diseases in women and men; 2) important ER target genes in cardiovascular tissues; and 3) an important role for ER and the genes they regulate in vascular and myocardial physiology. The hypothesis is investigated through

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genetic, molecular, cellular, animal and human studies in five highly integrated and cooperative projects that expand on existing strengths at New England Medical Center and Tufts University, as well as MIT, Boston University, and the Framingham, Heart Study. The five projects Proposed include: Project 1: "Genetics of Estrogen and Cardiovascular Responses", a genetic analysis of cardiovascular phenotypes and ER/ER-related genes from subjects in the Framingham Offspring study; Project 2: "Selective ER Modulation: Effects in Post Menopausal Women Following Myocardial Infarction", a secondary prevention trial at New England Medical Center with the selective ER modulator raloxifene; Project 3: "Cardiac ER and MI: Mouse Models", studies of ventricular remodeling, arrhythmogenic changes, and myocardial gene expression in wild-type, ERalphaKO and ERbetaKO ventricular remodeling, arrhythmogenic changes, and myocardial gene expression in wild-type, ERalphaKO and ERbetaKO mice following MI; Project 4: "ER Regulation of NO Synthases," studies of the rapid activation of endothelial eNOS by ERalpha, and the longer-term induction of vascular smooth muscle iNOS gene expression by ERbeta; and Project 5: "ER and Smooth Muscle BKCa Channels", studies of ER regulation of ion channel function ins ingle vascular smooth muscle cells. These Projects are served by three Cores: Administrative, Mouse (with Transgenic, Physiology, Cell Culture and Histology components), and Statistical, all build on existing Cores at the Molecular Cardiology Research Institute and Tufts-NEMC. Together, these five Projects define a broad-based program to explore new mechanisms of coronary myocardial regulation by ER with direct consequences for the diagnosis and management of ischemic cardiovascular diseases, and the potential to evolve a new class of therapies for these disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SPECIALIZED CENTER OF RESEARCH IN SUDDEN CARDIAC DEATH Principal Investigator & Institution: Marban, Eduardo; Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 20-JAN-1995; Project End 31-DEC-2004 Summary: Sudden cardiac death accounts for 30-50% 0f heart failure mortality. This proposal, which is the continuation of an existing SCOR program in Sudden Cardiac Death, investigates the biological basis of altered excitability in heart failure and how predisposes to fatal ventricular arrhythmias. The SCOR is motivated by the following central hypothesis: Abnormalities of ionic currents and calcium handling render repolarization unstable in failing myocardium, increasing spatiotemporal variability of repolarization and predisposing patients with heart failure to sudden death. This hypothesis has been tested and validated extensively in the first five years of the program. We now propose to probe the biological basis of the abnormal repolarization, with a view to developing novel strategies for the identification of patients at high risk. Our program features a central animal model (pacing tachycardia canine heart failure) as well as tissue and myocytes from explanted human hearts. The program consists of five projects and five cores. Project 1, directed by Eduardo Marban, will use gene transfer and cell fusion to dissect the molecular determinants of cardiac repolarization. Project 2 focuses on L- type calcium channel inactivation. Project 2 focuses on L-type calcium channel inactivation under the leadership of David Yue. Project 3, directed by Gordon Tomaselli, investigates the relative roles of voltage- dependent and calciumdependent mechanisms in the action potential prolongation of heart failure. Project 4 probes the neurohumoral modulation of electromechanical remodeling in heart failure, under the directorship of David Kass. Project 5, led by Ronald Berger, examines

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temporal QT interval variability as a predictor of severe arrhythmias and sudden cardiac death in patients. The five cores will provide support in the following areas: administrative matters, molecular genetics and vectors, animal models and cells, human cells and tissue, and quantitative modeling. The program in its first five years has been highly productive and interactive. The proposed continuation combines existing strengths with new approaches in a strongly synergistic manner. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURAL ANALYSIS OF VOLTAGE-GATED POTASSIUM CHANNELS Principal Investigator & Institution: Blaustein, Robert O.; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Potassium channels are specialized integral membrane proteins endowed with a remarkable capacity to accommodate the highly selective passage of potassium ions across cells. Some have the added ability to open and close in response to small changes in transmembrane voltage, and it is these voltage-gated (Kv) potassium channels that are the focus of this proposal. These proteins play crucial roles in a number of physiologic processes ranging from the propagation of information in the nervous system to the maintenance of a normal heart rhythm, and inherited mutations in many of them lead to forms of epilepsy, paralysis, and cardiac arrhythmias. The structures of some parts of Kv channels and their auxiliary subunits are now well understood, yet despite detailed study for over a decade, little is known about the construction of the voltage sensing region of these channels, or about the overall architecture of hetermultimeric channels. In light of this gap, a new method is introduced to complement established techniques of molecular biology and electrophysiology--the use of tethered quaternary ammonium blockers as molecular tape-measures. These compounds will be targeted to intracellular and extracellular regions of two classes of K+ channels: the prototypic voltage-dependent Shaker channel, and heteromultimeric channels formed from the co-assembly of Shakerlike subunits with minK-related peptides (MiRPs). The two specific aims, (1) mapping the extracellular portion of Shaker's gating module, and (2) probing the structure of MiRP-associated channels, will be instrumental in fulfilling the project's long-term objectives of creating a detailed physical map of the gating module of a Kv channel, and determining how the different parts of a Kv channel are molded together. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHANNELS

STRUCTURAL

STUDIES

ON

PROKARYOTIC

POTASSIUM

Principal Investigator & Institution: Gross, Adrian; Mol Pharm & Biol Chemistry; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 01-FEB-1999; Project End 31-JAN-2004 Summary: Voltage-dependent ion channels are instrumental in the generation of membrane potential, receptor potential, and action potential. They are implicated in the physiology and pathophysiology of all excitable tissues. These proteins underlie many disease processes including arrhythmias and epilepsies and are major targets of essential drugs used in clinical medicine. Despite the obvious biological and clinical importance of these proteins, very little is known about their structure. Obtaining this structural information is of paramount importance to a mechanistic understanding of

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their function. This proposal presents a new approach toward addressing the structure and function of these proteins. Bacterial model systems will be studied by two complimentary techniques: site-directed spin labeling and electrophysiology. The study will address two key properties of potassium channels: permeation and gating. It is thought that the structural elements underlying permeation and, to some extent, gating have been identified. All cation selective voltage-dependent ion channels share a common core domain that is sufficient for ion permeation. Also, a highly unusual transmembrane segment known as S4 has been implicated as part of the structural element responsible for voltage-dependent gating. These two structural elements will be studied with the two techniques. It is anticipated that the results of the spin labeling study will provide sufficient constraints to determine the structure of these two elements to the level of the backbone fold. The resulting folding model will provide the basis for a mechanistically inspired functional study using electrophysiology. The longterm goal of this proposal is to understand functional properties of ion channels at a structural level. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURE-FUNCTION OF THE CARDIAC SODIUM CHANNEL Principal Investigator & Institution: Fozzard, Harry A.; Professor; Neurobiology/Pharmacology/Phys; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 29-SEP-2000; Project End 31-JUL-2004 Summary: (the applicant's description verbatim): The long-term purpose of this project is to understand cardiac Na+ channel function at the molecular level, and to use the understanding to develop strategies for control of lethal arrhythmias. This project has three interdependent goals for the next five years: 1) resolving the molecular configuration of the Na+ channel permeation path/selectivity region, including the sites for local anesthetic drug binding, 2) examining the roles of charged vestibule residues in permeation and selectivity, and 3) determining the functional abnormalities resulting from naturally occurring channel mutants, especially alpha-subunit interactions. The Na+ channel is a major participant in most serious or lethal arrhythmias, and it is the target of some of our most powerful antiarrhythmic drugs. Considerable progress has been made in identifying the molecular structure of the outer vestibule (outer third of the permeation path) by effects of point mutations on permeation and selectivity and by determining the complimentary surface for binding of the pore-blocking toxins. Our unifying structural hypothesis is that the Na+ channel is related through evolution to the structurally determined KcsA bacterial channel, and that it spore motif of a helix teepee and a selectivity motif of helix-turn-strand is applicable to the Na+ channel. We propose to extend the complimentary interaction surface for outer vestibule toxins to identify the structure of the "turrets" in the outer path, perhaps also attempting to resolve the isoform selectivity of u-conotoxin in the process. These important carboxyls in the outer vestibule will be examined by mutation and pH titration for their contribution to dehydration of the permeating ions. The residues facing the inner pore will be identified by sequential mutation of the residues to cysteine, with access determined by methanesulfonate derivative interaction. Their roles in local anesthetic drug binding will be determined, in order to find all of the molecular parts of the drug binding site. State-dependent access of these residues will be examined to determine the changes in the site with channel gating. Each experimental step is developed based on the best molecular model we can develop, and in turn the model is improved as new experimental information is obtained in these experiments or published by others.

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

Project Title: SURGICAL TREATMENT OF CARDIAC ARRHYTHMIAS Principal Investigator & Institution: Boineau, John P.; Medical Science Service; Surgery; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 08-AUG-1983; Project End 31-JUL-2003 Summary: This renewal application requests five years' support for work now in continuous progress for over 15 years at Washington University. Dr. John Boineau, the new PI, has replaced Dr. James Cox, the former P1, who transferred to Georgetown University Hospital. Dr. Cox remains as a special consultant. The broad aims continue to be the direct or surgical ablation of cardiac arrhythmias. The emphasis of the current renewal is focused upon the development of a new procedure, the radial incisions approach (RIA), to eradicate atrial fibrillation (AF) and restore atrial transport function and is directed primarily toward patients undergoing surgery for valvular or ischemic heart disease. Conventional valve or CABG surgery does not eliminate and may not prevent AF in these patients. The availability of an effective means of eradicating this arrhythmia in these patients at the time of surgery would permit control of rate and rhythm, limit embolic stroke, and improve cardiac performance, outcome, and the quality of life. Whereas the Maze and RIA assume randomly distributed and changing reentry which are eliminated without prior activation mapping, new data indicate that some forms of AF result from (spatially) stable reentry which can be identified by new mapping methods and focally ablated. Thus, a second project is directed toward map guided, focal cryoablation of AF. This could be performed off bypass as a more limited and rapid alternative to the more extensive and (bypass) time consuming RIA procedure. A third project is targeted at prevention and correction of postoperative atrial flutter (AFL) after the Fontan operation in congenital heart patients or after lung transplant surgery. Studies will be performed in both realistic animal models with atrial enlargement and patients with AF and AFL and will center about the use of new automated, 3-D mapping techniques and rapid numerical analysis of potentials recorded simultaneously from to 512 electrodes during the arrhythmias. Preliminary observations indicate that the proposed studies are feasible, will provide new information regarding the different mechanisms of AF and AFL that are related to atrial enlargement and/or atrial surgery, and this data will be used to develop the new surgical ablation techniques to control or prevent these arrhythmias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SURGICAL TREATMENT OF CARDIAC ARRHYTHMIAS Principal Investigator & Institution: Damiano, Ralph J.; Professor; Surgery; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 08-AUG-1983; Project End 31-JUL-2007 Summary: Atrial fibrillation (AF) is the most common arrhythmia in the world, and a significant source of morbidity and mortality. Unfortunately, antiarrhythmic drugs have had limited efficacy and numerous side effects. Transvenous ablation techniques require prolonged, often multiple, procedures and have had high complication rates and questionable long-term efficacy. Over the last two decades, our laboratory has developed two successful surgical approaches for the treatment of AF. The Maze and Radial procedures have the best-documented long-term results in the treatment of atrial fibrillation, with over 90% of patients remaining arrhythmia-free at 10 years. Despite their proven efficacy, few surgeons around the world actually perform these

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procedures, both because of their invasiveness and complexity. Moreover, these operations are far from perfect, and still result in significant morbidity in terms of postoperative atrial arrhythmias, conduction disturbances, and atrial dysfunction. Our goal in this competing renewal is to develop a less invasive procedure with more widespread applicability by moving from an anatomically based operation that was designed to eliminate all possible mechanisms of AF to a mapping-directed procedure that addresses the specific focal mechanisms responsible for AF in each particular patient. To accomplish this goal and to evaluate the physiologic consequences of our interventions, the following specific aims are proposed: 1) Develop a real-time algorithm using intraoperative epicardial mapping to identify focal sources and substrates for AF to allow for mapping-directed therapy. 2) Develop less-invasive surgical procedures for the treatment of AF based on real time mapping data and the assessment of the physiological consequences and mechanistic insight from the operations. 3) Develop techniques to evaluate atrial function non-invasively to allow for the precise assessment of the hemodynamic consequences of surgery for AF. 4) Determine the causes of postoperative arrhythmias associated with surgical procedures to ablate AF, and modify these procedures to minimize their occurrence. If we can achieve these aims, the thousands of chronic AF patients yearly who undergo valvular and coronary surgery will have their arrhythmia cured in the operating room at the time of surgery, and our surgical treatment will become a viable option to a lifetime of anti-arrhythmic drug therapy and anticoagulation for millions of patients with lone AF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSCRIPTIONAL REMODELING IN CARDIAC ARRHYTHMIAS Principal Investigator & Institution: George, Alfred L.; Director, Division of Genetic Medicine a; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Electrical remodeling describes the electrophysiological changes occurring in chronic cardiac diseases associated with an increased susceptibility to arrhythmias. Changes reflecting remodeling in readily measured electrophysiologic characteristics (action potential duration, individual ionic currents) have been observed in large animal models with arrhythmias closely resembling those in humans. In the dog model of chronic complete AV block (CAVB), biventricular hypertrophy occurs along with substantial increases in action potential duration that render the animals prone to developing Torsades de Pointes during exposure to QT-prolonging antiarrhythmic agents. Similarly in chronic atrial fibrillation (both human and various pacing-induced animal models), atrial electrical remodeling produces a cellular substrate that perpetuates the arrhythmia (?atrial fibrillation begets atrial fibrillation?). Evidence points to long term changes in gene expression as an important element in the genesis of these arrhythmia prone states. However, our knowledge of the identity and temporal sequence of changes in gene expression underlying these two conditions is rudimentary. In this Project, we will use microarray technology to survey global patterns of transcriptional remodeling in dog hearts that occur following chronic AV block and with pacing-induced atrial fibrillation. This work requires that we develop a gene array from a panel of canine expressed sequence tags that we have started to collect. Development of a canine microarray will enable us to examine changes in gene expression in hypertrophied ventricular myocardium of CAVB dogs and assess differences between subgroups of animals that exhibit susceptibility or resistance to drug-induced Torsade de Pointes. We will also be able to characterize the transcriptional remodeling in atrial myocardium

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associated with induction of atrial fibrillation in dogs subjected to rapid atrial pacing. Robust statistical analyses of microarray data will be used to direct appropriate validation experiments using separate methods. These studies will provide new insights into the pathogenesis of arrhythmia susceptibility and contribute to identifying potential new targets for therapeutic interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VISUALIZATION ELECTRODYNAMICS

AND

ANALYSIS

OF

CARIDAC

Principal Investigator & Institution: Bray, Mark-Anthony P.; Biomedical Engineering; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAY-2003 Summary: An understanding of the response of cardiac tissue to an electrical stimulus is crucial for proper treatment and prevention of cardiac arrhythmias, for example in the application of a strong defibrillating shock to halt fibrillation. This project will apply novel techniques for data visualization and non-linear analysis to explore the dynamics of spiral wave formation, interaction, and termination, for electrical activity evident at the epicardial surface and also within the underlying myocardial substrate. Fibrillatory waves rotate about phase singularities (2-D) or filaments (3-D) which define many of the characteristics of the wave itself. Literature addressing a comparison between computational predictions and cardiac experimental observations of the interaction behavior between multiple spiral waves is virtually non-existent. Recent work has demonstrated that such non-linear dynamics of cardiac activation can be quantified using phase portrait analysis. The specific aims are to (1) localize and characterize phase singularity and filament behavior, (2) quantify the shifts in the phase portrait during multiple stimuli to an experimental preparation, and (3) further substantiate the above results by using a previously validated whole-heart panoramic imaging algorithm. This research will rely heavily on the development of new techniques to examine phase resetting during stimulation and defibrillation, and the creation and subsequent interaction of singularities and filaments, as well as whole-heart electrophysiological measurements with the ability of overcoming the difficulty of having phase singularities and filaments, as well as whole-heart electrophysiological with the ability of overcoming the difficulty of having phase singularities move out of the field-of-view. The research will clarify phase singularity and filament behavior as well as the dynamics of phase resetting, on both a regional and a global epicardial basis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: WEB-BASED INTERACTIVE ECG ARRHYTHMIA INSTRUCTION & TEST Principal Investigator & Institution: Criley, Stuart R.; Blaufuss Multimedia 115 Idora Ave San Francisco, Ca 94127 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-MAR-2004 Summary: (provided by applicant): Electrocardiography (ECG) is one of a triad of the oldest clinical tools (stethoscope 1816, radiography 1895, ECG 1902) still in use in the evaluation of patients with suspected cardiac disease, and remains one of the most costeffective cardiographic tools available to the clinician. Accurate electrocardiography recognition of arrhythmias facilitates appropriate therapy and avoids complications that could result from either failure to recognize the arrhythmia or failure to employ appropriate management. The objective is to develop a novel, highly interactive,

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Internet-based teaching and testing program on arrhythmia recognition of electrocardiograms (ECGs) for medical trainees, utilizing actual patient data and custom animations. Three components-tutorial animations, rapid assessment skills of printouts, and preparation for board exams--will improve medical trainees' ECG interpretation skills, and improve them more quickly than traditional education. In addition, the development of an authoring tool will allow instructors to create new content rapidly from their own ECG collection for teaching and testing. Internet distribution of the program will allow trainees and instructors to use the program without any special hardware or software other than a personal computer and a browser like Internet Explorer or Netscape. For situations where access to the Internet is not practical, a standalone version will be available for local networks or for single computers. To measure the program's effectiveness in improving skills, in Phase I the program will be evaluated in a small pilot study of medical trainees at two teaching hospitals, expanding to several other sites in Phase II. The market for effective ECG training software is large, and includes residency training programs, cardiology fellowships, as well as advanced practice nursing programs. As certification for ECG over-reading privileges becomes established in more health care facilities and networks, the demand for efficient, costeffective training for graduate physicians will increase for healthcare points of entry: emergency departments, urgent care clinics, and primary care. Large healthcare networks in particular are highly motivated to lower the number of false positive/false negative diagnoses from ECG interpretation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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

Brain-heart interactions. The neurocardiology of arrhythmia and sudden cardiac death. by Davis AM, Natelson BH.; 1993; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325088

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Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs: cohort study using administrative data. by Hennessy S, Bilker WB, Knauss JS, Margolis DJ, Kimmel SE, Reynolds RF, Glasser DB, Morrison MF, Strom BL.; 2002 Nov 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=131181

3 4

Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.

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•

Cardiac arrhythmia at high altitude: the progressive effect of aging. by Alexander JK.; 1999; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325660

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Cardiac arrhythmia classification using autoregressive modeling. by Ge D, Srinivasan N, Krishnan SM.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149374

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Cardiac Arrhythmias and Device Therapy: Results and Perspectives for the New Century. by Zaqqa M.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101094

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Determination of the Target Ventricular Rate in Patients with Atrial Fibrillation by Evaluation of Ventriculoarterial Coupling. by Nobuoka S, Hatano S, Nagashima J, Yoshida A, Adachi H, Imai Y, Shibamoto M, Ikeda K, Miyake F.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116734

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Distinct gene-specific mechanisms of arrhythmia revealed by cardiac gene transfer of two long QT disease genes, HERG and KCNE1. by Hoppe UC, Marban E, Johns DC.; 2001 Apr 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33210

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Hemodynamic effects after reversion from atrial fibrillation to sinus rhythm by precordial shock. by Killip T, Baer RA.; 1966 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=292743

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Identification of patients with atrial fibrillation in general practice: a study of screening methods. by Sudlow M, Rodgers H, Kenny RA, Thomson R.; 1998 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28628

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Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome. by Clancy CE, Tateyama M, Kass RS.; 2002 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151612

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Lone atrial fibrillation in vigorously exercising middle aged men: case-control study. by Karjalainen J, Kujala UM, Kaprio J, Sarna S, Viitasalo M.; 1998 Jun 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28577

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Long QT and ventricular arrhythmias in transgenic mice expressing the N terminus and first transmembrane segment of a voltage-gated potassium channel. by London B, Jeron A, Zhou J, Buckett P, Han X, Mitchell GF, Koren G.; 1998 Mar 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19671

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Low-energy internal cardioversion of atrial fibrillation after failed external cardioversion: Texas Heart Institute experience and review of the literature. by Zaqqa M, Afshar H, Khoshnevis GR, Lopez JA, Massumi A.; 1999; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325614

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Mechanisms Contributing to Malignant Dysrhythmias Induced by Ischemia in the Cat. by Corr PB, Witkowski FX, Sobel BE.; 1978 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=372519

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Nonlinear-dynamical arrhythmia control in humans. by Christini DJ, Stein KM, Markowitz SM, Mittal S, Slotwiner DJ, Scheiner MA, Iwai S, Lerman BB.; 2001 May 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33298

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Predisposition to Arrhythmia and Autonomic Dysfunction in Nhlh1-Deficient Mice. by Cogliati T, Good DJ, Haigney M, Delgado-Romero P, Eckhaus MA, Koch WJ, Kirsch IR.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139775

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Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin. by Hellemons BS, Langenberg M, Lodder J, Vermeer F, Schouten HJ, Lemmens T, van Ree JW, Knottnerus JA.; 1999 Oct 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28250

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Prospective cohort study to determine if trial efficacy of anticoagulation for stroke prevention in atrial fibrillation translates into clinical effectiveness. by Kalra L, Yu G, Perez I, Lakhani A, Donaldson N.; 2000 May 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27364

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Protocol for Birmingham Atrial Fibrillation Treatment of the Aged study (BAFTA): a randomised controlled trial of warfarin versus aspirin for stroke prevention in the management of atrial fibrillation in an elderly primary care population [ISRCTN89345269]. by Mant JW, Richards SH, Hobbs FD, Fitzmaurice D, Lip GY, Murray E, Banting M, Fletcher K, Rahman J, Allan T, Raftery J, Bryan S.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=201020

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Rhythm versus rate control for atrial fibrillation management: what recent randomized clinical trials allow us to affirm. by Nattel S.; 2003 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149253

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Risk of ventricular dysrhythmias during 1-hour infusions of amphotericin B in patients with preserved renal function. by Bowler WA, Weiss PJ, Hill HE, Hoffmeister KA, Fleck RP, Blacky AR, Oldfield EC 3rd.; 1992 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=284371

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Suppression of ventricular arrhythmias in man by d-propranolol independent of beta-adrenergic receptor blockade. by Murray KT, Reilly C, Koshakji RP, Roden DM, Lineberry MD, Wood AJ, Siddoway LA, Barbey JT, Woosley RL.; 1990 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296501

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The limited utility of electrocardiography variables used to predict arrhythmia in psychotropic drug overdose. by Buckley NA, Chevalier S, Leditschke IA, O'Connell DL, Leitch J, Pond SM.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=270716

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The relation between atrial fibrillation wavefront characteristics and accessory pathway conduction. by Ong JJ, Cha YM, Kriett JM, Boyce K, Feld GK, Chen PS.; 1995 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185879

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Ventricular Arrhythmias and K+ Transfer during Myocardial Ischemia and Intervention with Procaine Amide, Insulin, or Glucose Solution. by Regan TJ, Harman MA, Lehan PH, Burke WM, Oldewurtel HA.; 1967 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=292914

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Ventricular arrhythmias in congestive heart failure: clinical significance and management. by Khoshnevis GR, Massumi A.; 1999; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325598

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Ventricular Arrhythmias Induced in Monkeys by the Inhalation of Aerosol Propellants. by Taylor GJ IV, Harris WS, Bogdonoff MD.; 1971 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=292095

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

A mouse model of congenital heart disease: cardiac arrhythmias and atrial septal defect caused by haploinsufficiency of the cardiac transcription factor Csx/Nkx2.5. Author(s): Tanaka M, Berul CI, Ishii M, Jay PY, Wakimoto H, Douglas P, Yamasaki N, Kawamoto T, Gehrmann J, Maguire CT, Schinke M, Seidman CE, Seidman JG, Kurachi Y, Izumo S. Source: Cold Spring Harb Symp Quant Biol. 2002; 67: 317-25. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12858555

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A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias. Author(s): Hudson ER, Pan DA, James J, Lucocq JM, Hawley SA, Green KA, Baba O, Terashima T, Hardie DG. Source: Current Biology : Cb. 2003 May 13; 13(10): 861-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12747836

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

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A randomized prospective study of single coil versus dual coil defibrillation in patients with ventricular arrhythmias undergoing implantable cardioverter defibrillator therapy. Author(s): Rinaldi CA, Simon RD, Geelen P, Reek S, Baszko A, Kuehl M, Gill JS. Source: Pacing and Clinical Electrophysiology : Pace. 2003 August; 26(8): 1684-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12877701

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A risk score to predict arrhythmias in patients with unexplained syncope. Author(s): Sarasin FP, Hanusa BH, Perneger T, Louis-Simonet M, Rajeswaran A, Kapoor WN. Source: Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine. 2003 December; 10(12): 1312-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14644781

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ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias--executive summary. a report of the American college of cardiology/American heart association task force on practice guidelines and the European society of cardiology committee for practice guidelines (writing committee to develop guidelines for the management of patients with supraventricular arrhythmias) developed in collaboration with NASPE-Heart Rhythm Society. Author(s): Blomstrom-Lundqvist C, Scheinman MM, Aliot EM, Alpert JS, Calkins H, Camm AJ, Campbell WB, Haines DE, Kuck KH, Lerman BB, Miller DD, Shaeffer CW, Stevenson WG, Tomaselli GF, Antman EM, Smith SC Jr, Alpert JS, Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Hiratzka LF, Hunt SA, Jacobs AK, Russell RO Jr, Priori SG, Blanc JJ, Budaj A, Burgos EF, Cowie M, Deckers JW, Garcia MA, Klein WW, Lekakis J, Lindahl B, Mazzotta G, Morais JC, Oto A, Smiseth O, Trappe HJ; European Society of Cardiology Committee, NASPE-Heart Rhythm Society. Source: Journal of the American College of Cardiology. 2003 October 15; 42(8): 1493-531. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14563598

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ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias). Author(s): Blomstrom-Lundqvist C, Scheinman MM, Aliot EM, Alpert JS, Calkins H, Camm AJ, Campbell WB, Haines DE, Kuck KH, Lerman BB, Miller DD, Shaeffer CW Jr, Stevenson WG, Tomaselli GF, Antman EM, Smith SC Jr, Alpert JS, Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Hiratzka LF, Hunt SA, Jacobs AK, Russell RO Jr, Priori SG, Blanc JJ, Budaj A, Burgos EF, Cowie M, Deckers JW, Garcia MA, Klein WW, Lekakis J, Lindahl B, Mazzotta G, Morais JC, Oto A, Smiseth O, Trappe HJ; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines. Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias. Source: Circulation. 2003 October 14; 108(15): 1871-909. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14557344

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Acute pulmonary edema after cardioversion of cardiac arrhythmias. Author(s): Gowda RM, Misra D, Khan IA, Schweitzer P. Source: International Journal of Cardiology. 2003 December; 92(2-3): 271-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14659864

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Advances in ablation therapy for complex arrhythmias: atrial fibrillation and ventricular tachycardia. Author(s): Lin D, Marchlinski FE. Source: Current Cardiology Reports. 2003 September; 5(5): 407-14. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12917057

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Advances in the acute pharmacologic management of cardiac arrhythmias. Author(s): Sarkozy A, Dorian P. Source: Current Cardiology Reports. 2003 September; 5(5): 387-94. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12917054

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Age-related changes in arrhythmias and electrophysiologic properties. Author(s): Brembilla-Perrot B. Source: Cardiac Electrophysiology Review. 2003 January; 7(1): 88-91. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766527

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Amiodarone for cardiac arrhythmias. Key management issues for NPs. Author(s): McLemore R. Source: Adv Nurse Pract. 2001 April; 9(4): 69-71. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12420439

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An illustration of how physicians continue to interpret electrocardiographic artifacts as arrhythmias. Author(s): Bjerregaard P. Source: Pacing and Clinical Electrophysiology : Pace. 2002 July; 25(7): 1149; Author Reply 1149-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12164462

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Arrhythmias and ischemia-like ECG changes in Reye's syndrome. Author(s): Sarti A, Cecchi F, Manetti A, Busoni P. Source: Intensive Care Medicine. 1996 January; 22(1): 62-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8857440

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Arrhythmias during acute and chronic exercise in chronic heart failure. Author(s): Belardinelli R. Source: International Journal of Cardiology. 2003 August; 90(2-3): 213-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12957754

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Arrhythmias in off-pump coronary artery bypass grafting and the antiarrhythmic effect of regional ischemic preconditioning. Author(s): Wu ZK, Iivainen T, Pehkonen E, Laurikka J, Tarkka MR. Source: Journal of Cardiothoracic and Vascular Anesthesia. 2003 August; 17(4): 459-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12968233

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Arrhythmias in the intensive care patient. Author(s): Trappe HJ, Brandts B, Weismueller P. Source: Current Opinion in Critical Care. 2003 October; 9(5): 345-55. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14508146

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Atrial arrhythmias in congenital heart disease. Author(s): Balaji S, Harris L. Source: Cardiology Clinics. 2002 August; 20(3): 459-68, Vii. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12371013

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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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Autoantibodies produced against sarcolemmal Na-K-ATPase: possible upstream targets of arrhythmias and sudden death in patients with dilated cardiomyopathy. Author(s): Baba A, Yoshikawa T, Ogawa S. Source: Journal of the American College of Cardiology. 2002 September 18; 40(6): 1153-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12354443

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Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials. Author(s): La Rovere MT, Pinna GD, Hohnloser SH, Marcus FI, Mortara A, Nohara R, Bigger JT Jr, Camm AJ, Schwartz PJ; ATRAMI Investigators. Autonomic Tone and Reflexes After Myocardial Infarcton. Source: Circulation. 2001 April 24; 103(16): 2072-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11319197

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Baseline factors predicting early resumption of driving after life-threatening arrhythmias in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. Author(s): Hickey K, Curtis AB, Lancaster S, Larsen G, Warwick D, McAnulty J, Mitchell LB. Source: American Heart Journal. 2001 July; 142(1): 99-104. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11431664

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Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Author(s): Kleber AG, Rudy Y. Source: Physiological Reviews. 2004 April; 84(2): 431-88. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15044680

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Basic mechanisms of reentrant arrhythmias. Author(s): Antzelevitch C. Source: Current Opinion in Cardiology. 2001 January; 16(1): 1-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11124712

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Bedside pacetermination of arrhythmias using an explanted automatic defibrillator. Author(s): Singleton CB, Kuchar DL, Thorburn CW. Source: Aust N Z J Med. 1999 December; 29(6): 811-3. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10677126

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Behaviour of the adrenergic cardiovascular drive in atrial fibrillation and cardiac arrhythmias. Author(s): Grassi G, Seravalle G, Bertinieri G, Mancia G. Source: Acta Physiologica Scandinavica. 2003 March; 177(3): 399-404. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12609012

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Benzonatate overdose associated with seizures and arrhythmias. Author(s): Crouch BI, Knick KA, Crouch DJ, Matsumura KS, Rollins DE. Source: Journal of Toxicology. Clinical Toxicology. 1998; 36(7): 713-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9865240

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Beta blockade, ventricular arrhythmias, and sudden cardiac death. Author(s): Kennedy HL. Source: The American Journal of Cardiology. 1997 November 13; 80(9B): 29J-34J. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9375947

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Beta-adrenergic blocker withdrawal confounds the benefits of epidural analgesia with sympathectomy on supraventricular arrhythmias after cardiac surgery. Author(s): Amar D. Source: Anesthesia and Analgesia. 2002 October; 95(4): 1119, Author Reply 1119. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12351309

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Beta-blockers and ventricular arrhythmias in dilated cardiomyopathy. Author(s): Fauchier L, Giraudeau B. Source: Journal of the American College of Cardiology. 2000 June; 35(7): 1993-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10841254

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beta-blockers for atrial fibrillation: must we consider asymptomatic arrhythmias? Author(s): Page RL. Source: Journal of the American College of Cardiology. 2000 July; 36(1): 147-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10898426

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Beta-blockers for ventricular arrhythmias: have we underestimated their value? Author(s): Campbell TJ. Source: Aust N Z J Med. 1996 October; 26(5): 689-96. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8958366

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Beta-blockers, ventricular arrhythmias, and sudden death in heart failure: not as simple as it seems. Author(s): Mcmurray J. Source: European Heart Journal. 2000 August; 21(15): 1214-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10924310

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Beta-blocking agents vs. antiarrhythmic interventions in heart failure complicated by arrhythmias. Author(s): Meinertz T, Hofmann T, Zehender M, Drexler H, Hohnloser S, Just H. Source: Journal of Cardiovascular Pharmacology. 1990; 16 Suppl 5: S151-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11527120

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Beyond Fontan conversion: Surgical therapy of arrhythmias including patients with associated complex congenital heart disease. Author(s): Deal BJ, Mavroudis C, Backer CL. Source: The Annals of Thoracic Surgery. 2003 August; 76(2): 542-53; Discussion 553-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12902101

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Bi-atrial mapping of atrial arrhythmias. Author(s): Lemery R. Source: Cardiac Electrophysiology Review. 2002 December; 6(4): 378-82. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12438816

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Body surface mapping of atrial arrhythmias: atlas of paced P wave integral maps to localize the focal origin of right atrial tachycardia. Author(s): SippensGroenewegen A, Roithinger FX, Peeters HA, Linnenbank AC, van Hemel NM, Steiner PR, Lesh MD. Source: Journal of Electrocardiology. 1998; 31 Suppl: 85-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9988010

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Brief history of cardiac arrhythmias since the end of the nineteenth century: part I. Author(s): Surawicz B. Source: Journal of Cardiovascular Electrophysiology. 2003 December; 14(12): 1365-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678115

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Brief history of cardiac arrhythmias since the end of the nineteenth century: part II. Author(s): Surawicz B. Source: Journal of Cardiovascular Electrophysiology. 2004 January; 15(1): 101-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15028083

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Bronchoscopy related cardiac arrhythmias. Author(s): Khan GQ, Hassan G. Source: J Assoc Physicians India. 2002 February; 50: 286-7. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12038672

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Calcium and cardiac arrhythmias: DADs, EADs, and alternans. Author(s): Clusin WT. Source: Critical Reviews in Clinical Laboratory Sciences. 2003 June; 40(3): 337-75. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12892319

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Calmodulin kinase II and arrhythmias in a mouse model of cardiac hypertrophy. Author(s): Wu Y, Temple J, Zhang R, Dzhura I, Zhang W, Trimble R, Roden DM, Passier R, Olson EN, Colbran RJ, Anderson ME. Source: Circulation. 2002 September 3; 106(10): 1288-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12208807

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Cardiac arrhythmias after laparoscopic banding. Author(s): Reijnen MM, Janssen IM. Source: Obesity Surgery : the Official Journal of the American Society for Bariatric Surgery and of the Obesity Surgery Society of Australia and New Zealand. 2004 January; 14(1): 139-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14980051

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Cardiac arrhythmias and implantable devices. Author(s): Hayes DL. Source: Journal of the American College of Cardiology. 2003 July 16; 42(2): 392-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12875787

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Cardiac arrhythmias in aluminium phosphide poisoning studied by on continuous holter and cardioscopic monitoring. Author(s): Siwach SB, Singh H, Jagdish, Katyal VK, Bhardwaj G. Source: J Assoc Physicians India. 1998 July; 46(7): 598-601. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12152839

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Cardiac arrhythmias in cardiothoracic surgery. Author(s): Conti VR, Ware DL. Source: Chest Surg Clin N Am. 2002 May; 12(2): 439-60, Viii. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12122833

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Cardiopulmonary resuscitation. Detecting cardiac arrhythmias in cardiac arrest. Author(s): Jevon P. Source: Nurs Times. 2002 May 21-27; 98(21): 45-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12168444

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Catheter ablation for cardiac arrhythmias. Author(s): Lickfett L, Calkins H. Source: Minerva Cardioangiol. 2002 June; 50(3): 189-207. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12107400

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Catheter ablation of supraventricular arrhythmias: state of the art. Author(s): Morady F. Source: Journal of Cardiovascular Electrophysiology. 2004 January; 15(1): 124-39. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15028093

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Catheter ablation of supraventricular arrhythmias: state of the art. Author(s): Morady F. Source: Pacing and Clinical Electrophysiology : Pace. 2004 January; 27(1): 125-42. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14720171

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Characteristics of patients with ventricular arrhythmias induced with exercise testing. Author(s): Mayordomo J, Batalla A. Source: International Journal of Cardiology. 2002 June; 83(3): 299-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12036543

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Chronobiology of arrhythmias: interesting curiosity or important clue to pathophysiology? Author(s): Peters RW, Gold MR. Source: Journal of Cardiovascular Electrophysiology. 2002 October; 13(10): 1015-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12435188

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Circadian and seasonal variation of malignant arrhythmias in a pediatric and congenital heart disease population. Author(s): Stephenson EA, Collins KK, Dubin AM, Epstein MR, Hamilton RM, Kertesz NJ, Alexander ME, Cecchin F, Triedman JK, Walsh EP, Berul CI. Source: Journal of Cardiovascular Electrophysiology. 2002 October; 13(10): 1009-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12435187

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Clinical relevance of arrhythmias during sleep: guidance for clinicians. Author(s): Gula LJ, Krahn AD, Skanes AC, Yee R, Klein GJ. Source: Heart (British Cardiac Society). 2004 March; 90(3): 347-52. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14966068

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Clinical review of radiofrequency catheter ablation for cardiac arrhythmias. Author(s): Yee R, Connolly S, Noorani H. Source: The Canadian Journal of Cardiology. 2003 October; 19(11): 1273-84. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14571312

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Common cardiac arrhythmias. Author(s): Hand H. Source: Emergency Nurse : the Journal of the Rcn Accident and Emergency Nursing Association. 2002 June; 10(3): 29-38. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12078453

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Common electrocardiographic artifacts mimicking arrhythmias in ambulatory monitoring. Author(s): Marquez MF, Colin L, Guevara M, Iturralde P, Hermosillo AG. Source: American Heart Journal. 2002 August; 144(2): 187-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12177632

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Conduction delay within the coronary sinus in humans: implications for atrial arrhythmias. Author(s): Katritsis D, Ioannidis JP, Giazitzoglou E, Korovesis S, Anagnostopoulos CE, Camm AJ. Source: Journal of Cardiovascular Electrophysiology. 2002 September; 13(9): 859-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12380921

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Cryoablation of atrial arrhythmias. Author(s): Skanes AC, Yee R, Krahn AD, Klein GJ. Source: Cardiac Electrophysiology Review. 2002 December; 6(4): 383-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12438817

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Current and new drugs for the treatment of arrhythmias. Author(s): Auer J, Berent R, Weber T, Lassnig E, Eber B. Source: Curr Opin Investig Drugs. 2002 July; 3(7): 1029-36. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12186263

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Damage induced arrhythmias: mechanisms and implications. Author(s): ter Keurs HE, Zhang YM, Davidoff AW, Boyden PA, Wakayama Y, Miura M. Source: Canadian Journal of Physiology and Pharmacology. 2001 January; 79(1): 73-81. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11201504

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Dangerous ventricular arrhythmias--can we predict drug efficacy? Author(s): Ward DE, Camm AJ. Source: The New England Journal of Medicine. 1993 August 12; 329(7): 498-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8332156

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Defects in cardiac conduction system lineages and malignant arrhythmias: developmental pathways and disease. Author(s): St Amand TR, Lu JT, Chien KR. Source: Novartis Found Symp. 2003; 250: 260-70; Discussion 271-5, 276-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12956335

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Demise of the routine electrophysiologic study for survivors of life-threatening ventricular arrhythmias. Author(s): Curtis AB. Source: American Heart Journal. 2002 September; 144(3): 380-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12228772

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Dental management of the patient with cardiac arrhythmias: an update. Author(s): Rhodus NL, Little JW. Source: Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 2003 December; 96(6): 659-68. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14676755

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Destabilizing effects of mental stress on ventricular arrhythmias in patients with implantable cardioverter-defibrillators. Author(s): Lampert R, Jain D, Burg MM, Batsford WP, McPherson CA. Source: Circulation. 2000 January 18; 101(2): 158-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10637203

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Detecting and diagnosing arrhythmias in adults with congenital heart disease. Author(s): Collins KK, Dubin AM. Source: Current Cardiology Reports. 2003 July; 5(4): 331-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12801455

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Detection of the fingerprint of the electrophysiological abnormalities that increase vulnerability to life-threatening ventricular arrhythmias. Author(s): Cain ME, Arthur RM, Trobaugh JW. Source: Journal of Interventional Cardiac Electrophysiology : an International Journal of Arrhythmias and Pacing. 2003 October; 9(2): 103-18. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14574021

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Device therapy for cardiac arrhythmias. Author(s): Kusumoto FM, Goldschlager N. Source: Jama : the Journal of the American Medical Association. 2002 April 10; 287(14): 1848-52. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11939871

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Devices for the management of ventricular arrhythmias in cardiac failure. Author(s): Cooklin M. Source: Heart Failure Reviews. 2002 July; 7(3): 301-10. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12215734

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Differences in heart rate turbulence between patients with coronary artery disease and patients with ventricular arrhythmias but structurally normal hearts. Author(s): Sestito A, Valsecchi S, Infusino F, Sgueglia GA, Bellocci F, Zecchi P, Crea F, Lanza GA. Source: The American Journal of Cardiology. 2004 May 1; 93(9): 1114-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15110202

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Differential profile and biochemical effects of antiautonomic membrane receptor antibodies in ventricular arrhythmias and sinus node dysfunction. Author(s): Chiale PA, Ferrari I, Mahler E, Vallazza MA, Elizari MV, Rosenbaum MB, Levin MJ. Source: Circulation. 2001 April 3; 103(13): 1765-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11282908

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Digoxin in heart failure and cardiac arrhythmias. Author(s): Campbell TJ, MacDonald PS. Source: The Medical Journal of Australia. 2003 July 21; 179(2): 98-102. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12864722

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Do defects in ion channel glycosylation set the stage for lethal cardiac arrhythmias? Author(s): Fozzard HA, Kyle JW. Source: Science's Stke [electronic Resource] : Signal Transduction Knowledge Environment. 2002 April 30; 2002(130): Pe19. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11983936

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Do we understand the electrophysiologic mechanisms responsible for drug-induced cardiac arrhythmias? Author(s): Vos MA. Source: Journal of Cardiovascular Pharmacology. 2002 November; 40(5): 647-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12409972

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Driving after ventricular arrhythmias. Author(s): Smith TW. Source: The New England Journal of Medicine. 2001 August 9; 345(6): 451-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11496857

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Driving and arrhythmias. Author(s): Binns H, Camm J. Source: Bmj (Clinical Research Ed.). 2002 April 20; 324(7343): 927-8. Erratum In: Bmj 2002 June 29; 324(7353): 1555. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11964323

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Driving and arrhythmias: implications of new data. Author(s): Bleakley JF, Akiyama T; Canadian Cardiovascular Society; American Heart Association; North American Society of Pacing and Electrophysiology (NASPE); European Society of Cardiology. Source: Cardiac Electrophysiology Review. 2003 January; 7(1): 77-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766524

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Drug block of I(kr): model systems and relevance to human arrhythmias. Author(s): Yang T, Snyders D, Roden DM. Source: Journal of Cardiovascular Pharmacology. 2001 November; 38(5): 737-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11602820

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Drug therapy versus implantation of a cardiac defibrillator for the treatment of malignant arrhythmias in left ventricular dysfunction. Author(s): Mannino MM, Mehta D, Langan NM, Gomes JA. Source: American Heart Journal. 1996 June; 131(6): 1251-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8644621

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Early and late arrhythmias in patients in preoperative sinus rhythm submitted to mitral valve surgery through the superior septal approach. Author(s): Gaudino M, Nasso G, Minati A, Salica A, Luciani N, Morelli M, Possati G. Source: The Annals of Thoracic Surgery. 2003 April; 75(4): 1181-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12683559

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Early postoperative arrhythmias after cardiac operation in children. Author(s): Valsangiacomo E, Schmid ER, Schupbach RW, Schmidlin D, Molinari L, Waldvogel K, Bauersfeld U. Source: The Annals of Thoracic Surgery. 2002 September; 74(3): 792-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12238841

Studies

83

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ECG predictors of ventricular arrhythmias and biventricular size and wall mass in tetralogy of Fallot with pulmonary regurgitation. Author(s): Helbing WA, Roest AA, Niezen RA, Vliegen HW, Hazekamp MG, Ottenkamp J, de Roos A, van der Wall EE. Source: Heart (British Cardiac Society). 2002 November; 88(5): 515-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12381647

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Effect of oral sotalol on systemic hemodynamics and programmed electrical stimulation in patients with ventricular arrhythmias and structural heart disease. Author(s): Winters SL, Kukin M, Pe E, Stewart D, Deitchman D, Gomes JA. Source: The American Journal of Cardiology. 1993 August 12; 72(4): 38A-43A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8346725

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Effect of regional differences in cardiac cellular electrophysiology on the stability of ventricular arrhythmias: a computational study. Author(s): Clayton RH, Holden AV. Source: Physics in Medicine and Biology. 2003 January 7; 48(1): 95-111. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12564503

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Effect of sotalol on heart rate variability assessed by Holter monitoring in patients with ventricular arrhythmias. Author(s): Hohnloser SH, Klingenheben T, Zabel M, Just H. Source: The American Journal of Cardiology. 1993 August 12; 72(4): 67A-71A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8346729

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Effects of different steroid treatment on reperfusion-associated production of reactive oxygen species and arrhythmias during coronary surgery. Author(s): Volk T, Schmutzler M, Engelhardt L, Pantke U, Laule M, Stangl K, Grune T, Wernecke KD, Konertz W, Kox WJ. Source: Acta Anaesthesiologica Scandinavica. 2003 July; 47(6): 667-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12803583

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Effects of sildenafil (viagra) on human myocardial contractility, in vitro arrhythmias, and tension of internal mammaria arteries and saphenous veins. Author(s): Cremers B, Scheler M, Maack C, Wendler O, Schafers HJ, Sudkamp M, Bohm M. Source: Journal of Cardiovascular Pharmacology. 2003 May; 41(5): 734-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12717104

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Effects of sildenafil citrate (Viagra) on hemodynamic parameters during exercise testing and occurrence of ventricular arrhythmias in patients with erectile dysfunction and cardiovascular disease. Author(s): Vardi Y, Bulus M, Reisner S, Nassar S, Aboud L, Sprecher E, Gruenwald I. Source: European Urology. 2003 May; 43(5): 544-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12706001

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Effects of sulfonylurea hypoglycemic agents and adenosine triphosphate dependent potassium channel antagonists on ventricular arrhythmias in patients with decompensated heart failure. Author(s): Aronson D, Mittleman MA, Burger AJ. Source: Pacing and Clinical Electrophysiology : Pace. 2003 May; 26(5): 1254-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12765455

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Efficacy of a tiered therapy defibrillator system used to treat recurrent ventricular arrhythmias refractory to drugs. Author(s): Rankin AC, Zaim S, Powell A, Zaim B, Brooks R, McGovern BA, Garan H, Ruskin JN. Source: British Heart Journal. 1993 July; 70(1): 61-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8038001

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Electrical therapy of ventricular arrhythmias: the surgeon's approach. Author(s): Foster AH. Source: The Annals of Thoracic Surgery. 1993 August; 56(2): 206-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8346998

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Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagulation at the time of cardioversion. Author(s): Gallagher MM, Hennessy BJ, Edvardsson N, Hart CM, Shannon MS, Obel OA, Al-Saady NM, Camm AJ. Source: Journal of the American College of Cardiology. 2002 September 4; 40(5): 926-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12225717

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Ethnicity and arrhythmias. Author(s): Freestone B, Lip GY. Source: Cardiac Electrophysiology Review. 2003 January; 7(1): 92-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766528

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Evaluation of a dual chamber implantable cardioverter defibrillator for the treatment of atrial and ventricular arrhythmias. Author(s): Boriani G, Wollmann C, Biffi M, Kuhl M, Schuchert A, Sperzel J, Stiller S, Gasparini G, Bocker D. Source: Pacing and Clinical Electrophysiology : Pace. 2003 January; 26(1 Pt 2): 461-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12687868

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Every man and woman's guide to cardiac arrhythmias: what should Mr. & Ms. John Q Public know? Author(s): Saksena S. Source: Journal of Interventional Cardiac Electrophysiology : an International Journal of Arrhythmias and Pacing. 2002 October; 7(2): 125. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12397221

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Excellent survival and low incidence of arrhythmias, stroke and heart failure longterm after surgical ASD closure at young age. A prospective follow-up study of 21-33 years. Author(s): Roos-Hesselink JW, Meijboom FJ, Spitaels SE, van Domburg R, van Rijen EH, Utens EM, Bogers AJ, Simoons ML. Source: European Heart Journal. 2003 January; 24(2): 190-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12573276

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Exercise testing and training of patients with malignant ventricular arrhythmias. Author(s): Kelly TM. Source: Medicine and Science in Sports and Exercise. 1996 January; 28(1): 53-61. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8775355

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Exercise-induced ventricular arrhythmias in congestive heart failure and role of ACE inhibitors. Author(s): Hasija PK, Karloopia SD, Shahi BN, Chauhan SS. Source: J Assoc Physicians India. 1998 February; 46(2): 189-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11273109

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Exercise-induced ventricular arrhythmias in patients with healed myocardial infarction. Author(s): Casella G, Pavesi PC, Sangiorgio P, Rubboli A, Bracchetti D. Source: International Journal of Cardiology. 1993 July 15; 40(3): 229-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8225658

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Familial dilated cardiomyopathy and spontaneous ventricular arrhythmias. Author(s): Jordaens L, de Pauw M, Caes F. Source: The American Journal of Cardiology. 1996 September 12; 78(5A): 102-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8820844

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Familial effort polymorphic ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy map to chromosome 1q42-43. Author(s): Bauce B, Nava A, Rampazzo A, Daliento L, Muriago M, Basso C, Thiene G, Danieli GA. Source: The American Journal of Cardiology. 2000 March 1; 85(5): 573-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11078270

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Familial polymorphic ventricular arrhythmias: a quarter century of successful medical treatment based on serial exercise-pharmacologic testing. Author(s): Fisher JD, Krikler D, Hallidie-Smith KA. Source: Journal of the American College of Cardiology. 1999 December; 34(7): 2015-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10588218

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Favourable outcome in idiopathic ventricular fibrillation with treatment aimed at prevention of high sympathetic tone and suppression of inducible arrhythmias. Author(s): Crijns HJ, Wiesfeld AC, Posma JL, Lie KI. Source: British Heart Journal. 1995 October; 74(4): 408-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7488456

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Feasibility of spinal cord stimulation in angina pectoris in patients with chronic pacemaker treatment for cardiac arrhythmias. Author(s): Ekre O, Borjesson M, Edvardsson N, Eliasson T, Mannheimer C. Source: Pacing and Clinical Electrophysiology : Pace. 2003 November; 26(11): 2134-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14622316

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Female gender as a risk factor for drug-induced cardiac arrhythmias: evaluation of clinical and experimental evidence. Author(s): Ebert SN, Liu XK, Woosley RL. Source: Journal of Women's Health / the Official Publication of the Society for the Advancement of Women's Health Research. 1998 June; 7(5): 547-57. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9650155

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Fetal and neonatal arrhythmias. Author(s): Tanel RE, Rhodes LA. Source: Clin Perinatol. 2001 March; 28(1): 187-207, Vii. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11265506

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Fetal arrhythmias, pediatric arrhythmias, and pediatric electrophysiology. Author(s): Perry JC. Source: Current Opinion in Cardiology. 1995 January; 10(1): 52-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7787265

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Fetal arrhythmias. Author(s): Meijboom EJ, van Engelen AD, van de Beek EW, Weijtens O, Lautenschutz JM, Benatar AA. Source: Current Opinion in Cardiology. 1994 January; 9(1): 97-102. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8199375

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Fetal arrhythmias: intrauterine diagnosis, treatment and prognosis. Author(s): Maeno Y, Kiyomatsu Y, Rikitake N, Toyoda O, Miyake T, Akagi T, Ishii M, Kawano T, Kazue T, Ishimatu J, et al. Source: Acta Paediatr Jpn. 1995 August; 37(4): 431-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7572141

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Fetal cardiac arrhythmias: diagnosis and management. Author(s): Feit LR. Source: Medicine and Health, Rhode Island. 2001 May; 84(5): 161-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11392955

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Five-year experience with radiofrequency catheter ablation: implications for management of arrhythmias in pediatric and young adult patients. Author(s): Tanel RE, Walsh EP, Triedman JK, Epstein MR, Bergau DM, Saul JP. Source: The Journal of Pediatrics. 1997 December; 131(6): 878-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9427894

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Fluctuation in autonomic tone is a major determinant of sustained atrial arrhythmias in patients with focal ectopy originating from the pulmonary veins. Author(s): Zimmermann M, Kalusche D. Source: Journal of Cardiovascular Electrophysiology. 2001 March; 12(3): 285-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11294170

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Fractal dimension predicts arrhythmia recurrence in patients being treated for lifethreatening ventricular arrhythmias. ESVEM Investigators. Author(s): Karagounis LA, Stein KM, Bair T, Albright D, Anderson JL. Source: Journal of Electrocardiology. 1995; 28 Suppl: 71-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8656133

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Free radicals and cardiac arrhythmias following coronary surgery: actors of the drama or bystanders of the spectacle? Author(s): Marczin N, El-Habashi N, Royston D. Source: Acta Anaesthesiologica Scandinavica. 2003 July; 47(6): 639-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12803579

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Frequency of predischarge ventricular arrhythmias in postmyocardial infarction patients depends on residual left ventricular pump performance and is independent of the occurrence of acute reperfusion. The GISSI-2 Investigators. Author(s): Marino P, Nidasio G, Golia G, Franzosi MG, Maggioni AP, Santoro E, Santoro L, Zardini P. Source: Journal of the American College of Cardiology. 1994 February; 23(2): 290-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7507504

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Full-disclosure monitoring: a concept that will change the way arrhythmias are detected and interpreted in the hospitalized patient. Author(s): Kotar SL, Gessler JE. Source: Heart & Lung : the Journal of Critical Care. 1993 November-December; 22(6): 482-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8288450

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Functional and prognostic significance of exercise-induced ventricular arrhythmias in patients with suspected coronary artery disease. Author(s): Elhendy A, Chandrasekaran K, Gersh BJ, Mahoney D, Burger KN, Pellikka PA. Source: The American Journal of Cardiology. 2002 July 15; 90(2): 95-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12106835

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Future of device therapy for arrhythmias. Author(s): Wellens HJ. Source: Journal of Cardiovascular Electrophysiology. 2002 January; 13(1 Suppl): S122-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11852888

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Gender and cardiac arrhythmias. Author(s): Villareal RP, Woodruff AL, Massumi A. Source: Texas Heart Institute Journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital. 2001; 28(4): 265-75. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11777151

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Gender differences in arrhythmias. Author(s): Wolbrette D, Naccarelli G, Curtis A, Lehmann M, Kadish A. Source: Clin Cardiol. 2002 February; 25(2): 49-56. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11841151

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Gender differences in manifestation of cardiac arrhythmias. Author(s): Sexton E, Wyse DG. Source: Cardiology in Review. 1999 November-December; 7(6): 362-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11208249

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Gene polymorphisms and cardiac arrhythmias. Author(s): Firouzi M, Groenewegen WA. 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 July; 5(3): 235-42. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12842634

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Gene symbol: RYR2. Disease: Effort-induced polymorphic ventricular arrhythmias. Author(s): Bagattin A, Bauce B, Rampazzo A, Tiso N, Nava A, Danieli GA. Source: Human Genetics. 2004 March; 114(4): 406. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15046079

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Gene symbol: RYR2. Disease: Effort-induced polymorphic ventricular arrhythmias. Author(s): Bagattin A, Veronese C, Rampazzo A, Danieli GA. Source: Human Genetics. 2004 March; 114(4): 405. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15046073

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Gene symbol: RYR2. Disease: Effort-induced polymorphic ventricular arrhythmias. Author(s): Bagattin A, Veronese C, Rampazzo A, Danieli GA. Source: Human Genetics. 2004 March; 114(4): 404. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15046072

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Gene symbol: RYR2. Disease: Effort-induced polymorphic ventricular arrhythmias. Author(s): Veronese C, Bagattin A, Rampazzo A, Danieli GA. Source: Human Genetics. 2004 March; 114(4): 404. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15046070

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Gene symbol: RYR2. Disease: Effort-induced polymorphic ventricular arrhythmias. Author(s): Veronese C, Bagattin A, Rampazzo A, Danieli GA. Source: Human Genetics. 2004 March; 114(4): 405. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15046067

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Gene therapy for cardiac arrhythmias. Author(s): Marban E, Nuss HB, Donahue JK. Source: Cold Spring Harb Symp Quant Biol. 2002; 67: 527-31. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12858579

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Genetic aspects of arrhythmias. Author(s): Roberts R, Brugada R. Source: American Journal of Medical Genetics. 2000 Winter; 97(4): 310-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11376443

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Genetic basis for the origin of cardiac arrhythmias: implications for therapy. Author(s): Mbai M, Rajamani S, Delisle BP, Anson BD, Anderson C, Makielski JC, January CT. Source: Current Cardiology Reports. 2002 September; 4(5): 411-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12169238

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Genetic modifiers of cardiac arrhythmias. Author(s): Cheng CF, Kuo HC, Chien KR. Source: Trends in Molecular Medicine. 2003 February; 9(2): 59-66. Review. Erratum In: Trends Mol Med. 2003 October; 9(10): 413. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12615039

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Genetics and arrhythmias. Author(s): Roberts R, Brugada R. Source: Annual Review of Medicine. 2003; 54: 257-67. Epub 2002 August 19. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12525675

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Genetics and cardiac arrhythmias. Author(s): Towbin JA, Vatta M, Li H, Bowles NE. Source: Adv Pediatr. 2002; 49: 87-129. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12214781

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Genetics of familial cardiomyopathies and arrhythmias. Author(s): Keller DI, Carrier L, Schwartz K. Source: Swiss Medical Weekly : Official Journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology. 2002 July 27; 132(29-30): 401-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12428185

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Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Author(s): Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, Denjoy I, Guicheney P, Breithardt G, Keating MT, Towbin JA, Beggs AH, Brink P, Wilde AA, Toivonen L, Zareba W, Robinson JL, Timothy KW, Corfield V, Wattanasirichaigoon D, Corbett C, Haverkamp W, Schulze-Bahr E, Lehmann MH, Schwartz K, Coumel P, Bloise R. Source: Circulation. 2001 January 2; 103(1): 89-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11136691

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Geophysical variables and behavior: CIII. Days with sudden infant deaths and cardiac arrhythmias in adults share a factor with PC1 geomagnetic pulsations: implications for pursuing mechanism. Author(s): Persinger MA, O'Connor RP. Source: Percept Mot Skills. 2001 June; 92(3 Pt 1): 653-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11453188

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Giant cell myocarditis presenting as rapidly progressive congestive heart failure complicated by ventricular arrhythmias. Author(s): Greer RW, Taggart MW, Sartin BW, Angelica NJ, Johnson GM, Pappas ND, Newman WP 3rd, Glancy DL. Source: J La State Med Soc. 2003 July-August; 155(4): 198-202; Quiz 202. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14506826

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Guidelines for the use of flecainide in patients with supraventricular arrhythmias. Author(s): Smith W, Crozier I, McAlister H, O'Meeghan T, Stewart F. Source: N Z Med J. 2000 October 13; 113(1119): 420-1. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11127360

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Health-related quality-of-life assessment of patients with life-threatening ventricular arrhythmias. Author(s): Herbst JH, Goodman M, Feldstein S, Reilly JM. Source: Pacing and Clinical Electrophysiology : Pace. 1999 June; 22(6 Pt 1): 915-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10392390

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Heart rate variability and occurrence of ventricular arrhythmias during balloon occlusion of a major coronary artery. Author(s): Airaksinen KE, Ylitalo A, Niemela MJ, Tahvanainen KU, Huikuri HV. Source: The American Journal of Cardiology. 1999 April 1; 83(7): 1000-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10190509

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Heart rate variability before sudden blood pressure elevations or complex cardiac arrhythmias in phaeochromocytoma. Author(s): Dabrowska B, Dabrowski A, Pruszczyk P, Skrobowski A, Wocial B. Source: Journal of Human Hypertension. 1996 January; 10(1): 43-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8642190

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Heart rate variability before the onset of ventricular tachycardia: differences between slow and fast arrhythmias. Author(s): Meyerfeldt U, Wessel N, Schutt H, Selbig D, Schumann A, Voss A, Kurths J, Ziehmann C, Dietz R, Schirdewan A. Source: International Journal of Cardiology. 2002 August; 84(2-3): 141-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12127366

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Heart rate variability before ventricular arrhythmias in patients with coronary artery disease and an implantable cardioverter defibrillator. Author(s): Copie X, Lamaison D, Salvador M, Sadoul N, Da Costa A, Fauchier L, Legal F, Le Heuzey JY; VALID Investigators. Source: Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2003 July; 8(3): 179-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14510650

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Heritable arrhythmias, cardiomyopathies, and valvulopathies. Author(s): Thurmon TF. Source: J La State Med Soc. 1997 November; 149(11): 433-48. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9397665

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Hiccup as an electrocardiographic artifact simulating arrhythmias. Author(s): Cheng TO. Source: American Heart Journal. 2003 October; 146(4): E15; Author Reply E16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14564338

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High dose methadone and ventricular arrhythmias: a report of three cases. Author(s): Walker PW, Klein D, Kasza L. Source: Pain. 2003 June; 103(3): 321-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791438

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High dosing methadone and a possible relationship to serious cardia arrhythmias. Author(s): Hays H. Source: Pain Res Manag. 2001 Summer; 6(2): 64. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11873731

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High frequency of arrhythmias after Fontan operation indicates earlier anticoagulant therapy. Author(s): Sugimoto S, Takagi N, Hachiro Y, Abe T. Source: International Journal of Cardiology. 2001 March; 78(1): 33-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11259811

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High intensity anticoagulation for cardioversion of atrial arrhythmias? The shocking truth. Author(s): Olshansky B. Source: Journal of the American College of Cardiology. 2002 September 4; 40(5): 934-6. Erratum In: J Am Coll Cardiol 2002 October 16; 40(8): 1543. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12225718

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High prevalence of arrhythmias in elderly male athletes with a lifelong history of regular strenuous exercise. Author(s): Jensen-Urstad K, Bouvier F, Saltin B, Jensen-Urstad M. Source: Heart (British Cardiac Society). 1998 February; 79(2): 161-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9538309

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High prevalence of right ventricular involvement in endurance athletes with ventricular arrhythmias. Role of an electrophysiologic study in risk stratification. Author(s): Heidbuchel H, Hoogsteen J, Fagard R, Vanhees L, Ector H, Willems R, Van Lierde J. Source: European Heart Journal. 2003 August; 24(16): 1473-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12919770

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Hybrid approach for minimally-invasive operative therapy of arrhythmias. Author(s): Skanes AC, Klein GJ, Guiraudon G, Menkis AH, Jones DL, Krahn AD, Yee R. Source: Journal of Interventional Cardiac Electrophysiology : an International Journal of Arrhythmias and Pacing. 2003 October; 9(2): 289-94. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14574042

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Hyperkinetic ventricular arrhythmias in very elderly people with and without cardiac disease. Correlation with left ventricular echocardiographic parameters. Author(s): Lattanzi F, Paperini L, Reisenhofer B, Lucarini AR, Orsini E, Giaconi S, Levantesi D, Topi A, Paci AM, Squarcini G. Source: Minerva Cardioangiol. 1998 December; 46(12): 479-91. English, Italian. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10209939

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Hypertension and concurrent arrhythmias. Author(s): Lombardi F, Terranova P. Source: Current Pharmaceutical Design. 2003; 9(21): 1703-13. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12871203

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Hypertrophic cardiomyopathy: value of atrial programmed electrical stimulation in patients with or without syncope with special reference to the role of atrial arrhythmias. Author(s): Brembilla-Perrot B, Jacquot A, Beurrier D, Jacquemin L. Source: International Journal of Cardiology. 1997 March; 59(1): 47-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9080025

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Hypoglycemic effect of cibenzoline in patients with abnormal glucose tolerance and frequent ventricular arrhythmias. Author(s): Saikawa T, Arita M, Yamaguchi K, Ito M. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 2000 December; 14(6): 665-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11300368

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Ibutilide for cardioversion of atrial flutter: efficacy of a single dose in recent-onset arrhythmias. Author(s): Ando G, Di Rosa S, Rizzo F, Carerj S, Bramanti O, Giannetto M, Arrigo F. Source: Minerva Cardioangiol. 2004 February; 52(1): 37-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14765036

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Images in cardiovascular medicine. Pulmonary vein stenosis after catheter ablation of atrial arrhythmias. Author(s): Seshadri N, Novaro GM, Prieto L, White RD, Natale A, Grimm RA, Stewart WJ. Source: Circulation. 2002 May 28; 105(21): 2571-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12034667

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Impact of radiofrequency ablation procedures on the management of arrhythmias. Author(s): Lindsay BD. Source: Coronary Artery Disease. 1993 August; 4(8): 745-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8261246

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Implantable cardioverter defibrillator proarrhythmia due to an interaction with "noncompetitive atrial pacing": an algorithm to prevent atrial arrhythmias. Author(s): Cron TA, Schaer B, Osswald S. Source: Pacing and Clinical Electrophysiology : Pace. 2002 November; 25(11): 1656-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12494629

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Implantable cardioverter defibrillator therapy for life-threatening arrhythmias in young patients. Author(s): Stefanelli CB, Bradley DJ, Leroy S, Dick M 2nd, Serwer GA, Fischbach PS. Source: Journal of Interventional Cardiac Electrophysiology : an International Journal of Arrhythmias and Pacing. 2002 July; 6(3): 235-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12154326

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Implantable cardioverter-defibrillators in arrhythmias: a rapid and systematic review of effectiveness. Author(s): Parkes J, Bryant J, Milne R. Source: Heart (British Cardiac Society). 2002 May; 87(5): 438-42. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11997415

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Implantable diagnostic monitoring devices for evaluation of syncope, and tachy- and brady-arrhythmias. Author(s): Benditt DG, Ermis C, Pham S, Hiltner L, Vrudney A, Lurie KG, Sakaguchi S. Source: Journal of Interventional Cardiac Electrophysiology : an International Journal of Arrhythmias and Pacing. 2003 October; 9(2): 137-44. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14574024

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Improvement of left ventricular hypertrophy and arrhythmias after lanreotideinduced GH and IGF-I decrease in acromegaly. A prospective multi-center study. Author(s): Lombardi G, Colao A, Marzullo P, Biondi B, Palmieri E, Fazio S; Multicenter Italian Study Group on Lanreotide. Source: J Endocrinol Invest. 2002 December; 25(11): 971-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12553557

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Incidence and characteristics of maternal cardiac arrhythmias during labor. Author(s): Romem A, Romem Y, Katz M, Battler A. Source: The American Journal of Cardiology. 2004 April 1; 93(7): 931-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15050503

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Incidence and correlates of complex ventricular arrhythmias during dobutamine stress echocardiography after acute myocardial infarction. Author(s): Bigi R, Partesana N, Verzoni A, Bandini P, Maffi M, Longoni A, Occhi G, Fiorentini C. Source: European Heart Journal. 1995 December; 16(12): 1819-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8682013

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Incidence and management of arrhythmias in women. Author(s): Beauregard LA. Source: J Gend Specif Med. 2002 July-August; 5(4): 38-48. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12192885

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Incidence of complete atrioventricular block following attempted radiofrequency catheter modification of the atrioventricular node in 880 patients. Results of the Multicenter European Radiofrequency Survey (MERFS) The Working Group on Arrhythmias of the European Society of Cardiology. Author(s): Hindricks G. Source: European Heart Journal. 1996 January; 17(1): 82-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8682135

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Increased severity of reperfusion arrhythmias in mouse hearts lacking histamine H3receptors. Author(s): Koyama M, Heerdt PM, Levi R. Source: Biochemical and Biophysical Research Communications. 2003 July 4; 306(3): 7926. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12810089

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Indications for antiarrhythmic suppression of ventricular arrhythmias: a definition of life-threatening ventricular arrhythmias. Author(s): Morganroth J. Source: The American Journal of Cardiology. 1993 August 12; 72(4): 3A-7A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8346724

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Influence of early repair of tetralogy of fallot without an outflow patch on late arrhythmias and sudden death: a 27-year follow-up study following a uniform surgical approach. Author(s): Hamada H, Terai M, Jibiki T, Nakamura T, Gatzoulis MA, Niwa K. Source: Cardiology in the Young. 2002 July; 12(4): 345-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12206557

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Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome. Author(s): Clancy CE, Tateyama M, Kass RS. Source: The Journal of Clinical Investigation. 2002 November; 110(9): 1251-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12417563

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International consensus on nomenclature and classification of atrial fibrillation: A collaborative project of the Working Group on Arrhythmias and the Working Group of Cardiac Pacing of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Author(s): Levy S, Camm AJ, Saksena S, Aliot E, Breithardt G, Crijns HJ, Davies DW, Kay GN, Prystowsky EN, Sutton R, Waldo AL, Wyse DG; Working Group on Arrhythmias of European Society of Cardiology; Working Group of Cardiac Pacing of European Society of Cardiology; North American Society of Pacing and Electrophysiology. Source: Journal of Cardiovascular Electrophysiology. 2003 April; 14(4): 443-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12741724

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International consensus on nomenclature and classification of atrial fibrillation; a collaborative project of the Working Group on Arrhythmias and the Working Group on Cardiac Pacing of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Author(s): Levy S, Camm AJ, Saksena S, Aliot E, Breithardt G, Crijns H, Davies W, Kay N, Prystowsky E, Sutton R, Waldo A, Wyse DG; Working Group on Arrhythmias, Working Group on Cardiac Pacing of the European Society of Cardiology, North American Society of Pacing and Electrophysiology. 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 April; 5(2): 119-22. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12633634

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Is obstructive sleep apnea (OSA) a risk factor for myocardial infarction and cardiac arrhythmias in patients with coronary heart disease (CHD)? Author(s): Koehler U, Schafer H. Source: Sleep. 1996 May; 19(4): 283-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8776784

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Ischemic modulation of vulnerable period and the effects of pharmacological treatment of ischemia-induced arrhythmias: a simulation study. Author(s): Cimponeriu A, Starmer CF, Bezerianos A. Source: Ieee Transactions on Bio-Medical Engineering. 2003 February; 50(2): 168-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12665030

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Junctional arrhythmias. Author(s): Fisch C. Source: Cardiology in Review. 2000 March-April; 8(2): 78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11174876

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KATP channel openers, myocardial ischemia, and arrhythmias--should the electrophysiologist worry? Author(s): Remme CA, Wilde AA. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 2000 February; 14(1): 17-22. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10755196

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KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death. Author(s): Chen S, Zhang L, Bryant RM, Vincent GM, Flippin M, Lee JC, Brown E, Zimmerman F, Rozich R, Szafranski P, Oberti C, Sterba R, Marangi D, Tchou PJ, Chung MK, Wang Q. Source: Clinical Genetics. 2003 April; 63(4): 273-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12702160

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KvLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias. Author(s): Yang WP, Levesque PC, Little WA, Conder ML, Shalaby FY, Blanar MA. Source: Proceedings of the National Academy of Sciences of the United States of America. 1997 April 15; 94(8): 4017-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9108097

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Left ventricular remodeling and ventricular arrhythmias after myocardial infarction. Author(s): St John Sutton M, Lee D, Rouleau JL, Goldman S, Plappert T, Braunwald E, Pfeffer MA. Source: Circulation. 2003 May 27; 107(20): 2577-82. Epub 2003 May 05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12732606

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Lethal ventricular arrhythmias following one-step pacemaker reprogramming for rapid tracking of atrial tachyarrhythmias. Author(s): Pinski SL, Murphy J, Haw J, Trohman RG. Source: The American Journal of Cardiology. 2001 February 1; 87(3): 349-50, A9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11165977

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Leucine/isoleucine zipper coordination of ion channel macromolecular signaling complexes in the heart. Roles in inherited arrhythmias. Author(s): Kass RS, Kurokawa J, Marx SO, Marks AR. Source: Trends in Cardiovascular Medicine. 2003 February; 13(2): 52-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12586439

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Life threatening ventricular arrhythmias with transient or correctable causes. Author(s): Veenhuyzen GD, Wyse DG. Source: Minerva Cardioangiol. 2003 June; 51(3): 275-86. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12867879

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Life-threatening ventricular arrhythmias due to transient or correctable causes: high risk for death in follow-up. Author(s): Wyse DG, Friedman PL, Brodsky MA, Beckman KJ, Carlson MD, Curtis AB, Hallstrom AP, Raitt MH, Wilkoff BL, Greene HL; AVID Investigators. Source: Journal of the American College of Cardiology. 2001 November 15; 38(6): 171824. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11704386

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Localization of the origin of arrhythmias for ablation: from Electrocardiography to advanced endocardial mapping systems. Author(s): Darbar D, Olgin JE, Miller JM, Friedman PA. Source: Journal of Cardiovascular Electrophysiology. 2001 November; 12(11): 1309-25. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11761423

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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 arrhythmias in patients with myotonic dystrophy treated by pacing: a multicenter diagnostic pacemaker study. Author(s): Lazarus A, Varin J, Babuty D, Anselme F, Coste J, Duboc D. Source: Journal of the American College of Cardiology. 2002 November 6; 40(9): 1645-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12427418

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

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Long-term outcome in fetuses with cardiac arrhythmias. Author(s): Boldt T, Eronen M, Andersson S. Source: Obstetrics and Gynecology. 2003 December; 102(6): 1372-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14662229

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Long-term prognostic significance of complex ventricular arrhythmias induced during dobutamine stress echocardiography. Author(s): De Sutter J, Poldermans D, Vourvouri E, Van Donburg R, Elhendy A, Bax J, Sozzi F, Jordaens L, De Buyzere M, Roelandt J. Source: The American Journal of Cardiology. 2003 January 15; 91(2): 242-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12521644

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Magnesium-flush infusion into the aortic root just before reperfusion reduces the requirement for internal defibrillation and early post-perfusion arrhythmias. Author(s): Besogul Y, Tunerir B, Ozdemir C, Aslan R. Source: J Int Med Res. 2003 May-June; 31(3): 202-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12870373

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Management of common arrhythmias: Part I. Supraventricular arrhythmias. Author(s): Hebbar AK, Hueston WJ. Source: American Family Physician. 2002 June 15; 65(12): 2479-86. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12086237

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Management of common arrhythmias: Part II. Ventricular arrhythmias and arrhythmias in special populations. Author(s): Hebbar AK, Hueston WJ. Source: American Family Physician. 2002 June 15; 65(12): 2491-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12086238

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Management of ventricular arrhythmias in diverse populations in California. Author(s): Alexander M, Baker L, Clark C, McDonald KM, Rowell R, Saynina O, Hlatky MA. Source: American Heart Journal. 2002 September; 144(3): 431-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12228779

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Mechanisms of clinical arrhythmias. Author(s): Zipes DP. Source: Journal of Cardiovascular Electrophysiology. 2003 August; 14(8): 902-12. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12890064

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Mechanisms of clinical arrhythmias. Author(s): Zipes DP. Source: Pacing and Clinical Electrophysiology : Pace. 2003 August; 26(8): 1778-92. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12877718

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Mechanisms underlying the development of atrial arrhythmias in heart failure. Author(s): Markides V, Peters NS. Source: Heart Failure Reviews. 2002 July; 7(3): 243-53. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12215729

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Meta-analysis of flecainide safety in patients with supraventricular arrhythmias. Author(s): Wehling M. Source: Arzneimittel-Forschung. 2002; 52(7): 507-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12189773

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Multi-channel magnetocardiography for detecting beat morphology variations in fetal arrhythmias. Author(s): Sturm R, Muller HP, Pasquarelli A, Demelis M, Erne SN, Terinde R, Lang D. Source: Prenatal Diagnosis. 2004 January; 24(1): 1-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14755401

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Myocardial ultrasound tissue characterization in patients with hypertrophic cardiomyopathy: noninvasive evidence of electrical and textural substrate for ventricular arrhythmias. Author(s): Limongelli G, Pacileo G, Cerrato F, Verrengia M, Di Simone A, Severino S, Sarubbi B, Calabro R. Source: Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. 2003 August; 16(8): 803-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12878988

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Neurohumoral activation and ventricular arrhythmias in patients with decompensated congestive heart failure: role of endothelin. Author(s): Aronson D, Burger AJ. Source: Pacing and Clinical Electrophysiology : Pace. 2003 March; 26(3): 703-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12698670

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New approaches to antiarrhythmic therapy, Part I: emerging therapeutic applications of the cell biology of cardiac arrhythmias. Author(s): Members of the Sicilian Gambit. Source: Circulation. 2001 December 4; 104(23): 2865-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11733408

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New catheter ablation techniques for the treatment of cardiac arrhythmias. Author(s): Keane D. Source: Cardiac Electrophysiology Review. 2002 December; 6(4): 341-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12438811

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New techniques for mapping cardiac arrhythmias. Author(s): Sra J, Thomas JM. Source: Indian Heart J. 2001 July-August; 53(4): 423-44. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11759932

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New treatments for perioperative cardiac arrhythmias. Author(s): Hastings LA, Balser JR. Source: Anesthesiology Clinics of North America. 2003 September; 21(3): 569-86. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14562566

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Noninvasive diagnosis of cardiac arrhythmias using adenosine compounds. Author(s): Belhassen B. Source: Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2002 January; 7(1): 64-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11844294

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Nonpharmacological therapy for malignant ventricular arrhythmias: implantable defibrillator trials. Author(s): Saksena S, Breithardt G, Dorian P, Greene HL, Madan N, Block M. Source: Progress in Cardiovascular Diseases. 1996 May-June; 38(6): 429-44. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8638024

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Non-pharmacological treatment of supraventricular arrhythmias. Author(s): Josephson ME, Schibgilla VH. Source: European Heart Journal. 1996 July; 17 Suppl C: 26-34. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8809536

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Non-sedating antihistamine drugs and cardiac arrhythmias -- biased risk estimates from spontaneous reporting systems? Author(s): De Bruin ML, van Puijenbroek EP, Egberts AC, Hoes AW, Leufkens HG. Source: British Journal of Clinical Pharmacology. 2002 April; 53(4): 370-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11966667

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Normalization of peripheral thyroid hormone metabolism induced by successful chronic amiodarone treatment in patients with ventricular arrhythmias. Author(s): Iervasi G, Clerico A, Berti S, Pilo A, Biagini A, Bianchi R, Donato L. Source: European Journal of Clinical Investigation. 1996 May; 26(5): 382-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8796365

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Obesity drug sibutramine (Meridia): hypertension and cardiac arrhythmias. Author(s): Wooltorton E. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2002 May 14; 166(10): 1307-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12041851

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Occurrence of arrhythmias in general practice. Author(s): Zwietering P, Knottnerus A, Gorgels T, Rinkens P. Source: Scandinavian Journal of Primary Health Care. 1996 December; 14(4): 244-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8956453

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Oral amiodarone loading for the rapid treatment of frequent, refractory, sustained ventricular arrhythmias associated with coronary artery disease. Author(s): Russo AM, Beauregard LM, Waxman HL. Source: The American Journal of Cardiology. 1993 December 15; 72(18): 1395-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8256733

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Outcome from out-of-hospital cardiac arrest caused by nonventricular arrhythmias: contribution of successful resuscitation to overall survivorship supports the current practice of initiating out-of-hospital ACLS. Author(s): Stratton SJ, Niemann JT. Source: Annals of Emergency Medicine. 1998 October; 32(4): 448-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9774929

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Outcome of previous tricuspid valve operation and arrhythmias in adult patients with congenital heart disease. Author(s): Overgaard CB, Harrison DA, Siu SC, Williams WG, Webb GD, Harris L. Source: The Annals of Thoracic Surgery. 1999 December; 68(6): 2158-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10616994

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Outcome-based justification for implementing new point-of-care tests: there is no difference between magnesium replacement based on ionized magnesium and total magnesium as a predictor of development of arrhythmias in the postoperative cardiac surgical patient. Author(s): Steinberger HA, Hanson CW 3rd. Source: Clin Lab Manage Rev. 1998 March-April; 12(2): 87-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10178713

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Out-of-hospital symptomatic supraventricular arrhythmias. Epidemiological aspects derived from 10 years experience of the Florence Mobile Coronary Care Unit. Author(s): Rostagno C, Paladini B, Taddei T, Russo L, Giglioli C, Margheri M, Bertini G. Source: G Ital Cardiol. 1993 June; 23(6): 549-62. English, Italian. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8405817

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Outpatient cardioversion of atrial arrhythmias: efficacy, safety, and costs. Author(s): Botkin SB, Dhanekula LS, Olshansky B. Source: American Heart Journal. 2003 February; 145(2): 233-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12595839

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Over-the-counter sympathomimetics: a risk factor for cardiac arrhythmias in pregnancy. Author(s): Onuigbo M, Alikhan M. Source: Southern Medical Journal. 1998 December; 91(12): 1153-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9853729

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Overview of pediatric arrhythmias. Author(s): Boisvert JT, Reidy SJ, Lulu J. Source: Nurs Clin North Am. 1995 June; 30(2): 365-79. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7777412

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Patients with ventricular arrhythmias: who should be referred to an electrophysiologist? Author(s): Morgan JM. Source: Heart (British Cardiac Society). 2002 November; 88(5): 544-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12381654

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Pharmacogenetics. Gene mutation may boost risk of heart arrhythmias. Author(s): Marx J. Source: Science. 2002 August 23; 297(5585): 1252. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12193756

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Pharmacologic management of arrhythmias in patients with congenital heart disease. Author(s): Batra AS, Luna CF, Silka MJ. Source: American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions. 2001; 1(2): 91-103. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14728039

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Posterior pericardiotomy reduces the incidence of supra-ventricular arrhythmias and pericardial effusion after coronary artery bypass grafting. Author(s): Farsak B, Gunaydin S, Tokmakoglu H, Kandemir O, Yorgancioglu C, Zorlutuna Y. Source: European Journal of Cardio-Thoracic Surgery : Official Journal of the European Association for Cardio-Thoracic Surgery. 2002 August; 22(2): 278-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12142199

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Predictors of new malignant ventricular arrhythmias after coronary surgery: a casecontrol study. Author(s): Ascione R, Reeves BC, Santo K, Khan N, Angelini GD. Source: Journal of the American College of Cardiology. 2004 May 5; 43(9): 1630-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15120824

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Prevalence and incidence of arrhythmias and sudden death in heart failure. Author(s): Cleland JG, Chattopadhyay S, Khand A, Houghton T, Kaye GC. Source: Heart Failure Reviews. 2002 July; 7(3): 229-42. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12215728

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Prevalence of cardiac arrhythmias during and after pregnancy in women with Chagas' disease without apparent heart disease. Author(s): Acha RE, Rezende MT, Guzman Heredia RA, Silva AC, Rezende ES, Souza CA. Source: Arquivos Brasileiros De Cardiologia. 2002 July; 79(1): 1-9. English, Portuguese. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12163940

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Prevention of and medical therapy for atrial arrhythmias in heart failure. Author(s): Khand AU, Cleland JG, Deedwania PC. Source: Heart Failure Reviews. 2002 July; 7(3): 267-83. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12215732

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Prevention of cardiac arrhythmias in pediatric patients with normotensivehypokalemic tubulopathy. Current attitude among European pediatricians. Author(s): Cortesi C, Foglia PE, Bettinelli A, Bianchetti MG. Source: Pediatric Nephrology (Berlin, Germany). 2003 August; 18(8): 729-30. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12921106

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Prevention of fatal cardiac arrhythmias by polyunsaturated fatty acids. Author(s): Leaf A. Source: Nutr Health. 2002; 16(1): 47-9. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12083413

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QRS duration and prediction of mortality in patients undergoing risk stratification for ventricular arrhythmias. Author(s): Kalahasti V, Nambi V, Martin DO, Lam CT, Yamada D, Wilkoff BL, Niebauer MJ, Jaeger FJ, Tchou PJ, Chung MK. Source: The American Journal of Cardiology. 2003 October 1; 92(7): 798-803. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14516879

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QT interval dispersion in ventricular beats: a noninvasive marker of susceptibility to sustained ventricular arrhythmias. Author(s): Kulakowski P, Karczmarewicz S, Czepiel A, Makowska E, Soszynska M, Ceremuzynski L. Source: Pacing and Clinical Electrophysiology : Pace. 2001 March; 24(3): 352-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11310305

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QT lengthening and life-threatening arrhythmias associated with fexofenadine. Author(s): Craig-McFeely PM, Freemantle SL, Pearce GL, Shakir SA. Source: The British Journal of General Practice : the Journal of the Royal College of General Practitioners. 2000 February; 50(451): 148. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10750216

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QT lengthening and life-threatening arrhythmias associated with fexofenadine. Author(s): Pinto YM, van Gelder IC, Heeringa M, Crijns HJ. Source: Lancet. 1999 March 20; 353(9157): 980. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10459910

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QT prolongation and fatal arrhythmias: a review of clinical implications and effects of drugs. Author(s): Cubeddu LX. Source: American Journal of Therapeutics. 2003 November-December; 10(6): 452-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14624285

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QTc dispersion and complex ventricular arrhythmias in untreated newly presenting hypertensive patients. Author(s): Saadeh A, Evans S, James M, Jones J. Source: Journal of Human Hypertension. 1999 October; 13(10): 665-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10516735

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QTc-prolonging drugs and hospitalizations for cardiac arrhythmias. Author(s): De Bruin ML, Hoes AW, Leufkens HG. Source: The American Journal of Cardiology. 2003 January 1; 91(1): 59-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12505572

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Quality of life in patients with life-threatening arrhythmias: does choice of therapy make a difference? Author(s): Exner DV. Source: American Heart Journal. 2002 August; 144(2): 208-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12177635

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Quality of life issues in the management of patients with ventricular arrhythmias. Author(s): Irvine J, Newman D. Source: The Canadian Journal of Cardiology. 2000 June; 16 Suppl C: 41C-4C. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10887278

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Quantifying intracardiac organization of atrial arrhythmias using temporospatial phase of the electrocardiogram. Author(s): Narayan SM, Feld GK, Hassankhani A, Bhargava V. Source: Journal of Cardiovascular Electrophysiology. 2003 September; 14(9): 971-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12950543

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Radiofrequency catheter ablation of supraventricular arrhythmias. Author(s): Calkins H. Source: Heart (British Cardiac Society). 2001 May; 85(5): 594-600. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11303019

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Radiofrequency catheter ablation of various kinds of arrhythmias guided by virtual electrograms using a noncontact, computerized mapping system. Author(s): Okishige K, Kawabata M, Umayahara S, Yamashiro K, Gotoh M, Isobe M, Strickberger SA. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2003 May; 67(5): 455-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12736487

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Randomised trial on the influence of continuous magnesium infusion on arrhythmias following cardiopulmonary bypass surgery for congenital heart disease. Author(s): Dittrich S, Germanakis J, Dahnert I, Stiller B, Dittrich H, Vogel M, Lange PE. Source: Intensive Care Medicine. 2003 July; 29(7): 1141-4. Epub 2003 May 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12774159

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Rationale and patient selection for "hybrid" drug and device therapy in atrial and ventricular arrhythmias. Author(s): Camm AJ, Savelieva I. Source: Journal of Interventional Cardiac Electrophysiology : an International Journal of Arrhythmias and Pacing. 2003 October; 9(2): 207-14. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14574033

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Recent advances in the treatment of arrhythmias. Author(s): Grant AO. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2003 August; 67(8): 651-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12890903

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Reperfusion arrhythmias and ST-segment resolution. Author(s): Zahger D, Ilia R. Source: The American Journal of Cardiology. 2004 March 1; 93(5): 671. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14996611

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Reperfusion arrhythmias during coronary angioplasty for acute myocardial infarction predict ST-segment resolution. Author(s): Ilia R, Amit G, Cafri C, Gilutz H, Abu-Ful A, Weinstein JM, Yaroslavtsev S, Gueron M, Zahger D. Source: Coronary Artery Disease. 2003 September; 14(6): 439-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12966264

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Reperfusion arrhythmias. Author(s): Adams MG, Pelter MM. Source: American Journal of Critical Care : an Official Publication, American Association of Critical-Care Nurses. 2002 July; 11(4): 397-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12102442

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Reversal of atrial mechanical stunning after cardioversion of atrial arrhythmias: implications for the mechanisms of tachycardia-mediated atrial cardiomyopathy. Author(s): Sanders P, Morton JB, Morgan JG, Davidson NC, Spence SJ, Vohra JK, Kalman JM, Sparks PB. Source: Circulation. 2002 October 1; 106(14): 1806-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12356634

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Review of economic evaluations of radiofrequency catheter ablation for cardiac arrhythmias. Author(s): Marshall DA, O'Brien BJ, Nichol G. Source: The Canadian Journal of Cardiology. 2003 October; 19(11): 1285-304. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14571313

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Screening for ryanodine receptor type 2 mutations in families with effort-induced polymorphic ventricular arrhythmias and sudden death: early diagnosis of asymptomatic carriers. Author(s): Bauce B, Rampazzo A, Basso C, Bagattin A, Daliento L, Tiso N, Turrini P, Thiene G, Danieli GA, Nava A. Source: Journal of the American College of Cardiology. 2002 July 17; 40(2): 341-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12106942

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Serious ventricular arrhythmias among users of cisapride and other QT-prolonging agents in the United States. Author(s): Enger C, Cali C, Walker AM. Source: Pharmacoepidemiology and Drug Safety. 2002 September; 11(6): 477-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12426932

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Sibutramine warning: hypertension and cardiac arrhythmias reported. Author(s): Deitel M. Source: Obesity Surgery : the Official Journal of the American Society for Bariatric Surgery and of the Obesity Surgery Society of Australia and New Zealand. 2002 June; 12(3): 422. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12082902

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Significance and control of cardiac arrhythmias in patients with congestive cardiac failure. Author(s): Singh BN. Source: Heart Failure Reviews. 2002 July; 7(3): 285-300. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12215733

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Sleep-related breathing disorders are associated with ventricular arrhythmias in patients with an implantable cardioverter-defibrillator. Author(s): Fichter J, Bauer D, Arampatzis S, Fries R, Heisel A, Sybrecht GW. Source: Chest. 2002 August; 122(2): 558-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12171831

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Spontaneous adverse event reports of serious ventricular arrhythmias, QT prolongation, syncope, and sudden death in patients treated with cisapride. Author(s): Barbey JT, Lazzara R, Zipes DP. Source: Journal of Cardiovascular Pharmacology and Therapeutics. 2002 April; 7(2): 6576. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12075394

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Survival of antiarrhythmic or implantable cardioverter defibrillator treated patients with varying degrees of left ventricular dysfunction who survived malignant ventricular arrhythmias. Author(s): Domanski MJ, Epstein A, Hallstrom A, Saksena S, Zipes DP. Source: Journal of Cardiovascular Electrophysiology. 2002 June; 13(6): 580-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12108501

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Sustained ventricular arrhythmias among patients with acute coronary syndromes with no ST-segment elevation: incidence, predictors, and outcomes. Author(s): Al-Khatib SM, Granger CB, Huang Y, Lee KL, Califf RM, Simoons ML, Armstrong PW, Van de Werf F, White HD, Simes RJ, Moliterno DJ, Topol EJ, Harrington RA. Source: Circulation. 2002 July 16; 106(3): 309-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12119245

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Sympathetic activation and malignant ventricular arrhythmias: a molecular link? Author(s): Kalra PR, Ponikowski PP, Anker SD. Source: European Heart Journal. 2002 July; 23(14): 1078-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12090743

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The effects of hormones on arrhythmias in women. Author(s): Bailey MS, Curtis AB. Source: Curr Womens Health Rep. 2002 April; 2(2): 83-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12116606

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The incidence and outcome of ventricular arrhythmias after noncardiac thoracic surgery. Author(s): Amar D, Zhang H, Roistacher N. Source: Anesthesia and Analgesia. 2002 September; 95(3): 537-43, Table of Contents. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12198031

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The independent association of renal dysfunction and arrhythmias in critically ill patients. Author(s): Soman SS, Sandberg KR, Borzak S, Hudson MP, Yee J, McCullough PA. Source: Chest. 2002 August; 122(2): 669-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12171849

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The problem of atrial arrhythmias after noncardiac thoracic surgery. Author(s): Creswell LL. Source: The Journal of Thoracic and Cardiovascular Surgery. 2004 March; 127(3): 629-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15001888

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The prognostic significance of exercise-induced atrial arrhythmias. Author(s): Bunch TJ, Chandrasekaran K, Gersh BJ, Hammill SC, Hodge DO, Khan AH, Packer DL, Pellikka PA. Source: Journal of the American College of Cardiology. 2004 April 7; 43(7): 1236-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15063436

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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 role of neuropeptides and neurohormones in neurogenic cardiac arrhythmias. Author(s): Saleh TM. Source: Current Drug Targets. Cardiovascular & Haematological Disorders. 2003 September; 3(3): 240-53. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12871042

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Trends in hospital treatment of ventricular arrhythmias among Medicare beneficiaries, 1985 to 1995. Author(s): McDonald KM, Hlatky MA, Saynina O, Geppert J, Garber AM, McClellan MB. Source: American Heart Journal. 2002 September; 144(3): 413-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12228777

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Triptan use preceding life-threatening arrhythmias in charcot-marie-tooth: a case report and review of the literature. Author(s): Rubinstein J, Moghe R, Mizrachi A, Dissin J. Source: Clinical Neuropharmacology. 2004 January-February; 27(1): 14-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15090931

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Twenty-five years of insights into the mechanisms of supraventricular arrhythmias. Author(s): Wellens HJ. Source: Journal of Cardiovascular Electrophysiology. 2003 September; 14(9): 1020-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12950557

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Unexplained syncope in patients with structural heart disease and no documented ventricular arrhythmias: value of electrophysiologically guided implantable cardioverter defibrillator therapy. Author(s): Pezawas T, Stix G, Kastner J, Wolzt M, Mayer C, Moertl D, Schmidinger H. 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 July; 5(3): 305-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12842649

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Unsuspected Wolff-Parkinson-White syndrome causing arrhythmias after cardiac surgery. Author(s): Wheeler DW, Sayeed RA, Ritchie AJ. Source: Journal of Cardiothoracic and Vascular Anesthesia. 2002 June; 16(3): 354-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12073211

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Use of fluoroscopic views for detecting Marshall's vein in patients with cardiac arrhythmias. Author(s): Tuan TC, Tai CT, Lin YK, Hsieh MH, Tsai CF, Ding YA, Chen SA. Source: Journal of Interventional Cardiac Electrophysiology : an International Journal of Arrhythmias and Pacing. 2003 December; 9(3): 327-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14618052

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Use of the insertable loop recorder to detect cardiac arrhythmias during syncopal episodes. Author(s): Reiff PA, Gutierrez JD. Source: Medsurg Nursing : Official Journal of the Academy of Medical-Surgical Nurses. 2004 April; 13(2): 105-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15119423

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Use of tissue velocity imaging in the diagnosis of fetal cardiac arrhythmias. Author(s): Rein AJ, O'Donnell C, Geva T, Nir A, Perles Z, Hashimoto I, Li XK, Sahn DJ. Source: Circulation. 2002 October 1; 106(14): 1827-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12356637

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Use of transesophageal atrial pacing for documentation of arrhythmias suspected in infants and children. Author(s): Ko JK, Ryu SJ, Ban JE, Kim YH, Park IS. Source: Japanese Heart Journal. 2004 January; 45(1): 63-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14973351

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Usefulness of frequent arrhythmias after epicardial recanalization in anterior wall acute myocardial infarction as a marker of cellular injury leading to poor recovery of left ventricular function. Author(s): Engelen DJ, Gressin V, Krucoff MW, Theuns DA, Green C, Cheriex EC, Maison-Blanche P, Dassen WR, Wellens HJ, Gorgels AP. Source: The American Journal of Cardiology. 2003 November 15; 92(10): 1143-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14609586

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Usefulness of propafenone for supraventricular arrhythmias in infants and children. Author(s): Janousek J, Paul T, Reimer A, Kallfelz HC. Source: The American Journal of Cardiology. 1993 August 1; 72(3): 294-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8342507

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Usefulness of sotalol for life-threatening ventricular arrhythmias. Author(s): Roden DM. Source: The American Journal of Cardiology. 1993 August 12; 72(4): 51A-55A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8346727

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Utility of patient-activated cardiac event recorders in the detection of cardiac arrhythmias. Author(s): Wu CC, Hsieh MH, Tai CT, Chiang CE, Yu WC, Lin YK, Tsao HM, Ding PY, Chen SA. Source: Journal of Interventional Cardiac Electrophysiology : an International Journal of Arrhythmias and Pacing. 2003 April; 8(2): 117-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766502

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Value of heart rate variability to predict ventricular arrhythmias in recipients of prophylactic defibrillators with idiopathic dilated cardiomyopathy. Author(s): Grimm W, Herzum I, Muller HH, Christ M. Source: Pacing and Clinical Electrophysiology : Pace. 2003 January; 26(1 Pt 2): 411-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12687856

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Valvular hemodynamics and arrhythmias with exercise following the Ross procedure. Author(s): Phillips JR, Daniels CJ, Orsinelli DA, Orsinelli MH, Cohen DM, Brown DA, Allen HD. Source: The American Journal of Cardiology. 2001 March 1; 87(5): 577-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11230842

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Ventricular arrhythmias and autonomic profile in patients with primary pulmonary hypertension. Author(s): Folino AF, Bobbo F, Schiraldi C, Tona F, Romano S, Buja G, Bellotto F. Source: Lung. 2003 November-December; 181(6): 321-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14749936

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Ventricular arrhythmias and sudden cardiac death in end-stage renal disease patients on chronic hemodialysis. Author(s): Meier P, Vogt P, Blanc E. Source: Nephron. 2001 March; 87(3): 199-214. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11287755

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Ventricular arrhythmias associated with hypoglycaemia. Author(s): Chelliah YR. Source: Anaesthesia and Intensive Care. 2000 December; 28(6): 698-700. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11153301

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Ventricular arrhythmias in hypertensive patients with mild metabolic alterations. Author(s): Sorrentino F, Busa A, Averna M, Nigro P. Source: Minerva Cardioangiol. 2003 February; 51(1): 63-7, 68-70. English, Italian. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12652262

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Ventricular arrhythmias in patients with COPD are associated with QT dispersion. Author(s): Yildiz P, Tukek T, Akkaya V, Sozen AB, Yildiz A, Korkut F, Yilmaz V. Source: Chest. 2002 December; 122(6): 2055-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12475847

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Ventricular arrhythmias in Takayasu arteritis. Author(s): Siburian G, Hashimoto Y, Numano F. Source: International Journal of Cardiology. 1993 July 15; 40(3): 243-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7901173

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Ventricular arrhythmias: Q-T prolongation and left ventricular hypertrophy in adult Nigerians with hypertensive heart disease. Author(s): Opadijo OG, Omotoso AB, Araoye MA. Source: Niger Postgrad Med J. 2003 June; 10(2): 76-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14567039

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Ventricular dyssynchrony and risk markers of ventricular arrhythmias in nonischemic dilated cardiomyopathy: a study with phase analysis of angioscintigraphy. Author(s): Fauchier L, Marie O, Casset-Senon D, Babuty D, Cosnay P, Fauchier JP. Source: Pacing and Clinical Electrophysiology : Pace. 2003 January; 26(1 Pt 2): 352-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12687844

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Wavelet formation in excitable cardiac tissue: the role of wavefront-obstacle interactions in initiating high-frequency fibrillatory-like arrhythmias. Author(s): Starobin JM, Zilberter YI, Rusnak EM, Starmer CF. Source: Biophysical Journal. 1996 February; 70(2): 581-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8789078

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What are the risk factors for arrhythmias after thoracic operations? A retrospective multivariate analysis of 267 consecutive thoracic operations. Author(s): Asamura H, Naruke T, Tsuchiya R, Goya T, Kondo H, Suemasu K. Source: The Journal of Thoracic and Cardiovascular Surgery. 1993 December; 106(6): 1104-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8246546

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What have we learned about cardiac arrhythmias? Author(s): Zipes DP, Wellens HJ. Source: Circulation. 2000 November 14; 102(20 Suppl 4): Iv52-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11080132

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Which cardiac potassium channel subtype is the preferable target for suppression of ventricular arrhythmias? Author(s): Rees S, Curtis MJ. Source: Pharmacology & Therapeutics. 1996; 69(3): 199-217. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8783371

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Why do exercise-induced ventricular arrhythmias increase with age? Role of M-mode echocardiographic aging changes. Author(s): Mayuga R, Arrington CT, O'Connor FC, Fleg JL. Source: The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 1996 January; 51(1): M23-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8548509

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Will the body surface map replace the signal averaged electrocardiogram and other computerized techniques for the diagnosis and treatment of arrhythmias? Author(s): Cohen TJ. Source: J Invasive Cardiol. 1995 December; 7(9): 275-6. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10158380

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WinArrhythmia: a Windows based application for studying cardiac arrhythmias. Author(s): Takeuchi A, Ikeda N, Nara Y, Miyahara H, Mitobe H. Source: Computer Methods and Programs in Biomedicine. 1998 March; 55(3): 199-206. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9617519

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Women and arrhythmias. Author(s): Linde C. Source: Pacing and Clinical Electrophysiology : Pace. 2000 October; 23(10 Pt 1): 1550-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11060878

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

Finding Nutrition Studies on Arrhythmias The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail: [email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “arrhythmias” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

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

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

Use of phenytoin to treat digitalis-induced cardiac arrhythmias in a miniature Shetland pony. Author(s): Veterinary Pharmacy, Faculty of Veterinary Medicine, Utrecht University, PO Box 80.152, 3508 TD Utrecht (Netherlands) Source: Wijnberg, I.D. Kolk, J.H. van der Hiddink, E.G. Veterinary-Record (United Kingdom). (1999). volume 144(10) page 259-261.

Additional physician-oriented references include: •

7-oxo-PGI2 induced late protective action from arrhythmias due to local myocardial ischemia. Author(s): Department of Pharmacology, Albert Szent-Gyorgyi Medical University, Szeged, Hungary. Source: Udvary, E Vegh, A Szekeres, L Bratisl-Lek-Listy. 1991 Mar-April; 92(3-4): 146-9 0006-9248

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A novel modified tissue-type plasminogen activator (t-PA), E6010, reduces reperfusion arrhythmias induced after coronary thrombolysis--comparison of native t-PA and urokinase. Author(s): Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan. Source: Saito, M Suzuki, S Yui, Y Kawai, C Jpn-Circ-J. 1995 August; 59(8): 556-64 00471828

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Analysis of perioperative ventricular arrhythmias in valvular heart diseases by Holter ECG recording. Author(s): Second Department of Surgery, Medical College of Oita, Japan. Source: Shigemitsu, O Hadama, T Takasaki, H Uchida, Y Shirabe, J Ito, M Jpn-Circ-J. 1991 October; 55(10): 951-61 0047-1828

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Antiarrhythmic action of naloxone. Suppression of picrotoxin-induced cardiac arrhythmias in the rat. Author(s): Department of Cardiology, Taichung Veterans General Hospital, Taiwan, Republic of China. Source: Lin, C J Chen, Y T Kuo, J S Lee, A Y Jpn-Heart-J. 1992 May; 33(3): 365-72 00214868

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Antiarrhythmic effects of prostaglandins E2 and I2 on ouabain-induced cardiac arrhythmias in cats: effect of vagotomy and adrenergic neuron blockade. Author(s): Department of Pharmacology, All India Institute of Medical Sciences, New Delhi. Source: Rao, T S Seth, S D Manchanda, S C Nayar, U Pharmacol-Res. 1990 Mar-April; 22(2): 151-60 1043-6618

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Cardiac arrhythmia and ischaemic events after combination chemotherapy for testicular cancer. Author(s): Divisione di Cardiologia e Fisiopatologia Respiratoria, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy. Source: Villani, F Misrachi, D Galimberti, M Eur-Heart-J. 1994 November; 15(11): 1533-6 0195-668X

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Carrier-mediated norepinephrine release and reperfusion arrhythmias induced by protracted ischemia in isolated perfused guinea pig hearts: effect of presynaptic modulation by alpha(2)-adrenoceptor in mild hypothermic ischemia. Author(s): Department of Cardiovascular Surgery, Hokkaido University School of Medicine, N14W5, Kita-Ku, Sapporo 060-8648, Japan. [email protected] Source: Oka, J Imamura, M Hatta, E Maruyama, R Isaka, M Murashita, T Yasuda, K JPharmacol-Exp-Ther. 2002 November; 303(2): 681-7 0022-3565

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Cesium chloride induced ventricular arrhythmias in dogs: three-dimensional activation patterns and their relation to the cesium dose applied. Author(s): Medizinische Universitatsklinik, Abteilung Innere Medizin III, Heidelberg, Germany. [email protected] Source: Senges, J C Sterns, L D Freigang, K D Bauer, A Becker, R Kubler, W Schoels, W Basic-Res-Cardiol. 2000 April; 95(2): 152-62 0300-8428

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Contrastive effects of prostaglandin F2 alpha on normal cardiac rhythm and ouabaininduced cardiac arrhythmias in cats: possible neural basis. Author(s): Department of Pharmacology, All-India Institute of Medical Sciences, New Delhi. Source: Rao, T S Seth, S D Manchanda, S C Nayar, U Arch-Int-Pharmacodyn-Ther. 1989 Nov-December; 302128-44 0003-9780

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Correlations between ventricular arrhythmias and electrolyte disturbances after acute myocardial infarction. Author(s): Institut fur Wasser-, Boden- und Lufthygiene, Freie Universitat Berlin, FRG. Source: Ising, H Rebentisch, E Bertschat, F Gunther, T Magnes-Trace-Elem. 1990; 9(4): 205-11 1015-3845

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Deleterious effects of digitalis on reperfusion-induced arrhythmias and myocardial injury in ischemic rat hearts: possible involvements of myocardial Na+ and Ca2+ imbalance. Author(s): Department of Geriatrics, Keio University School of Medicine, Tokyo, Japan. Source: Tani, M Neely, J R Basic-Res-Cardiol. 1991 Jul-August; 86(4): 340-54 0300-8428

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Effects of cyclooxygenase and lipoxygenase inhibitors on digoxin-induced arrhythmias and haemodynamics in guinea-pigs. Author(s): Department of Pharmacology, Faculty of Pharmacy, Gazi University, Etiler, Ankara, Turkey. Source: Kanzik, I Cakici, I Ersoy, S Ark, M Abacioglu, N Zengil, H Pharmacol-Res. 1992 Oct-November; 26(3): 305-16 1043-6618

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Endogenous adenosine suppresses norepinephrine-induced ventricular arrhythmias in rat heart. Author(s): Medizinische Klinik II, Medizinische Universitat zu Lubeck, Germany. Source: Gorge, B Kurz, T Katus, H A Richardt, G Basic-Res-Cardiol. 1998 August; 93(4): 264-8 0300-8428

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Epinephrine-aminophylline-induced arrhythmias after midazolam or thiopentone in halothane-anaesthetized dogs. Author(s): Department of Anesthesiology, Case Western Reserve University, School of Medicine, Cleveland, Ohio. Source: Lina, A A Dauchot, P J Anton, A H Can-J-Anaesth. 1991 November; 38(8): 103742 0832-610X

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Evidence for a direct noncholinergic effect of an organophosphorous compound on guinea-pig papillary muscles: are ventricular arrhythmias related to a Na+/K+ ATPase inhibition? Author(s): Centre d'Etudes du Bouchet, Division of Pharmacology, Vert-Le-Petit, France. Source: Corbier, A Robineau, P Arch-Int-Pharmacodyn-Ther. 1989 Jul-August; 300218-30 0003-9780

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Gadolinium suppresses stretch-induced increases in the differences in epicardial and endocardial monophasic action potential durations and ventricular arrhythmias in dogs. Author(s): Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. [email protected] Source: Takagi, S Miyazaki, T Moritani, K Miyoshi, S Furukawa, Y Ito, S Ogawa, S JpnCirc-J. 1999 April; 63(4): 296-302 0047-1828

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Histamine enhances hypoxia-induced ventricular arrhythmias in isolated rat hearts. Author(s): Department of Pharmacology, Faculty of Medicine, University of Hong Kong. Source: Dai, S Clin-Exp-Pharmacol-Physiol. 1989 December; 16(12): 925-31 0305-1870

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Hypertension-related intermyocyte junction remodelling is associated with a higher incidence of low-K(+)-induced lethal arrhythmias in isolated rat heart. Author(s): Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovak Republic. [email protected] Source: Tribulova, N Okruhlicova, L Novakova, S Pancza, D Bernatova, I Pechanova, O Weismann, P Manoach, M Seki, S Mochizuki, S Exp-Physiol. 2002 March; 87(2): 195-205 0958-0670

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Induction and termination of afterdepolarizations and triggered arrhythmias by drugs in cat heart in vivo. Author(s): Department of Biology, Nankai University, Tianjin, PR of China. Source: Xie, J T Li, C L Methods-Find-Exp-Clin-Pharmacol. 1992 June; 14(5): 347-54 03790355

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Influence of spontaneous hypertension and cardiac hypertrophy on the severity of ischemic arrhythmias in the rat. Author(s): Centre de Recherche, Laboratoires Fournier S.A., Dijon, France. Source: Belichard, P Pruneau, D Rochette, L Basic-Res-Cardiol. 1988 Sep-October; 83(5): 560-6 0300-8428

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Inhibitory effect of CV4151, a thromboxane A2 synthetase inhibitor, on ventricular arrhythmias induced by coronary artery occlusion in rats. Author(s): Second Department of Internal Medicine, Yamanashi Medical University, Japan. Source: Umetani, K Tamura, K Komori, S Watanabe, A Ishihara, T Mochizuki, S Li, B Ijiri, H Jpn-Circ-J. 1996 June; 60(6): 349-54 0047-1828

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Intoxication with taxus baccata: cardiac arrhythmias following yew leaves ingestion. Author(s): Department of Cardiology, Imelda Ziekenhuis, Bonheiden, Belgium. Source: Willaert, W Claessens, P Vankelecom, B Vanderheyden, M Pacing-ClinElectrophysiol. 2002 April; 25(4 Pt 1): 511-2 0147-8389

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Magnesium therapy of cardiac arrhythmias in critical-care medicine. Author(s): Cardiology Division, University of California Irvine Medical Center, Orange. Source: Iseri, L T Allen, B J Brodsky, M A Magnesium. 1989; 8(5-6): 299-306 0252-1156

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Manipulation of myocardial alpha-tocopherol levels fails to affect reperfusion arrhythmias or functional recovery following ischemic challenge in the rat heart. Author(s): Biochemistry Department, Brunel University, Uxbridge, Middlesex, England. Source: Shuter, S L Bernier, M Davies, M J Kusama, Y Takahashi, A Slater, T F Hearse, D J Garlick, P B Basic-Res-Cardiol. 1989 Jul-August; 84(4): 421-30 0300-8428

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Modified method for the production of cardiac arrhythmias by ouabain in anesthetized cats. Author(s): Department of Pharmacology, All-India Institute of Medical Sciences, New Delhi. Source: Rao, T S Seth, S D Nayar, U Manchanda, S C J-Pharmacol-Methods. 1988 November; 20(3): 255-63 0160-5402

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Neurobehavioral contributions to cardiac arrhythmias during aversive pavlovian conditioning in the rabbit receiving digitalis. Author(s): University of Vermont, Department of Psychology, Burlington 05405. Source: Markgraf, C G Kapp, B S J-Auton-Nerv-Syst. 1988 June; 23(1): 35-46 0165-1838

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On the 7-oxo-PgI2 induced lasting protection against ouabain arrhythmias in anesthetized guinea pigs. Author(s): Department of Pharmacology, Szent-Gyorgyi University Medical School, Szeged, Hungary. Source: Szilvassy, Z Szekeres, L Udvary, E Vegh, A Biomed-Biochim-Acta. 1988; 47(1011): S35-8 0232-766X

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Protective effect of Crataegus oxyacantha against reperfusion arrhythmias after global no-flow ischemia in the rat heart. Author(s): Institut fur Arbeits- und Sozialmedizin, Tubingen, Germany. Source: al Makdessi, S Sweidan, H Dietz, K Jacob, R Basic-Res-Cardiol. 1999 April; 94(2): 71-7 0300-8428

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Reperfusion arrhythmias after cardioplegia using Bretschneider-HTK solution. Author(s): Department of Heart Surgery, Martin-Luther University, Halle-Wittenberg, FRG. Source: Panzner, R Wollert, H G Hermann, M Taha, M Schischka, F Thorac-CardiovascSurg. 1990 December; 38(6): 370 0171-6425

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Role of peptido-leukotrienes in the genesis of early ventricular arrhythmias during acute myocardial ischaemia in rats. Author(s): Department of Pharmacology, Faculty of Medicine, University of Hong Kong. Source: Chang, A C Dai, S Ogle, C W Tom, W M Agents-Actions. 1992 March; 35(3-4): 212-9 0065-4299

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Sympathetic microneurography and neurocirculatory function: studies of ventricular arrhythmias in humans. Author(s): Mayo Clinic and Foundation Rochester, Minnesota 55905, USA. Source: Rea, R F Adv-Pharmacol. 1998; 42548-51 1054-3589

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The effects of PAF antagonists on arrhythmias and platelets during acute myocardial ischaemia and reperfusion. Author(s): Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, Scotland, U.K. Source: Wainwright, C L Parratt, J R Bigaud, M Eur-Heart-J. 1989 March; 10(3): 235-43 0195-668X

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The interrelationship of morphine and the parasympathetic nervous system in digoxin-induced arrhythmias in the guinea-pig. Author(s): Department of Medicine, University of British Columbia, Vancouver, Canada. Source: Rabkin, S W Clin-Exp-Pharmacol-Physiol. 1988 August; 15(8): 565-73 0305-1870

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The role of lipid peroxidation in pathogenesis of arrhythmias and prevention of cardiac fibrillation with antioxidants. Source: Meerson, F Z Belkina, L M Sazontova, T G Saltykova, V A Arkhipenko YuV Basic-Res-Cardiol. 1987 Mar-April; 82(2): 123-37 0300-8428

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Ventricular arrhythmias with left bundle branch block pattern and inferior axis: assessment of their mechanisms on the basis of response to ATP, nicorandil and verapamil. Author(s): The Third Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan. [email protected] Source: Kobayashi, Y Yazawa, T Adachi, T Kawamura, M Ryu, S Asano, T Obara, C Katagiri, T Jpn-Circ-J. 2000 November; 64(11): 835-41 0047-1828

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

•

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

•

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

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

Vitamins Vitamin D Source: Healthnotes, Inc.; www.healthnotes.com Vitamin E Source: Prima Communications, Inc.www.personalhealthzone.com

•

Minerals Calcium Source: Integrative Medicine Communications; www.drkoop.com Calcium-Channel Blockers Source: Healthnotes, Inc.; www.healthnotes.com Carnitine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10012,00.html Carnitine (l-Carnitine) Source: Integrative Medicine Communications; www.drkoop.com Chromium Source: Healthnotes, Inc.; www.healthnotes.com

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Copper Source: Healthnotes, Inc.; www.healthnotes.com Copper Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,886,00.html L-Carnitine Source: Healthnotes, Inc.; www.healthnotes.com L-Carnitine Source: Integrative Medicine Communications; www.drkoop.com Magnesium Source: Healthnotes, Inc.; www.healthnotes.com Magnesium Source: Integrative Medicine Communications; www.drkoop.com Magnesium Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,890,00.html Magnesium Hydroxide Source: Healthnotes, Inc.; www.healthnotes.com Potassium Source: Healthnotes, Inc.; www.healthnotes.com Potassium Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10086,00.html Selenium Source: Healthnotes, Inc.; www.healthnotes.com Zinc Source: Healthnotes, Inc.; www.healthnotes.com •

Food and Diet Coffee Source: Healthnotes, Inc.; www.healthnotes.com Omega-3 Fatty Acids Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,992,00.html

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

Acute aconitine poisoned patients with ventricular arrhythmias successfully reversed by charcoal hemoperfusion. Author(s): Lin CC, Chou HL, Lin JL. Source: The American Journal of Emergency Medicine. 2002 January; 20(1): 66-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11781926

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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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Antiarrhythmic and cardiohemodynamic effects of a novel Ca(2+) channel blocker, AH-1058, assessed in canine arrhythmia models. Author(s): Takahara A, Sugiyama A, Dohmoto H, Yoshimoto R, Hashimoto K.

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Source: European Journal of Pharmacology. 2000 June 9; 398(1): 107-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10856454 •

Antiarrhythmic effects of a novel class III drug, KCB-328, on canine ventricular arrhythmia models. Author(s): Xue Y, Tanabe S, Nabuchi Y, Hashimoto K. Source: Journal of Cardiovascular Pharmacology. 1998 August; 32(2): 239-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9700986

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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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Betel nut chewing and cardiac arrhythmia. Author(s): Chittivelu S, Chittivelu KS. Source: Vet Hum Toxicol. 1998 December; 40(6): 368. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9830701

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Bradyarrhythmia due to Rauwolfia in homeopathic doses. Author(s): Wadhwa S. Source: J Assoc Physicians India. 2000 September; 48(9): 937-8. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11198804

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Caffeine-induced cardiac arrhythmia: an unrecognised danger of healthfood products. Author(s): Cannon ME, Cooke CT, McCarthy JS. Source: The Medical Journal of Australia. 2001 May 21; 174(10): 520-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11419773

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Cardiac arrhythmia and betel nut chewing--is there a causal effect? Author(s): Chiang WT, Yang CC, Deng JF, Bullard M. Source: Vet Hum Toxicol. 1998 October; 40(5): 287-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9778766

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Cardiac effects of the extract and active components of radix stephaniae tetrandrae. II. Myocardial infarct, arrhythmias, coronary arterial flow and heart rate in the isolated perfused rat heart. Author(s): Yu XC, Wu S, Wang GY, Shan J, Wong TM, Chen CF, Pang KT.

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Source: Life Sciences. 2001 May 11; 68(25): 2863-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11432452 •

Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils. Author(s): Leaf A, Kang JX, Xiao YF, Billman GE. Source: Circulation. 2003 June 3; 107(21): 2646-52. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12782616

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Clinical trials update from the American Heart Association meeting: Omega-3 fatty acids and arrhythmia risk in patients with an implantable defibrillator, ACTIV in CHF, VALIANT, the Hanover autologous bone marrow transplantation study, SPORTIF V, ORBIT and PAD and DEFINITE. Author(s): Cleland JG, Freemantle N, Kaye G, Nasir M, Velavan P, Lalukota K, Mudawi T, Shelton R, Clark AL, Coletta AP. Source: European Journal of Heart Failure : Journal of the Working Group on Heart Failure of the European Society of Cardiology. 2004 January; 6(1): 109-15. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15012926

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Complex ventricular arrhythmia induced by overuse of potassium supplementation in a young male football player. Case report. Author(s): Parisi A, Alabiso A, Sacchetti M, Di Salvo V, Di Luigi L, Pigozzi F. Source: The Journal of Sports Medicine and Physical Fitness. 2002 June; 42(2): 214-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12032418

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Dehydroepiandrosterone and cardiac arrhythmia. Author(s): Sahelian R, Borken S. Source: Annals of Internal Medicine. 1998 October 1; 129(7): 588. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9758585

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Dietary n-3 fatty acids in the prevention of cardiac arrhythmias. Author(s): Leaf A, Kang JX, Xiao YF, Billman GE. Source: Current Opinion in Clinical Nutrition and Metabolic Care. 1998 March; 1(2): 2258. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10565352

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Differential effects of various eicosanoids on the production or prevention of arrhythmias in cultured neonatal rat cardiac myocytes. Author(s): Li Y, Kang JX, Leaf A. Source: Prostaglandins. 1997 August; 54(2): 511-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9380795

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Effect of long-term application of Crataegus oxyacantha on ischemia and reperfusion induced arrhythmias in rats. Author(s): Rothfuss MA, Pascht U, Kissling G. Source: Arzneimittel-Forschung. 2001 January; 51(1): 24-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11215322

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Effects of EGb 761 on nitric oxide and oxygen free radicals, myocardial damage and arrhythmia in ischemia-reperfusion injury in vivo. Author(s): Shen J, Wang J, Zhao B, Hou J, Gao T, Xin W. Source: Biochimica Et Biophysica Acta. 1998 April 28; 1406(3): 228-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9630646

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Effects of extracts from flowering tops of Crataegus meyeri A. Pojark. on ischaemic arrhythmias in anaesthetized rats. Author(s): Garjani A, Nazemiyeh H, Maleki N, Valizadeh H. Source: Phytotherapy Research : Ptr. 2000 September; 14(6): 428-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10960896

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Fetal tachyarrhythmia associated with vibroacoustic stimulation. Author(s): Laventhal NT, Dildy GA 3rd, Belfort MA. Source: Obstetrics and Gynecology. 2003 May; 101(5 Pt 2): 1116-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12738121

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Ginkgo biloba-induced frequent ventricular arrhythmia. Author(s): Cianfrocca C, Pelliccia F, Auriti A, Santini M. Source: Ital Heart J. 2002 November; 3(11): 689-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12506530

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Herbal medicine: beneficial effects, side effects, and promising new research in the treatment of arrhythmias. Author(s): Stout CW, Weinstock J, Homoud MK, Wang PJ, Estes NA 3rd, Link MS. Source: Current Cardiology Reports. 2003 September; 5(5): 395-401. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12917055

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Hypomagnesemia in heart failure with ventricular arrhythmias. Beneficial effects of magnesium supplementation. Author(s): Ceremuzynski L, Gebalska J, Wolk R, Makowska E. Source: Journal of Internal Medicine. 2000 January; 247(1): 78-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10672134

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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.

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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 •

Increased susceptibility to ventricular arrhythmias in a rodent model of experimental depression. Author(s): Grippo AJ, Santos CM, Johnson RF, Beltz TG, Martins JB, Felder RB, Johnson AK. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2004 February; 286(2): H619-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14715499

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Inositol 1,4,5-trisphosphate and reperfusion arrhythmias. Author(s): Woodcock EA, Arthur JF, Matkovich SJ. Source: Clinical and Experimental Pharmacology & Physiology. 2000 September; 27(9): 734-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10972542

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Magnesium supplementation in the prevention of arrhythmias in pediatric patients undergoing surgery for congenital heart defects. Author(s): Dorman BH, Sade RM, Burnette JS, Wiles HB, Pinosky ML, Reeves ST, Bond BR, Spinale FG. Source: American Heart Journal. 2000 March; 139(3): 522-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10689268

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Malignant ventricular arrhythmias due to Aconitum napellus seeds. Author(s): Imazio M, Belli R, Pomari F, Cecchi E, Chinaglia A, Gaschino G, Ghisio A, Trinchero R, Brusca A. Source: Circulation. 2000 December 5; 102(23): 2907-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11104752

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n-3 fatty acids in the prevention of cardiac arrhythmias. Author(s): Leaf A, Kang JX, Xiao YF, Billman GE. Source: Lipids. 1999; 34 Suppl: S187-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10419144

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Partitioning of polyunsaturated fatty acids, which prevent cardiac arrhythmias, into phospholipid cell membranes. Author(s): Pound EM, Kang JX, Leaf A. Source: Journal of Lipid Research. 2001 March; 42(3): 346-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11254745

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Postoperative atrial tachyarrhythmias in patients undergoing coronary artery bypass graft surgery without cardiopulmonary bypass: a role for intraoperative magnesium

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supplementation. Author(s): Maslow AD, Regan MM, Heindle S, Panzica P, Cohn WE, Johnson RG. Source: Journal of Cardiothoracic and Vascular Anesthesia. 2000 October; 14(5): 524-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11052432 •

Prevention of fatal cardiac arrhythmias by polyunsaturated fatty acids. Author(s): Kang JX, Leaf A. Source: The American Journal of Clinical Nutrition. 2000 January; 71(1 Suppl): 202S-7S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10617972

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Protective effect of Crataegus oxyacantha against reperfusion arrhythmias after global no-flow ischemia in the rat heart. Author(s): al Makdessi S, Sweidan H, Dietz K, Jacob R. Source: Basic Research in Cardiology. 1999 April; 94(2): 71-7. Erratum In: Basic Res Cardiol 1999 August; 94(4): 294. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10326654

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Rationale and design of a randomised controlled clinical trial on supplemental intake of n-3 fatty acids and incidence of cardiac arrhythmia: SOFA. Author(s): Brouwer IA, Zock PL, Wever EF, Hauer RN, Camm AJ, Bocker D, OttoTerlouw P, Katan MB, Schouten EG. Source: European Journal of Clinical Nutrition. 2003 October; 57(10): 1323-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14506496

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Respiratory sinus arrhythmia biofeedback therapy for asthma: a report of 20 unmedicated pediatric cases using the Smetankin method. Author(s): Lehrer P, Smetankin A, Potapova T. Source: Applied Psychophysiology and Biofeedback. 2000 September; 25(3): 193-200. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10999237

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Silymarin and vitamin E do not attenuate and vitamin E might even enhance the antiarrhythmic activity of amiodarone in a rat reperfusion arrhythmia model. Author(s): Gyonos I, Agoston M, Kovacs A, Szenasi G, Vereckei A. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 2001; 15(3): 233-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11713891

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Somatic gene and cell therapy strategies for the treatment of cardiac arrhythmias. Author(s): Gepstein L, Feld Y, Yankelson L.

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Source: American Journal of Physiology. Heart and Circulatory Physiology. 2004 March; 286(3): H815-22. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14766670 •

Sudden death due to cardiac arrhythmias. Author(s): Goldstein MR. Source: The New England Journal of Medicine. 2002 March 21; 346(12): 946-7; Author Reply 946-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11911139

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The effects of tetramethylpyrazine on the incidence of arrhythmias and the release of PGI2 and TXA2 in the ischemic rat heart. Author(s): Feng J, Wu G, Tang S. Source: Planta Medica. 1999 April; 65(3): 268-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10232078

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The effects of tubulin-binding agents on stretch-induced ventricular arrhythmias. Author(s): Parker KK, Taylor LK, Atkinson JB, Hansen DE, Wikswo JP, Atkinson B. Source: European Journal of Pharmacology. 2001 April 6; 417(1-2): 131-40. Erratum In: Eur J Pharmacol 2001 August 31; 426(3): 207. Atkinson B [corrected to Atkinson Jb]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11301068

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Trace elements and cardioprotection: increasing endogenous glutathione peroxidase activity by oral selenium supplementation in rats limits reperfusion-induced arrhythmias. Author(s): Tanguy S, Boucher F, Besse S, Ducros V, Favier A, de Leiris J. Source: Journal of Trace Elements in Medicine and Biology : Organ of the Society for Minerals and Trace Elements (Gms). 1998 March; 12(1): 28-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9638610

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Use of phenytoin to treat digitalis-induced cardiac arrhythmias in a miniature Shetland pony. Author(s): Wijnberg ID, van der Kolk JH, Hiddink EG. Source: The Veterinary Record. 1999 March 6; 144(10): 259-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10209818

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Vitamins, supplements, herbal medicines, and arrhythmias. Author(s): Chung MK. Source: Cardiology in Review. 2004 March-April; 12(2): 73-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14766022

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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

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

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

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

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

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

•

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

•

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

•

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

•

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

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

General Overview Arteriosclerosis Source: Integrative Medicine Communications; www.drkoop.com Atherosclerosis Source: Healthnotes, Inc.; www.healthnotes.com Atherosclerosis Source: Integrative Medicine Communications; www.drkoop.com Cardiac Arrhythmia Source: Healthnotes, Inc.; www.healthnotes.com Cardiovascular Disease Overview Source: Healthnotes, Inc.; www.healthnotes.com Congestive Heart Failure Source: Healthnotes, Inc.; www.healthnotes.com

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Coronary Artery Disease Source: Integrative Medicine Communications; www.drkoop.com Endocarditis Source: Integrative Medicine Communications; www.drkoop.com Fainting Source: Integrative Medicine Communications; www.drkoop.com Heart Attack Source: Healthnotes, Inc.; www.healthnotes.com Histoplasmosis Source: Integrative Medicine Communications; www.drkoop.com Hyperkalemia Source: Integrative Medicine Communications; www.drkoop.com Stroke Source: Healthnotes, Inc.; www.healthnotes.com Stroke Source: Integrative Medicine Communications; www.drkoop.com Syncope Source: Integrative Medicine Communications; www.drkoop.com Systemic Lupus Erythematosus Source: Healthnotes, Inc.; www.healthnotes.com TIAs Source: Integrative Medicine Communications; www.drkoop.com Transient Ischemic Attacks Source: Integrative Medicine Communications; www.drkoop.com •

Chinese Medicine Gancao Alternative names: Liquorice Root; Radix Glycyrrhizae Source: Chinese Materia Medica Lingbao Huxin Dan Alternative names: Lingbao Huxin Micropills Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China Shuxiong Pian Alternative names: huxiong Tablets; Shuxiong Pian (Shu Xiong Pi An Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China

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Zhigancao Alternative names: Prepared Liauorice Root; Radix Glycyrrhizae Preparata Source: Chinese Materia Medica •

Herbs and Supplements Acebutolol Source: Healthnotes, Inc.; www.healthnotes.com Adenosine Monophosphate Source: Healthnotes, Inc.; www.healthnotes.com Amiodarone Source: Healthnotes, Inc.; www.healthnotes.com Beta-Adrenergic Blockers Source: Healthnotes, Inc.; www.healthnotes.com Coenzyme Q Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,768,00.html Coenzyme Q10 Source: Healthnotes, Inc.; www.healthnotes.com Corydalis Alternative names: Corydalis turtschaninovii, Corydalis yanhusuo Source: Healthnotes, Inc.; www.healthnotes.com Crataegus Alternative names: Hawthorn; Crataegus oxyacantha L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Crataegus Laevigata Source: Integrative Medicine Communications; www.drkoop.com Crataegus Monogyna Source: Integrative Medicine Communications; www.drkoop.com Dehydroepiandrosterone (DHEA) Source: Healthnotes, Inc.; www.healthnotes.com Devil's Claw Alternative names: Harpagophytum procumbens, Harpagophytum zeyheri Source: Integrative Medicine Communications; www.drkoop.com Digoxin Source: Healthnotes, Inc.; www.healthnotes.com Diltiazem Source: Healthnotes, Inc.; www.healthnotes.com

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Eleuthero Alternative names: Siberian Ginseng, Eleuthero; Acanthopanax/Eleutherococcus senticosus Rupr. & Maxim. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Ephedra Source: Healthnotes, Inc.; www.healthnotes.com Ginkgo Alternative names: Ginkgo biloba Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Glycyrrhiza Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Harpagophytum Procumbens Source: Integrative Medicine Communications; www.drkoop.com Harpagophytum Zeyheri Source: Integrative Medicine Communications; www.drkoop.com Hawthorn Alternative names: Crataegus laevigata, Crataegus oxyacantha, Crataegus monogyna Source: Healthnotes, Inc.; www.healthnotes.com Hawthorn Alternative names: Crataegus monogyna, Crataegus laevigata Source: Integrative Medicine Communications; www.drkoop.com Hawthorn Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Hawthorn Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10035,00.html Melatonin Source: Healthnotes, Inc.; www.healthnotes.com Propafenone Source: Healthnotes, Inc.; www.healthnotes.com Quinidine Source: Healthnotes, Inc.; www.healthnotes.com Sotalol Source: Healthnotes, Inc.; www.healthnotes.com

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Taurine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10059,00.html Thioridazine Source: Healthnotes, Inc.; www.healthnotes.com Trace Minerals Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10061,00.html Uncaria Asian Alternative names: Asian species; Uncaria sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Verapamil Source: Healthnotes, Inc.; www.healthnotes.com Warfarin Source: Healthnotes, Inc.; www.healthnotes.com

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

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CHAPTER 4. DISSERTATIONS ON ARRHYTHMIAS Overview In this chapter, we will give you a bibliography on recent dissertations relating to arrhythmias. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “arrhythmias” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on arrhythmias, we have not necessarily excluded nonmedical dissertations in this bibliography.

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

Models of border zone arrhythmias in acute cardiac ischemia by Peercy, Bradford Eugene; PhD from The University of Utah, 2003, 107 pages http://wwwlib.umi.com/dissertations/fullcit/3105812

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The actions of calcium antagonists on arrhythmias and other responses to myocardial ischaemia in the rat by Curtis, Michael John; PhD from The University of British Columbia (Canada), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL36620

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The relationship of the availability of the slow inward current to the genesis of cardiac arrhythmias during ischemic conditions and reperfusion by Mohabir, Rajendra; PhD from Dalhousie University (Canada), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL33135

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

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CHAPTER 5. PATENTS ON ARRHYTHMIAS Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.8 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “arrhythmias” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on arrhythmias, we have not necessarily excluded nonmedical patents in this bibliography.

Patents on Arrhythmias By performing a patent search focusing on arrhythmias, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 8Adapted from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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

Apparatus for emitting therapeutic energy within tissue Inventor(s): Motamedi; Massoud (2656 Waverly Dr., League City, TX 77573), Ware; David L. (2527 Avenue O, Galveston, TX 77550) Assignee(s): none reported Patent Number: 6,736,808 Date filed: November 6, 2000 Abstract: A catheter capable of both sensing myocardial electrical activity and delivering ablating energy within myocardial tissue is disclosed. The catheter comprises electrodes on the outer sheath and contains a movable fiber optic cable that can be percutaneously advanced beyond the catheter body and into the myocardium for myocardial heating and coagulation, or modification of tissues responsible for cardiac arrhythmias. The fiber optic tip is designed to diffuse ablating energy radially to ablate a larger volume of tissue than is possible with a bare fiber optic tip. In addition, the tip is treated so that energy is not propagated in a forward direction, thus helping to prevent unwanted perforation of the heart tissue. Also disclosed is a method of cardioprotection from ischemia comprising inducing local hyperthermia in heart tissue. Excerpt(s): The present invention relates generally to the field of medical apparatus and instrumentation and more particularly to the field of non-pharmacologic treatment of cardiac disorders including arrhythmias and ischemias, including percutaneous treatment, with specific application to the ablation or modification of tissues responsible for the arrhythmia, and for protection of ischemia reperfusion injury by application of local hyperthermal treatment. Cardiac arrhythmias arise when the rhythmic electrical signal from the heart's intrinsic pacemaker is not correctly propagated throughout the heart. A particular type of cardiac arrhythmia is a ventricular tachycardia, in which an ectopic focus occurs in the ventricle of the heart resulting in a heartbeat of over 100 beats per minute. This problem often occurs near a site of damaged myocardial tissue caused by an infarction or other injury. Heating and thus coagulating ("ablating") myocardial tissues responsible for cardiac arrhythmias has been shown to be of great therapeutic value and is frequently done percutaneously ("catheter ablation"). By far the most common method involves delivering radiofrequency energy (RF) via a catheter with a flexible tip equipped with electrodes for sensing ("mapping") the endocardial electrical activation sequence, and for delivering RF energy or laser energy (see Svenson et al., U.S. Pat. No. 5,172,699). The arrhythmias which respond best to this therapy (with a >90% cure rate) are supraventricular. This is due (1) to well-defined mapping criteria highly predictive of cure and (2) to the small volume of tissue which, when ablated, prevents recurrent arrhythmia. Thus only few, or sometimes one, relatively superficial but well targeted, RF-induced lesion(s) may be necessary for success. Web site: http://www.delphion.com/details?pn=US06736808__

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Atrial and ventricular tachyarrhythmia detection system and method Inventor(s): Seim; Gary (Minneapolis, MN) Assignee(s): Cardiac Pacemakers, Inc. (St. Paul, MN) Patent Number: 6,658,286 Date filed: April 6, 2001 Abstract: Detecting atrial and ventricular tachyarrhythmias involves classifying atrial interval rates in an atrial window having a first length and ventricular interval rates in a ventricular window having a second length. The second length of the ventricular window differs from the first length of the atrial window to enhance detection of ventricular arrhythmias relative to atrial arrhythmia detection. The atrial and ventricular interval rates in the respective windows are classified as fast or acceptable with respect to predefined thresholds. A ventricular episode is declared in response to satisfying the ventricular window according to a second satisfaction criterion. An atrial episode is declared in response to satisfying the atrial window according to a first satisfaction criterion. Excerpt(s): The present invention relates generally to implantable medical devices and, more particularly, to implantable pacemakers and cardioverter-defibrillators for detecting and treating atrial and ventricular tachyarrhythmias. Implantable cardioverter-defibrillators (ICDs) have been developed that employ detection algorithms capable of recognizing and treating ventricular tachycardias and ventricular fibrillation. Detection algorithms are also being developed to recognize and treat atrial tachycardias and atrial fibrillation. In general, ICDs are designed to treat such tachycardias with antitachycardia pacing and low-energy cardioversion shocks in conjunction with back-up defibrillation therapy. These ICDs monitor the heart rate and the onset of the arrhythmia by sensing endocardial signals and determining when the heart is in need of either cardioversion to treat a given tachycardia or of defibrillation to treat a fibrillation condition. Certain ICDs have been designed with dual chamber sensing capabilities to detect and analyze both ventricular and atrial endocardial signals. This increase in cardiac signal input to the ICD has provided an opportunity to determine the origin and the nature of atrial and ventricular tachyarrhythmia, and to reduce the frequency of inappropriate therapy being delivered to an implant patient. Web site: http://www.delphion.com/details?pn=US06658286__

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Cardiac ablation system and method for treatment of cardiac arrhythmias and transmyocardial revascularization Inventor(s): Rastegar; Hassan (Newton, MA), Wang; Paul J. (Chestnut Hill, MA) Assignee(s): New England Medical Center (Boston, MA) Patent Number: 6,527,767 Date filed: May 20, 1998 Abstract: A medical device, and related method, use epicardial ablators and detectors for intraoperative epicardial approaches to ablation therapy of cardiac conduction pathways. An epicardial gripper is sized to grasp the cardiac circumference or smaller structures on the epicardial surface of the heart. Ablators are disposed on the arms of the gripper for epicardial ablation of cardiac conduction tissue. In another embodiment of the invention, an electrode system includes a flexible, adjustable probe forming a loop

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for epicardial ablation. Ablators are provided on one or multiple surfaces of the probe for epicardial ablation of cardiac conduction tissue. In yet another embodiment of the invention, an endocardial ablator detection system provides an indicator adjacent an ablator on an endocardial catheter, and a detector on an epicardial probe. The epicardial probe detects signals transmitted by the indicator on the endocardial catheter to localize the position of the endocardial ablator relative to the epicardial surface. The surgeon uses this information for guidance in adjusting the position of the endocardial ablator according to therapeutic objectives of cardiac ablation. Excerpt(s): Tachycardia is a type of cardiac arrhythmia and is a serious, often-times, fatal condition characterized by rapid, uncontrolled, and ineffective beating of the heart. Most tachycardia is one of two broad categories: ventricular tachycardia (hereinafter VT) and supraventricular tachycardia (hereinafter SVT). VT occurs in the lower chambers of the heart, the ventricles, and frequently leads to serious complications, including sudden cardiac death. Atrial fibrillation and flutter, forms of SVT, originate in the upper chambers of the heart, the atria, and often result in chest pain, fatigue and dizziness and, while generally not life-threatening, is a leading cause of stroke in the United States. Currently, many cases of VT and SVT are treated by drugs that modify the electrical characteristics of the heart tissue. However, the drugs do not eliminate or may not completely control the arrhythmia. In many cases of sustained VT, implantable cardiac defibrillators are used which deliver powerful shocks to the heart when fibrillation is detected. Concurrent treatment with drugs is standard therapy and each implantation of a cardiac defibrillator, of which there may be more than one per patient, is very expensive. In atrial fibrillation the regular pumping action of the atria is replaced by a disorganized, ineffective quivering caused by chaotic conduction of electrical signals through the upper chambers of the heart. Although not immediately life threatening, atrial fibrillation may cause up to a 30% reduction in cardiac output and can lead to more serious conditions, including the formation of blood clots in the atria that can dislodge and travel to the brain resulting in stroke. Currently, the only curative treatment for atrial fibrillation is the surgical "maze procedure", an open heart procedure in which the surgeon makes several incisions in the right and left atria creating scar tissue to electrically separate portions of the atria. Despite clinical success of the maze procedure, it is time-consuming and demanding. The procedure requires open heart surgery and is very expensive. Accordingly, only a modest number of maze procedures are performed annually in a limited number of centers. Web site: http://www.delphion.com/details?pn=US06527767__ •

Cardiac rhythm management system with ultrasound for autocapture or other applications Inventor(s): Sweeney; Robert J. (Woodbury, MN) Assignee(s): Cardiac Pacemakers, Inc. (St. Paul, MN) Patent Number: 6,539,262 Date filed: September 10, 2001 Abstract: A cardiac rhythm management system provides ultrasound autocapture capability for determining whether a stimulation has evoked a desired response from the heart, and for adjusting an energy of the stimulation based on the observed response from the heart. A first ultrasound element is disposed on a lead in the heart. A second ultrasound element is disposed elsewhere in the heart or in the implanted device. An autocapture determination circuit determines whether motion of the heart chamber

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indicates a contraction in response to the stimulation, and adjusts the stimulation energy to provide only that energy which is needed to obtain capture. This saves energy, prolonging the life of the implanted device, minimizing the risk and expense to patient associated with early explantation and replacement of the implanted device. Other applications include using ultrasound for (1) determining the strength of heart contractions (2) determining dissociation between electrical and mechanical heart activity, (3) determining the volume of the heart, (4) determining the origin of sensed intrinsic electrical heart activity signals, (5) recognizing particular arrhythmias (6) disrupting cell membranes for lowering stimulation thresholds, (7) controlling the delivery of a steroid, and (8) obtaining blood flow information. Excerpt(s): This invention relates generally to cardiac rhythm management systems and particularly, but not by way of limitation, to a cardiac rhythm management system with ultrasound autocapture capability for determining whether a stimulation has evoked a desired response from the heart. When functioning properly, the human heart maintains its own intrinsic rhythm, and is capable of pumping adequate blood throughout the body's circulatory system. However, some people have irregular cardiac rhythms, referred to as cardiac arrhythmias. Such arrhythmias result in diminished blood circulation. One mode of treating cardiac arrhythmias uses drug therapy. Drugs are often effective at restoring normal heart rhythms. However, drug therapy is not always effective for treating arrhythmias of certain patients. For such patients, an alternative mode of treatment is needed. One such alternative mode of treatment includes the use of a cardiac rhythm management system. Such systems are often implanted in the patient and deliver therapy to the heart. Cardiac rhythm management systems include, among other things, pacemakers, also referred to as pacers. Pacers deliver timed sequences of low energy electrical stimuli, called pace pulses, to the heart, such as via a transvenous leadwire or catheter (referred to as a "lead") having one or more electrodes disposed in or about the heart. Heart contractions are initiated in response to such pace pulses (this is referred to as "capturing" the heart). By properly timing the delivery of pace pulses, the heart can be induced to contract in proper rhythm, greatly improving its efficiency as a pump. Pacers are often used to treat patients with bradyarrhythmias, that is, hearts that beat too slowly, or irregularly. Web site: http://www.delphion.com/details?pn=US06539262__ •

Continuous localization and guided treatment of cardiac arrhythmias Inventor(s): Grimbergen; Cornelis (Amsterdam, NL), Groenewegen; Arne Sippens (Burlingame, CA), Linnenbank; Andre (Zaandam, NL), Potse; Mark (Amsterdam, NL) Assignee(s): Resolution Medical, Inc. (Pleasanton, CA) Patent Number: 6,658,285 Date filed: March 14, 2001 Abstract: Systems, devices, and methods localize and/or treat arrhythmias of a heart of a patient using signals sensed at an accessible body surface. Based on a database of known heart signals and associated ectopic origin sites or exit sites for treatment guidance, continuous localization identifies candidate ectopic or exit sites throughout a continuous region of tissue. An integral from a selected time interval of a reference heart cycle can be compared statistically with known body surface maps. Statistical interpolation can identify a candidate ectopic or exit site which is different than the known ectopic or exit sites. Relative localization provides accurate site identification

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from one or more known pacing sites (and the associated heart signals) taken from the patient. Excerpt(s): The present invention generally relates to devices, systems, and methods for diagnosing and/or treating the heart. In a particular embodiment, the invention provides techniques for localizing and/or treating arrhythmias. Significant progress has recently been made toward effective treatments of many cardiac arrhythmias. Contraction of a healthy human heart generally propagates through the heart tissue from the sinus node in the right atrium, and eventually the associated ventricles. This normal propagation of contraction forces blood to flow from the atria to the ventricles in a synchronized pumping action. Arrhythmias of the heart often originate at and/or propagate from alternative heart tissues, resulting in rapid irregular or regular contractions of some or all of the heart. Radiofrequency intracardiac catheter ablation of the alternative ectopic origin, an abnormal contraction pathway, or an abnormal pathway exit site is now used to effectively treat a variety of arrhythmias. Although quite effective, current catheter ablation for treatment of cardiac arrhythmias has significant disadvantages. A particular challenge in an effective catheter ablation treatment is the time required for proper identification of the treatment site. As it is generally desirable to limit the size of the ablation, significant time is often spent testing candidate ablation sites. The testing often involves pacing, in which an artificial arrhythmia is initiated with a small electrical pulse from a catheter. The candidate sites are often tested sequentially by positioning the intracardiac catheter against a site within (for example) the right ventricle, identifying the engaged tissue location within the ventricle, sensing and/or pacing the heart cycles at the candidate site, repositioning the intracardiac catheter to a new candidate site, and repeating this process until an ectopic origin or an abnormal pathway exit site has been identified. Web site: http://www.delphion.com/details?pn=US06658285__ •

Enantiomeric compounds for treatment of cardiac arrhythmias and methods of use Inventor(s): Druzgala; Pascal (Santa Rosa, CA), Milner; Peter G. (Los Altos Hills, CA) Assignee(s): ARYx Therapeutics (Santa Clara, CA) Patent Number: 6,683,195 Date filed: April 15, 2002 Abstract: The subject invention pertains to novel enantiomerically pure compounds, and compositions comprising the compounds, for the treatment of cardiac arrhythmias. The subject invention further concerns a method of making and purifying the compounds. The enantiomerically purified compounds, and compositions of these compounds, exhibit unexpectedly distinct and advantageous characteristics, such as a markedly superior ability to reduce or inhibit ventricular premature beats, as compared to racemic mixtures of the compounds. Excerpt(s): Congestive heart failure (CHF) is a disease affecting approximately 2% of the population of the United States (Sami, M. H. [1991] J. Clin. Pharmacol. 31:1081). Despite advances in the diagnosis and treatment of CHF, the prognosis remains poor with a 5year mortality rate higher than 50% from the time of diagnosis (McFate Smith, W. [1985] Am. J. Cardiol. 55:3A; McKee, P. A., W. P. Castelli, P. M. McNamara, W. B. Kannel [1971] N. Engl. J. Med. 285:1441). In patients with CHF, the rate of survival is lowest in those patients with severe depression of left ventricular function and patients who have frequent ventricular arrhythmias. Patients with ventricular arrhythmias and ischemic

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cardiomyopathy have an increased risk of sudden death. The presence of ventricular tachycardia in patients with severe CHF results in a three-fold increase in sudden death compared to those without tachycardia (Bigger, J. T., Jr. [1987] Circulation 75(suppl.IV):28). Because of the high prevalence of sudden unexpected death in patients with CHF, there has been a growing interest in the prognostic significance of arrhythmias in these patients. Several compounds have been used in the management of cardiac arrhythmias in patients with congestive heart failure. Unfortunately, antiarrhythmic drug therapy has been disappointing. The efficacy of anti-arrhythmic drugs markedly decreases as left ventricular function declines, such that only a small fraction of patients with CHF are responsive to anti-arrhythmic therapy. No anti-arrhythmic drug has prevented sudden death in patients with CHF and there is even a question of increased mortality associated with certain anti-arrhythmic drugs (the CAST investigators [1989] N. Engl. J. Med. 321:406). Scientists define tachycardia and ventricular fibrillation as being of multiple nature. It now seems clear, and is accepted in the art, that re-entry is the underlying mechanism to most sustained arrhythmias. Prolonging ventricular repolarization as a means of preventing ventricular arrhythmias has consequently received renewed attention. This points to Class-III agents as drugs of choice in the treatment of arrhythmias. A Class-III agent, as referred to herein, is an agent which is classified as such in the Vaughan-Williams classification of antiarrhythmic drugs. A Class-III agent exerts its primary anti-arrhythmic activity by prolonging cardiac action potential duration (APD), and thereby the effective refractory period (ERP), with no effect on conduction. These electrophysiological changes, which are brought about by blockade of cardiac potassium channels, are well known in the art. Because the blockade of cardiac potassium channels is not associated with depression of the contractile function of the heart, Class-III agents are particularly attractive for use in patients with CHF. Unfortunately, the existing Class-III agents are limited in their utility by additional pharmacological activities, lack of good oral bioavailability, or a poor toxicity profile. Two Class III agents currently marketed are bretylium (i.v. only) and amiodarone (i.v. and p.o.). Web site: http://www.delphion.com/details?pn=US06683195__ •

Implantable cardiac stimulation device and method utilizing electrogram spectral analysis for therapy administration Inventor(s): Thacker; James R. (Eureka, MO) Assignee(s): Pacesetter, Inc. (Sylmar, CA) Patent Number: 6,622,042 Date filed: May 9, 2001 Abstract: An implantable cardiac stimulation device and method utilizes electrogram spectral analysis to administer electrical stimulation therapy to a heart to treat accelerated arrhythmias of the heart. The device includes an arrhythmia detector that initially detects an accelerated arrhythmia of the heart. An acquisition system then acquires an electrogram of the heart having both atrial and ventricular depolarization components. A processor then spectral analyzes the electrogram to provide spectral data related to the accelerated arrhythmia. The spectral data may be used for arrhythmia discrimination, arrhythmia tolerance discernment, and/or by a pulse generator to control stimulation therapy delivery timing. Excerpt(s): The present invention generally relates to an implantable cardiac stimulation device. The present invention more particularly relates to such a device and a method

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utilizing spectral analysis of electrograms to administer arrhythmia therapy. Implantable cardiac stimulation devices are well known in the art. They include implantable pacemakers which provide stimulation pulses to a heart to cause a heart, which would normally or otherwise beat too slowly or at an irregular rate, to beat at a controlled normal rate. They also include defibrillators which detect when the atria and/or the ventricles of the heart are in fibrillation and apply cardioverting or defibrillating electrical energy to the heart to restore the heart to a normal rhythm. Implantable cardiac stimulation devices may also include the combined functionalities of a pacemaker and a defibrillator. As is well known, implantable cardiac stimulation devices sense cardiac activity for monitoring the cardiac condition of the patient in which the device is implanted. By sensing the cardiac activity of the patient, the device is able to provide cardiac stimulation therapy when it is required. Web site: http://www.delphion.com/details?pn=US06622042__ •

Implantable stimulation device and method for discrimination atrial and ventricular arrhythmias Inventor(s): Badelt; Steven W. (Granada Hills, CA), Mouchawar; Gabriel A. (Newhall, CA), Street; Anne M. (San Rafael, CA) Assignee(s): Pacesetter, Inc. (Sylmar, CA) Patent Number: 6,671,548 Date filed: August 30, 2000 Abstract: By redistributing the running totals for various preliminary classifications to other preliminary classifications based upon the values of the most recent cardiac events, the present invention biases the running totals (thereby biasing the duration criteria) to help overcome common discrimination problems which permits the stimulation device to make a correct and final therapy decision more quickly. To identify a patient's heart rhythm, various electrical events such as P-waves and R-waves, and their timing, relationship, and stability, are detected and a preliminary classification is made for each detected event. Running totals of the numbers of all events detected within each of the preliminary classifications are maintained, along with sliding totals covering only the most recently detected events. Then, the arrhythmia is identified based upon an analysis of both the running totals and the sliding totals. In a preferred embodiment, the arrhythmia is identified by first determining whether the sliding total of the number of detected events in any one of the preliminary classifications exceeds a corresponding sliding total threshold. If so, the running totals are then selectively redistributed based upon the sliding totals. The final decision is then made based upon whether the running total corresponding to any one of the preliminary classifications exceeds a corresponding running total threshold. Both method and apparatus embodiments are disclosed. Methods are further described for determining the preliminary classifications of the detected events. Excerpt(s): The present invention generally relates to implantable cardiac stimulation devices, and in particular, a stimulation device capable of discriminating among various atrial and ventricular arrhythmias and delivering high voltage shocks to treat such arrhythmias. An ICD device is a particular type of cardiac stimulation device, which recognizes ventricular tachycardia (VT), ventricular fibrillation (VF) and other arrhythmias, and delivers high voltage electrical therapy to terminate such arrhythmias. These ICD patients may receive inappropriate therapy if the implanted device is not capable of reliably discriminating between VT and SVT and inappropriately classifies

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the rhythm as VT. It is unlikely that these arrhythmias would respond to ventricular therapy, and application of such therapy may accelerate an existing arrhythmia or induce additional arrhythmias. Web site: http://www.delphion.com/details?pn=US06671548__ •

Implantable syncope monitor and method of using the same Inventor(s): Lade; Kipton P. (Stevenson Ranch, CA) Assignee(s): Pacesetter, Inc. (Sylmar, CA) Patent Number: 6,719,701 Date filed: January 28, 2002 Abstract: An implantable monitor and method to acquire, store, and display physiological data for the diagnosis of vasovagal syncope or intermittent cardiac arrhythmias. Physiological data monitored preferably comprises heart rate, blood pressure, and body posture. Physiological signals are monitored until detection of an event that triggers the storage of data. A storage-triggering event may be a maximum or minimum heart rate or blood pressure, a dramatic change in heart rate or blood pressure, or a patient-activated signal. In one embodiment, confirmed detection of vasovagal syncope by the monitor causes a telemetric command to enable a syncope therapy. Storage of physiologic data is triggered by predetermined arrhythmia or syncope detection criteria and appropriate stimulation therapy for the detected condition may be enabled. Excerpt(s): The present invention relates generally to an implantable medical device for monitoring physiological signals. More specifically, the present invention is directed at providing a device and method for storing physiological signals during episodes of syncope or cardiac arrhythmias for use in the diagnosis of syncope or intermittent arrhythmias. Syncope, or fainting, as a result of inadequate cerebral blood flow may be caused by a number of neurocardiogenic or cardiac-related factors. A common form of syncope is vasovagal syncope, a type of neurocardiogenic syncope, that is believed to be precipitated by a reflex of the vagal nerves of the left ventricle that causes hypotension and can be accompanied by a sudden drop in heart rate. Though normally not lifethreatening, vasovagal syncope may have serious consequences on a patient's quality of life and can result in injury and hospitalization. Syncope as a result of underlying cardiac dysfunction is a more serious form since the cardiac-related cause may be a lifethreatening cardiac illness or arrhythmia. Commonly used tests for diagnosing syncope may include a head-up tilt table test, an electrophysiological study, 24 to 48-hour ECG monitoring in the form of a Holter monitor, or external event recorders which may be used to record ECG events over a period of several weeks. The limitation of electrophysiological studies and Holter monitoring is again the fact that syncopal episodes, and the cardiac rhythms associated with syncope, may be intermittent and infrequent and therefore entirely missed by short-term monitoring. Even external ECG event recorders that can monitor for several weeks may not provide a long enough period of data collection to record a syncopal event. Another limitation of external devices is patient compliance in keeping skin electrodes well attached and wearing the external unit at all times. Web site: http://www.delphion.com/details?pn=US06719701__

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Method and apparatus for delivering an optimum shock duration in treating cardiac arrhythmias Inventor(s): Hahn; Stephen J. (Roseville, MN), Ideker; Raymond E. (Durham, NC), Walcott; Gregory P. (Durham, NC) Assignee(s): Cardiac Pacemakers Inc. (St. Paul, MN), Duke University (Durham, NC) Patent Number: 6,643,545 Date filed: July 26, 2001 Abstract: The present invention provides apparatus and methods for delivering an optimum electrical shock in treating cardiac arrhythmias. The apparatus comprises means for producing an electrical waveform signal at least two electrodes The voltage or current of the signal is then detected to determine the signal time constant. The signal time constant is then used in conjunction with a model time constant to determine when the peak amplitude is reached. The waveform is then interrupted when the peak amplitude is reached. Also provided are methods of selecting a cardiac defibrillator by measuring the impedance of implanted electrodes and then selecting a defibrillator having a capacitor which provides an RC time constant equal to that of a model time constant. Excerpt(s): The invention relates to the field of treatment for cardiac arrhythmias, and more particularly to methods and apparatus for delivering the optimum duration of an electrical shock to the heart during treatment of cardiac arrhythmias. Ventricular fibrillation, an often fatal heart arrhythmia, can be terminated by the application of one or more electrical current pulses delivered to the heart through electrodes applied to the chest or implanted within the body. Since the first use on humans of a completely implantable cardiac defibrillator in 1980, research has focussed on making continually smaller and more efficient defibrillation devices. In addition, reducing the defibrillation threshold (DFT) energy level applied to the heart by the defibrillation pulses reduces the likelihood of damaging tissue adjacent the electrodes. A conventional implantable defibrillator includes an electrical pulse generator and an arrhythmia detection circuit coupled to the heart by a series of two or more electrodes implanted in the body. A battery power supply, and one or more charge storage capacitors are used for delivering defibrillation shocks in the form of electrical current pulses to the heart. Web site: http://www.delphion.com/details?pn=US06643545__

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Method and apparatus for MR perfusion image acquisition using a notched RF saturation pulse Inventor(s): Foo; Thomas K. F. (Rockville, MD), Slavin; Glenn S. (Rockville, MD), Wolff; Steven D. (New York, NY) Assignee(s): General Electric Company (Schenectady, NY) Patent Number: 6,618,605 Date filed: September 8, 1999 Abstract: A method and apparatus is disclosed for MR perfusion acquisition using a notched RF saturation pulse. In acquiring such MR data, a volume of slice locations is selected in which MR data is to be acquired. Each given slice is prepared with a notched RF saturation pulse which has a stop-band between a pair of pass-bands. The stop-band is designed to not affect the spins in the next slice in which MR data is to be acquired

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thereby effectively increasing the TI and increasing SNR and contrast simultaneously. Since the notched saturation pulse saturates all the spins outside of the notched stopband, the blood in the ventricular chamber is effectively saturated so that the resulting perfusion images have blood pool suppression. Additionally, the use of a 90.degree. presaturation RF pulse provides a high level of immunity to the effects of arrhythmias or other variations in the patient's heart rate. In order to keep the stop-band, or the notch, as wide as possible to overlap the boundaries of each slice location, it is preferable to interleave the acquisition of slice locations. Excerpt(s): The present invention relates generally to magnetic resonance imaging (MRI), and more particularly to, a method and apparatus to acquire MR images with improved image signal and contrast using an interleaved, notched RF saturation pulse as applied to MRI perfusion imaging. When a substance such as human tissue is subjected to a uniform magnetic field (polarizing field B.sub.0), the individual magnetic moments of the spins in the tissue attempt to align with this polarizing field, but precess about it in random order at their characteristic Larmor frequency. If the substance, or tissue, is subjected to a magnetic field (excitation field B.sub.1) which is in the x-y plane and which is near the Larmor frequency, the net aligned moment, or "longitudinal magnetization", M.sub.z, may be rotated, or "tipped", into the x-y plane to produce a net transverse magnetic moment M.sub.t. A signal is emitted by the excited spins after the excitation signal B.sub.1 is terminated and this signal may be received and processed to form an image. When utilizing these signals to produce images, magnetic field gradients (G.sub.x G.sub.y and G.sub.z) are employed. Typically, the region to be imaged is scanned by a sequence of measurement cycles in which these gradients vary according to the particular localization method being used. The resulting set of received NMR signals are digitized and processed to reconstruct the image using one of many well known reconstruction techniques. Web site: http://www.delphion.com/details?pn=US06618605__ •

Method and apparatuses for monitoring hemodynamic activities using an intracardiac impedance-derived parameter Inventor(s): Huvelle; Etienne (Frasnes-lez-Gosselies, BE), Sanchez; Francisca Cuesta (Machelen, BE) Assignee(s): Cardiac Pacemakers, Inc. (St. Paul, MN) Patent Number: 6,522,914 Date filed: July 14, 2000 Abstract: An intracardiac impedance-derived parameter, Half Cycle Activity (HCA) is used in sensing and controlling cardiac activities in implantable cardiac devices such as bradycardia pacemakers and cardioverter defibrillators. This impedance-derived parameter correlates closely with physical workload and at the same time provides hemodynamic feedback information. Thus, it allows a pacemaker system to implement accurately an increase in hemodynamically driven pacing rate, as well as to limit an inappropriate decrease of driven pacing rate advised by another sensor such as an accelerometer. In addition, it determines the maximum pacing rate for the pacemaker so as to prevent hemodynamic compromise. Therefore, the HCA parameter may be used to determine a Hemodynamic Upper Rate Limit and a Hemodynamic Lower Rate Limit, and thus define a Hemodynamic Pacing Range that is compatible with the range of physiological rate. This allows a closed-loop control of the pacing rate. In an implantable cardioverter defibrillator system, the hemodynamic tolerance of arrhythmias can also be

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assessed by using the HCA parameter to adjust therapy provided to a heart, such as antitachycardia pacing and/or cardioverting shocks. Excerpt(s): This invention relates in general to sensing and controlling cardiac activities in implantable devices including, but not limited to, bradycardia pacemakers and cardioverter defibrillators. More particularly, the invention concerns such a device in which an intracardiac impedance-derived parameter, Half Cycle Activity (HCA) is used as a key variable. It is a well-recognized challenge to monitor accurately physical demands on cardiac support imposed by different levels of work or exercise a patient engages in (Barold et al., Clin Cardiol (1997), Vol 20 (8): 726-9; Alt, Am J Cardiol (1999), Vol 83(5B): 17D-23D). And yet, it is essential for a cardiac pacemaker to operate at a pacing rate that correlates with the workload presented. It is equally essential for a cardioverter defibrillator to determine hemodynamic status of a patient before diagnosing a life-threatening arrhythmia and exerting ventricular anti-tachy therapy (Johnston et al., Eur Heart J (1998), Vol. 19 (12):1879-88). A variety of physiologic or nonphysiologic sensors have been designed during the last two decades to produce a signal directly related to the metabolic demand, including blood pH (U.S. Pat. No. 4,009,721), QT interval (U.S. Pat. No. 4,228,803), blood O.sub.2 saturation (U.S. Pat. No. 4,399,820), blood temperature (U.S. Pat. No. 4,543,954), pressure sensor (U.S. Pat. Nos. 4,899,752 and 5,105,819), piezoelectric crystal (U.S. Pat. Nos. 4,140,132 and 4,428,378), accelerometer (U.S. Pat. Nos. 5,235,237 and 5,383,473), micro-accelerometer (U.S. Pat. Nos. 5,423,883, 5,480,412, Rickards et al., The Multicenter PEA Study Group--PACE (1996) 19:12 Pt1, 2066-2071), thoracic and intracardiac impedance (U.S. Pat. Nos. 3,593,718, 4,291,699, 4,773,401, 5,085,583, 5,235,976, 5,562,711 and 5,782,884) etc. These sensors are less than optimal and have led to little commercial success for various reasons, including difficulty to implement due to the need for specific hardware, lack of correlation between the signal and actual workload, lack of hemodynamic feedback information, slow response, and lack of robustness, i.e., high sensitivity to noise or artifacts inherent to the signal. To resolve the above problems, the present invention is directed to an improved method and apparatus for monitoring hemodynamic activities in implantable cardiac devices. In particular, the present invention relates to cardiac pacemakers, cardioverter defibrillators and like devices that use a physiologic sensing parameter, Half Cycle Activity (HCA) to monitor and adjust cardiac activities. Web site: http://www.delphion.com/details?pn=US06522914__ •

Method of identifying partial adenosine A1 receptor agonists Inventor(s): Belardinelli; Luiz (Menlo Park, CA), Gao; Zhenhai (San Jose, CA) Assignee(s): CV Therapeutics, Inc. (Palo Alto, CA) Patent Number: 6,576,620 Date filed: December 1, 2000 Abstract: The present invention provides a method for identifying partial adenosine A1 receptor agonists that are useful in the treatment of arrhythmias. Partial adenosine A1 receptor agonists and methods for using partial adenosine A1 receptor agonists to treat arrhythmias in mammals. Excerpt(s): This invention relates to a method of identifying compounds with partial adenosine A1 receptor activity, compounds with partial A1 agonist activity identified by the method, and a method of treating arrhythmias in mammals comprising administering an effective amount of a partial Adenosine A1 receptor agonist to a

Patents 151

mammal in need of such treatment. Atrial arrhythmias, such as primary atrial fibrillation, atrial flutter and paroxysmal atrial tachycardia, are largely due to the rapid transmission of electrical impulses through the AV node, a critical regulator of heart rate. Prompt slowing of this rapid AV nodal conduction is often the immediate goal of treatment to slow the abnormally rapid heart rate. Arrhythmias are treated with a variety of compounds including adenosine, a naturally occurring compound that has a wide variety of physiological and pharmacological effects. The biological effects of adenosine are mediated by interaction with several adenosine receptor subtypes known as known as adenosine A1, A2A, A2B, and A3. Web site: http://www.delphion.com/details?pn=US06576620__ •

Method of noninvasively determining a patient's susceptibility to arrhythmia Inventor(s): Hoium; Harold H. (Eden Prairie, MN), Malik; Marek (London, GB), Ryan; Stephen J. (Chaska, MN) Assignee(s): Harbinger Medical, Inc. (Eden Prairie, MN) Patent Number: 6,625,483 Date filed: August 6, 2002 Abstract: A system and method for detecting a patient's susceptibility to arrhythmias and cardiac tissue abnormality is disclosed. The method consists of using a computer, a display, software loaded onto the computer that generates graphical user interfaces (GUIs), an electronic interface, and a plurality of electrodes. The electronics interface is in electronic communication with the computer, and further in electronic communication with the electrodes that are placed by self-adhesion at predetermined locations on a test subject. According to one aspect of the invention, the method enables a user, typically a medical professional, to initiate, with minimal input, certain diagnostic tests involving observing and analyzing a series of QRS complexes, some of which are biased by passively altering the impedance of the patient's body, and others of which are unbiased. The signals are then compared, and the differences are analyzed to detect a patient's susceptibility to arrhythmias and cardiac tissue abnormality. Excerpt(s): The invention relates to the detection of patients' susceptibility to arrhythmias and, more particularly, to various techniques for improving the detection of signals to achieve this goal. There are various devices known in the art for monitoring heart function. Many of these devices typically function by analyzing signals such as an electrocardiogram signal, which can be representative of heart function. There is a need to identify patients at high risk for life-threatening arrhythmias. Various means have been proposed for detecting patient susceptibility to arrhythmias. U.S. Pat. No. 5,117,834 discloses one method by which pulses of electromagnetic energy are injected into a patient and the changes in the patient's electrocardiographic signals caused by the injection are recorded. U.S. Pat. No. 5,351,687 is similar in concept to U.S. Pat. No. 5,117,834, but it describes the use of a magnetic sensor for use in detecting the cardiographic signals. U.S. Pat. No. 5,555,888 discloses various means for adapting and automatically facilitating the assessment techniques and means similar to that shown in the above patents for determining patient susceptibility to arrhythmias. Web site: http://www.delphion.com/details?pn=US06625483__

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Methods and apparatus for preventing atrial arrhythmias by overdrive pacing and prolonging atrial refractoriness using an implantable cardiac stimulation device Inventor(s): Boileau; Peter (Valencia, CA), Bornzin; Gene A. (Simi Valley, CA), Florio; Joseph J. (La Canada, CA), Kurschinski; Douglas T. (Valencia, CA), Park; Euljoon (Stevenson Ranch, CA), Poore; John W. (South Pasadena, CA), Sloman; Laurence S. (West Hollywood, CA) Assignee(s): Pacesetter, Inc. (Sylmar, CA) Patent Number: 6,606,517 Date filed: April 12, 2000 Abstract: A method and apparatus for reducing the incidence of atrial arrhythmias by using an overdrive algorithm to determine the application of overdrive stimulation pulses to a patient's heart, e.g., in the atria. In a first aspect of the invention, the apparatus first determines an overdrive pacing rate and then applies pairs of temporally spaced (staggered) pacing pulses, i.e., primary and secondary pacing pulses, at the determined overdrive pacing rate. In a further aspect of the invention, the pairs of pacing pulses are applied at the overdrive pacing rate to multiple spatially spaced electrodes, i.e., electrodes distributed among multiple sites in a patient's heart, e.g., in the atria. In accordance with a first preferred embodiment, the electrodes may be distributed within a single atrium, e.g., the right atrium, of the patient's heart. Alternatively, a first electrode may be placed in the right atrium and a second electrode may be placed in the coronary sinus or the left atrium or multiple electrodes may be placed proximate to the left atrium. Furthermore, the invention relates to techniques for controlling overdrive pacing to multiple sites in a patient's heart so as to achieve and maintain a target degree of pacing and thus suppress tachycardias. Excerpt(s): The invention generally relates to implantable cardiac stimulation devices such as pacemakers, and in particular, to techniques for overdrive pacing heart tissue to prevent or terminate dysrhythmia. A dysrhythmia is an abnormal heart beat pattern. One example of a dysrhythmia is a bradycardia wherein the heart beats at an abnormally slow rate or where significant pauses occur between consecutive beats. Other examples of dysrhythmias include tachyarrhythmias where the heart beats at an abnormally fast rate, e.g., atrial tachycardia where the atria of the heart beat abnormally fast. One technique for preventing or terminating dysrhythmias is to overdrive pace the heart where an implantable cardiac stimulation device, such as a pacemaker or implantable cardioverter defibrillator (ICD), applies electrical pacing pulses to the heart at a rate somewhat faster than the intrinsic heart rate of the patient. For bradycardia, the implantable cardiac stimulation device may be programmed to artificially pace the heart at a rate of 60 to 80 pulses per minute (ppm) to thereby prevent the heart from beating too slow and to eliminate any long pauses between heart beats. To prevent tachyarrhythmias from occurring, the implantable cardiac stimulation device artificially paces the heart at a rate of at least five to ten pulses per minute faster than the intrinsic tachyarrhythmia heart rate of the patient. In other words, a slight artificial tachycardia is induced and maintained in an effort to prevent an actual tachycardia from arising. Web site: http://www.delphion.com/details?pn=US06606517__

Patents 153

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Methods for sensing arrhythmias in a pacemaker/defibrillator pacemaker/defibrillator programmed to implement the same

and

a

Inventor(s): Olson; Timothy (San Jose, CA), Williams; Michael O. (Mt. Shasta, CA) Assignee(s): Pacesetter, Inc. (Sunnyvale, CA) Patent Number: 6,564,097 Date filed: September 20, 2002 Abstract: A method for detecting an arrhythmia hidden by rapid pacing in a rate adaptive pacemaker/defibrillator. Unmasking a potential arrhythmia is accomplished by lengthening the pace cycle length by a small amount for a number of cycles followed by a shortening of the pace cycle length for the same number of cycles giving an average pacing rate equivalent to the desired rate. This can occur at all times or only when conditions make arrhythmia masking possible. Changing the pace cycle by a small amount over a number of cycles will move the arrhythmia and paced rhythm out of synchronization. Forcing the pacer to continue sensing the arrhythmia is accomplished by insuring that the pacer's sense refractory is less than one half of the pacing cycle length. This is done by constraining the programming of that value to one half the minimum pacing cycle length or using an adaptive sense refractory period. In another embodiment, a hidden arrhythmia is detected by periodically checking a relative refractory portion of the pace refractory period to see if a signal indicative of arrhythmia can be detected. This relative refractory period is produced by shortening the established refractory period by a calculated adaptive relative refractory period. Excerpt(s): Implantable cardioverter defibrillators (ICDs) are sophisticated medical devices which are surgically implanted (abdominally or pectorally) in a patient to monitor the cardiac activity of the patient's heart, and to deliver electrical stimulation as required to correct cardiac arrhythmias which occur due to disturbances in the normal pattern of electrical conduction within the heart muscle. Cardiac arrhythmias can generally be thought of as disturbances of the normal rhythm of the heart beat. Cardiac arrhythmias are broadly divided into two major categories, namely, bradyarrhythmia and tachyarrhythmia. Tachyarrhythmiacan be broadly defined as an abnormally rapid heart rate (e.g., over 100 beats/minute, at rest), and bradyarrhythmia can be broadly defined as an abnormally slow heart rate (e.g., less than 50 beats/minute). Tachyarrhythmias are further subdivided into two major sub-categories, namely, tachycardia and fibrillation. Tachycardia is a condition in which the electrical activity and rhythms of the heart are rapid, but organized. Fibrillation is a condition in which the electrical activity and rhythm of the heart are rapid, chaotic, and disorganized. Tachycardia and fibrillation are further classified according to their location within the heart, namely, either atrial or ventricular. Web site: http://www.delphion.com/details?pn=US06564097__ •

Pacemaker having adaptive arrhythmia detection windows Inventor(s): Assad; Fareed (Minneapolis, MN), Ericksen; James H. (Roseville, MN), Rossing; Martin A. (Coon Rapids, MN) Assignee(s): Medtronic, Inc. (Minneapolis, MN) Patent Number: 6,708,062 Date filed: October 30, 2001

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Abstract: Methods for improving detection of arrhythmias by adaptively increasing arrhythmia detection intervals. One method includes increasing the V2V, the overall cardiac cycle length, thereby decreasing the pacing rate in the presence of ventricular safety paces (VSPs). Another method includes shortening the trigger interval following the atrial pace event, during which time the pacemaker will detect V-sense events, while leaving the A2V VSP interval unchanged, at the end of which any required VSP will be generated. In yet another method, the interval from A-pace to V-pace, the PAV interval, is shortened, while leaving the overall V2V cycle interval unchanged. This increases the ventricular to artial V2A interval, increasing the detection window for arthythmias. The PAV interval can be shortened in response to a recent history of VSP events. Excerpt(s): The present invention relates generally to cardiac pacemakers. More particularly, the present invention relates to cardiac pacemakers having improved methods for detecting arrhythmias. An arrhythmia is a heart rhythm disorder which interferes with the life sustaining blood pumping action of the heart. Examples of arrhythmias include ventricular tachycardia and atrial tachycardia. Ventricular tachycardia effects the lower chambers of the heart, the ventricles, and atrial tachycardia effects the upper chambers of the heart, the atria. Ventricular tachycardia is a rapid heart beat initiated within the ventricles, characterized by three or more consecutive premature ventricular beats. Ventricular tachycardia is a potentially lethal arrhythmia, as it may cause the heart to become unable to pump adequate blood through the body. Companies such as Medtronic, Inc., have developed implantable pacemakers which may be used to successfully treat ventricular tachycardia by delivering ventricular pacing pulses to the heart when ventricular tachycardia is detected. Dual chamber pacing modes have been widely adopted for pacing therapy. Among the dual chamber operating modes is the "DDD" mode, which can pace an atrium and a ventricle, senses both the atrium and the ventricle, and can either inhibit or trigger pacing stimuli for both chambers. This mode has a sensor augmented variant mode called "DDDR", where the "R" stands for rate-adaptive or rate modulation. Web site: http://www.delphion.com/details?pn=US06708062__ •

Prioritized rule based method and apparatus for diagnosis and treatment of arrhythmias Inventor(s): Brown; Mark L. (North Oaks, MN), Kaemmerer; William F. (Edina, MN), Olson; Walter H. (North Oaks, MN) Assignee(s): Medtronic, Inc. (Minneapolis, MN) Patent Number: 6,731,978 Date filed: October 30, 2002 Abstract: An implantable antiarrhytmia device which detects and classifies arrhythmias of the human heart, and delivers appropriate therapy. The device employs a method of arrhythmia classification based on a set of prioritized rules, each of the rules defining a plurality of criteria based upon characteristics of sensed depolarizations of heart tissue, each rule being met when the criteria associated with the rule are met. Some rules, when met, trigger delivery of antiarrhythmia therapy. Other rules, when met, inhibit delivery of antiarrhythmia therapy. The rules may be met simultaneously, and if so, the highest priority rule governs the behavior of the device. Excerpt(s): This invention relates to devices which detect and/or treat tachyarrhythmias (rapid heart rhythms), and more specifically, to mechanisms to distinguish among

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various tachyarrhythmias and to provide appropriate therapies to treat the identified tachyarrhythmias. Early automatic tachyarrhythmias detection systems for automatic cardioverter/defibrillators relied upon the presence or absence of electrical and mechanical heart activity (such as intra-myocardial pressure, blood pressure, impedance, stroke volume or heart movement) and/or the rate of the electrocardiogram to detect hemodynamically compromising ventricular tachycardia or fibrillation. In pacemaker/cardioverter/defibrillators presently in commercial distribution or clinical evaluation, fibrillation is generally distinguished from ventricular tachycardia using ventricular rate based criteria. In such devices, it is common to specify the rate or interval ranges that characterize a tachyarrhythmia as opposed to fibrillation. However, some patients may suffer from ventricular tachycardia and ventricular fibrillation which have similar or overlapping rates, making it difficult to distinguish low rate fibrillation from high rate tachycardia. In addition, ventricular fibrillation may display R-R intervals which vary considerably, resulting in intervals that may fall within both the tachycardia and fibrillation rate or interval ranges or outside both. Web site: http://www.delphion.com/details?pn=US06731978__ •

Pulmonary vein ablation with myocardial tissue locating Inventor(s): Acker; David E. (Setauket, NY) Assignee(s): Transurgical, Inc. (Setauket, NY) Patent Number: 6,672,312 Date filed: January 31, 2002 Abstract: A method of treating cardiac arrhythmias by ablating a portion of the myocardial fibers within a pulmonary vein. Myocardial fibers within a pulmonary vein are located and ablated to block conduction of electrical signals to the heart from ectopic foci within the pulmonary vein. The myocardial fibers are located and selectively ablated so as to avoid having to create a circumferential conduction block around the pulmonary vein or ostium. Devices for locating the myocardial fibers, selectively ablating such fibers, and directing ablative energy, are also disclosed. Excerpt(s): The present invention relates to the treatment of cardiac arrhythmias such as atrial fibrillation. The normal contractions of the heart muscle arrives from electrical impulses generated at a focus within the heart and transmitted through the heart muscle tissue or "myocardial" tissue. This tissue includes fibers which can carry electrical signals. The tissue of the pulmonary vein normally merges with the myocardial tissue of the heart wall at a border near the opening or ostium of the pulmonary vein. In some individuals, fibers of myocardial tissue extend from the wall of the left atrium, through the ostium and along the wall of the pulmonary vein. In some individuals, elongated strands of myocardial tissue extend within the wall of pulmonary vein away from the heart (distally), so that the strains of myocardial tissue project beyond the normal border. It has been recognized that atrial fibrillation can be caused by an abnormal electrical focus in such strands of myocardial tissue within the pulmonary vein. Because these strains of myocardial tissue merge with myocardial tissue of the heart wall, electrical signals from such an abnormal focus can propagate proximately along one or more strands of myocardial tissue through the myocardial tissue and into the heart wall itself, resulting in abnormal contractions. Web site: http://www.delphion.com/details?pn=US06672312__

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QRST subtraction using an adaptive template for analysis of TU wave obscured atrial activity Inventor(s): Groenewegen; Arne Sippens (Burlingame, CA), Lesh; Michael D. (Mill Valley, CA), Mlynash; Michael D. (Mountain View, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,615,075 Date filed: March 14, 2001 Abstract: The present invention provides a noninvasive localization, characterization and classification apparatus and method for cardiac arrhythmias. The invention enables discrete isolation of the intricate spatial and temporal detail in morphology of the atrial activity of interest from superimposed ventricular activity of a preceding heartbeat in a particular arrhythmia. An adaptive QRST subtraction template is used that is modulated for discrepancies in voltage and rate between the QRST template and arrhythmia signal. The QRST template modulation is accomplished by using one or more fiducial points and windows that are annotated in both the QRST template and the arrhythmia signal. The invention includes, but is not limited to, the isolation of atrial activity that are commonly known as: (1) P waves in case of focal atrial fibrillation, atrial tachycardia, and orthodromic AV reentrant tachycardia; (2) fibrillation waves in case of chronic atrial fibrillation; and (3) flutter waves in case of atrial flutter. Excerpt(s): This invention relates generally to electrocardiographic localization and classification of cardiac arrhythmias. More particularly, the present invention relates to noninvasive analysis of TU wave obscured atrial activity. An arrhythmia is any deviation from or disturbance of the normal heart rhythm. This is when the heart's natural pacemaker develops an abnormal rate or rhythm (e.g. a tachycardia where the heart rate is faster than normal), the normal conduction pathway is interrupted, an abnormal or accessory conduction pathway controls the rhythm, or when another part of the heart takes over as an ectopic pacemaker. Arrhythmias may be benign, life threatening or even fatal depending on the type of arrhythmia. Several different types of arrhythmias can be distinguished, for example atrial tachycardia, atrioventricular (AV) node reentrant tachycardia, atrial fibrillation, atrial flutter, and ventricular tachycardia. Although electrocardiographic arrhythmia evaluation is currently feasible by capturing spontaneous tachycardia episodes via ambulatory or emergency electrocardiogram (ECG) recording, analysis of the timing and presumed origin of atrial activation on the body surface is frequently hampered by the simultaneous occurrence of the higher voltage ventricular activation or recovery potentials. During both focal and incisional reentrant atrial tachycardia, the low-amplitude P wave (atrial activity) may be obscured by the preceding high-amplitude QRST segment (ventricular activity). Difficulties are encountered when visually assessing the P wave morphology of TU wave superimposed ectopic atrial beats that are critically related to atrial fibrillation triggered by a focal source, typically situated in one of the pulmonary veins. Similarly, localization of the atrial insertion site using the retrograde P wave morphology obtained during orthodromic AV reentrant tachycardia may be difficult due to partial or complete concealment by the TU wave. Web site: http://www.delphion.com/details?pn=US06615075__

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Surgical ablation with radiant energy Inventor(s): Sinofsky; Edward L. (Dennis, MA) Assignee(s): CardioFocus, Inc. (Norton, MA) Patent Number: 6,676,656 Date filed: August 7, 2001 Abstract: Surgical ablation instruments are disclosed for creating lesions in tissue, including cardiac tissue for treatment of arrhythmias and other diseases. The hand held instruments are especially useful in open chest or port access cardiac surgery for rapid and efficient creation of curvilinear lesions to serve as conduction blocks. Photoablative instruments are disclosed that can achieve rapid and effective photoablation through the use of distributed (e.g., diffuse or defocused) radiant energy. Excerpt(s): The present invention relates to surgical ablation instruments for ablation of tissue for the treatment of diseases, and, in particular, to surgical instruments employing radiant energy. Methods of ablating tissue using radiant energy are also disclosed. The instruments can be used, for example, in the treatment of cardiac conditions such as cardiac arrhythmias. Cardiac arrhythmias, e.g., fibrillation, are irregularities in the normal beating pattern of the heart and can originate in either the atria or the ventricles. For example, atrial fibrillation is a form of arrhythmia characterized by rapid randomized contractions of the atrial myocardium, causing an irregular, often rapid ventricular rate. The regular pumping function of the atria is replaced by a disorganized, ineffective quivering as a result of chaotic conduction of electrical signals through the upper chambers of the heart. Atrial fibrillation is often associated with other forms of cardiovascular disease, including congestive heart failure, rheumatic heart disease, coronary artery disease, left ventricular hypertrophy, cardiomyopathy or hypertension. Various surgical techniques have been proposed for the treatment of arrhythmia. Although these procedures were originally performed with a scalpel, these techniques may also use ablation (also referred to as coagulation) wherein the tissue is treated, generally with heat or cold, to cause tissue necrosis (i.e., cell destruction). The destroyed muscle cells are replaced with scar tissue which cannot conduct normal electrical activity within the heart. Web site: http://www.delphion.com/details?pn=US06676656__

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System and method for treating atrial arrhythmias Inventor(s): Hsu; William (Circle Pines, MN), KenKnight; Bruce H. (Maple Grove, MN) Assignee(s): Cardiac Pacemakers, Inc. (St. Paul, MN) Patent Number: 6,526,317 Date filed: January 23, 2001 Abstract: A system for defibrillating an atrial region of a heart experiencing a supraventricular arrhytmia. The defibrillation system senses and analyzes both atrial and ventricular cardiac signals of the heart to determine if the heart is experiencing a supraventricular arrhythmia. Upon detecting a supraventricular arrhythmia, the defibrillation system begins delivering a train of atrial pacing pulses to the atria of the heart and a series of ventricular pacing pulses to the ventricles of the heart to synchronize the contractions of the heart with the pacing pulses. The defibrillation system then delivers a defibrillation electrical energy pulse across the atrial region at a

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predetermined coupling interval time after delivering a final atrial pacing pulse and a final ventricular pacing pulse so that the defibrillation pulse will fall outside the occurrence of a T-wave of the heart, thus reducing the likelihood of inducing ventricular fibrillation. Excerpt(s): The present invention relates generally to implantable medical devices and in particular to the use of implantable medical devices for treating supraventricular tachyarrhythmias. Clinically, atrial arrhythmias are one of the most frequently encountered of the cardiac arrhythmias. Annually, more than 500,000 individuals are diagnosed with atrial arrhythmias, including atrial fibrillation, flutter and tachycardia. While these conditions are not immediately life-threatening, they can lead to serious health risks if left untreated. These include the increased potential for developing chronic fibrillation, embolic strokes and for transferring the aberrant atrial electrical signals to the ventricles, which can result in ventricular tachycardia and/or ventricular fibrillation. Treating atrial fibrillation has traditionally involved the use of antiarrhythmic agents. However, patients who have experienced only one episode or infrequent paroxysmal episodes of atrial fibrillation may not want the inconvenience of daily medication and follow-up. Alternatively, patients with recurrent episodes are at the highest risk for a thromboembolism and often are candidates for maintenance antiarrhythmic and anticoagulation therapies. This long-term therapy, however, can have potential drawbacks as chronic use of some antiarrhytmnic agents may have toxic side effects. As a result, effective alternatives to chronic pharmacological treatment have been sought. Web site: http://www.delphion.com/details?pn=US06526317__ •

Tissue ablation device and methods of using Inventor(s): Friedman; Paul (Rochester, MN) Assignee(s): Mayo Foundation for Medical Education and Research (Rochester, MN) Patent Number: 6,669,693 Date filed: November 13, 2001 Abstract: The invention provides for a tissue ablation device and methods of using such a tissue ablation device for treating cardiac arrhythmias. Excerpt(s): This invention relates to cardiac arrhythmias, and more particularly to a tissue ablation device and methods of using such a device. Atrial fibrillation is the most common sustained arrhythmia encountered in clinical practice and affects over 2 million Americans. Atrial fibrillation is often initiated by rapidly firing triggers located in the pulmonary veins. One method for treating atrial fibrillation includes placement of a catheter adjacent to the arrhythmogenic substrate that contains the trigger or electrically connects the trigger to the atrium, followed by subsequent ablation of the tissue containing the trigger. These triggers may only discharge intermittently, which makes it difficult to precisely position the catheter with respect to the trigger location and precisely ablate the tissue necessary to eradicate the trigger. The anatomy of the pulmonary veins is complex, and technical limitations make localizing and eliminating pulmonary vein potentials difficult. Multiple procedures, therefore, are often required to precisely locate the triggers in the pulmonary veins. Once the triggers are located, complications often arise during the ablation procedure. For example, ablation within the pulmonary vein increases the risk of pulmonary vein stenosis. In addition, effective

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monitoring of the pulmonary vein (e.g., assessment of edema, thrombosis, and/or narrowing) during energy delivery remains difficult. Web site: http://www.delphion.com/details?pn=US06669693__ •

Treatment of arrhythmias via inhibition of a multifunctional calcium/calmodulindependent protein kinase Inventor(s): Anderson; Mark E. (Nashville, TN), Braun; Andrew P. (Calgary, CA), Schulman; Howard (Palo Alto, CA), Sung; Ruey J. (Hillsborough, CA) Assignee(s): The Board of Trustees of the Leland Stanford Jr. University (Palo Alto, CA) Patent Number: 6,518,245 Date filed: January 30, 1998 Abstract: This invention provides a method for treating or preventing arrhythmias in a human subject comprising the administration of an effective amount of a calcium/calmodulin-dependent protein kinase inhibitor. Also provided are pharmaceutical compositions comprising a calcium/calmodulin-dependent protein kinase inhibitor and a pharmaceutically acceptable carrier and methods for identifying agents useful for the treatment of arrhythmias. Excerpt(s): The present invention relates to methods for the treatment of arrhythmias by inhibition of a multifunctional calcium/calmodulin-dependent protein kinase (CaM kinase), pharmaceutical compositions useful in such treatments, and methods for identifying new agents useful for such treatments. Arrhythmias are a leading cause of cardiac-related death in the United States. Prolongation of the cardiac action potential is an important predisposing condition for these arrhythmias. Many antiarrhythmic drugs directly prolong the action potential duration and so may further contribute to these arrhythmias (i.e. the proarrhythmic effects of antiarrhythmic drugs). Despite their cost, implantable cardiac defibrillators (ICDs) have become the treatment of choice for arrhythmias. In order to prevent painful shocks.about.50% of patients with ICDs require additional treatment with antiarrhythmic drugs. Thus there is an important need to develop better antiarrhythmic drug therapies. Early afterdepolarizations (EADs) are depolarizing oscillations in the action potential (AP) that occur during repolarization. One cause of EADs is inward L-type Ca.sup.2+ current (I.sub.Ca). I.sub.Ca is present at cell membrane potentials (Vm) within the window of I.sub.Ca steady state activation and inactivation overlap; such as occur during action potential repolarization. Prolongation of action potential repolarization may increase the time that the Vm is in the window current range for I.sub.Ca and thus the likelihood of EADs. EADs are important because they are one probable cause of lethal arrhythmias associated with long QT intervals including torsade de pointes. A long QT interval reflects prolonged action potential repolarization in ventricular myocardium and is due to a wide variety of conditions including bradycardia and hypokalemia. One important cause of long QT intervals are antiaffhythmic drugs and the ventricular proarrhythmic effects of many antiarrhythmic agents are due to QT interval prolongation. Web site: http://www.delphion.com/details?pn=US06518245__

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Patent Applications on Arrhythmias As of December 2000, U.S. patent applications are open to public viewing.9 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to arrhythmias: •

Algorithms for detecting atrial arrhythmias from discriminatory signatures of ventricular cycle lengths Inventor(s): Ritscher, David E.; (Minneapolis, MN), Sarkar, Shantanu; (St. Paul, MN) Correspondence: Medtronic, INC.; 710 Medtronic Parkway NE; Ms-Lc340; Minneapolis; MN; 55432-5604; US Patent Application Number: 20040092836 Date filed: November 11, 2002 Abstract: Detection of arrhythmias is facilitated using irregularity of ventricular beats measured by delta-RR (.DELTA.RR) intervals that exhibit discriminatory signatures when plotted in a Lorenz scatter-plot. An "AF signature metric" is established characteristic of episodes of AF that exhibit highly scattered (sparse) distributions or formations of 2-D data points. An "AFL signature metric" is established characteristic of episodes of AFL that exhibit a highly concentrated (clustered) distribution or formation of 2-D data points. A set of heart beat interval data is quantified to generate highly scattered (sparse) formations as a first discrimination metric and highly concentrated (clustered) distributions or formations as a second discrimination metric. The first discrimination metric is compared to the AF signature metric, and/or the second discrimination metric is compared to the AFL signature metric. AF or HFL is declared if the first discrimination metric satisfies either one of the AF signature metric. Excerpt(s): The present invention relates to detection of atrial arrhythmias, particularly atrial fibrillation (AF) and atrial flutter (AFL) using discriminatory signatures of the ventricular cycle lengths. The mechanical events of the heart are preceded and initiated by the electrochemical activity of the heart (i.e., the propagation of the action potential). In a healthy heart, the electrical and mechanical operation of the heart is regulated by electrical signals produced by the heart's sino-atrial (SA) node located in the right atrial wall. Each atrial depolarization signal produced by the SA node spreads across the atria, causing the depolarization and contraction of the atria, and arrives at the atrioventricular (A-V) node. The A-V node responds by propagating a ventricular depolarization signal through the "Bundle of His" of the ventricular septum and thereafter to the "Bundle Branches" and the Purkinje muscle fibers of the right and left ventricles. The signals propagated through the Bundle Branches effects depolarization and accompanying contraction of the left ventricle and the right ventricle in close order. Following contraction, the myocardial cells repolarize during a short period of time, returning to their resting state. The right and left atria refill with venous and oxygenated blood, respectively, until the cardiac cycle is again commenced by a signal originating from the SA node. At rest, the normal adult SA node produces an atrial depolarization signal approximately 60 to 85 times a minute, causing the heart muscle to contract, and thereby pumping blood to the remainder of the body. The electrical signal passes through the heart chambers as a wave front that can be characterized as a plane advancing from cell to cell through the cardiac muscle that separates cells of different

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

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electrical potential as a function of the time that it takes to complete the cardiac cycle. The above-described cardiac cycle is disrupted in diseased or injured hearts, and the chronic or episodic disrupted electrical activity has long been employed to diagnose the state of the heart. A variety of techniques have been developed for collecting and interpreting data concerning the electrical activity of the heart using external medical devices (EMDs) both in the clinical setting and by way of portable external monitors worn by an ambulatory patient or implantable medical devices (IMDs) implanted in an ambulatory patient to collect data relating to electrical heart function during daily activities of the patient. Such techniques include electrocardiography, vectorcardiography and polarcardiography. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Anthranilamides and methods of their use Inventor(s): Brendel, Joachim; (Bad Vilbel, DE), Hemmerle, Horst; (Indianapolis, IN), Kleemann, Heinz-Werner; (Bischofsheim, DE), Peukert, Stefan; (Frankfurt, DE), Pirard, Bernard; (Frankfurt, DE) Correspondence: Finnegan, Henderson, Farabow,; Garrett & Dunner, L.L.P.; 1300 I Street, N.W.; Washington; DC; 20005-3315; US Patent Application Number: 20030187033 Date filed: April 26, 2002 Abstract: The present invention is related to anthranilamides of formula I, 1in which R(1) to R(7) have the meanings indicated herein, a process for their preparation, their use as medicaments, and pharmaceutical preparations containing them. The compounds act on the Kv1.5 potassium channel and inhibit a potassium current which is referred to as the ultra-rapidly activating delayed rectifier in the atrium of the human heart. The compounds are therefore suitable for use as novel antiarrhythmic agents for the treatment and prophylaxis of atrial arrhythmias (e.g., atrial fibrillation (AF) or atrial flutter). Excerpt(s): in which R(1), R(2), R(3), R(4), R(5), R(6) and R(7) have the meanings indicated hereinafter, to their preparation and use, and in particular, to their use as pharmaceuticals. The compounds of formula I have not previously been disclosed. They act on the Kv1.5 potassium channel in the atrium of the human heart, which is referred to as ultra-rapidly activating delayed rectifier, and inhibit the potassium current. The compounds are therefore suitable as novel antiarrhythmic agents for the treatment and prophylaxis of atrial arrhythmias, e.g., atrial fibrillation (AF) or atrial flutter. Atrial fibrillation (AF) and atrial flutter are the most common and persistent cardiac arrhythmias. Their occurrence increases with increasing age and frequently leads to other fatal symptoms, such as stroke. AF affects about 1 million Americans each year and leads to more than 80,000 strokes annually in the USA. The class I and III antiarrhythmic agents in use at present reduce the rate of AF occurrence, but can only be used in a limited manner due to their proarrhythmic side effects. Consequently, there is a great medical need to develop better medicaments for the treatment of atrial arrhythmias (S. Nattel (1995) "Newer developments in the management of atrial fibrillation," Am. Heart J., 130:1094-1106). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Apparatus for detecting and treating ventricular arrhythmia Inventor(s): Brown, Ward M.; (Lacrosse, WI) Correspondence: Finnegan, Henderson, Farabow, Garrett & Dunner; Llp; 1300 I Street, NW; Washington; DC; 20005; US Patent Application Number: 20030212436 Date filed: June 13, 2003 Abstract: A system and method for long-term monitoring of cardiac conditions such as arrhythmias is disclosed. The invention includes a pulse generator including means for sensing an arrhythmia. The pulse generator is coupled to at least one subcutaneous electrode or electrode array for providing electrical stimulation such as cardioversion/defibrillation shocks and/or pacing pulses. The electrical stimulation may be provided between multiple subcutaneous electrodes, or between one or more such electrodes and the housing of the pulse generator. In one embodiment, the pulse generator includes one or more electrodes that are isolated from the can. These electrodes may be used to sense cardiac signals. Excerpt(s): This invention relates to a method and apparatus for treating ventricular arrhythmias; and more particularly, relates to a method and apparatus for long-term monitoring of arrhythmias, and for the delivery of acute tachyarrhythmia and bradyarrhythmia therapy using a subcutaneous stimulation device. It has long been known to use implantable systems to protect patients that are at risk for life-threatening arrhythmias. For example, rapid heart rhythms commonly referred to as tachyarrhythmias are generally treated using implantable devices such as the Medtronic Model 7273 GEM II DR or the 7229 GEM II SR, both commercially available from the Medtronic Corporation. These systems detect the presence of tachyarrhythmia conditions by monitoring the electrical and mechanical heart activity (such as intramyocardial pressure, blood pressure, impedance, stroke volume or heart movement) and/or the rate of the electrocardiogram. These devices require that one or more defibrillation electrodes be positioned within the atrium and/or ventricle of a patient's heart using current endocardial lead placement techniques. The use of such systems provides consistent long-term monitoring capabilities, and relatively good protection against life-threatening tachyarrhythmias. Similarly, bradyarrhythmias, which are heart rhythms that are too slow, are generally treated using implantable pulse generators. Such devices are described in U.S. Pat. Nos. 5,158,078, 4,958,632, and 5,318,593, for example. As with devices to treat tachyarrhythmias, most implantable pulse generators that treat these types of conditions generally require leads that are implanted within one or more cardiac chambers. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Apparatus, methods, and computer program products for evaluating a risk of cardiac arrhythmias from restitution properties Inventor(s): Banville, Isabelle; (Alabaster, AL), Chen, Xiaozhong; (Birmingham, AL), Gray, Richard A.; (Vestavia Hills, AL) Correspondence: Myers Bigel Sibley & Sajovec; PO Box 37428; Raleigh; NC; 27627; US Patent Application Number: 20040015088 Date filed: May 31, 2002

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Abstract: Methods, systems, and computer program products can be provided for evaluating a risk of the occurrence of cardiac arrhythmias in a heart. The system can include at least one sensing electrode and a controller. The sensing electrode can be configured to sense electrical signals from a heart over a range of heart rates. The controller can be configured to determine values of a at least one restitution property of the heart from the sensed electrical signals and to evaluate the risk of the occurrence of cardiac arrhythmias from the determine values of the at least one restitution property. Excerpt(s): The present invention is related to evaluating a risk of cardiac arrhythmias. Despite advances in antiarrhythmic therapies, cardiac arrhythmias remain a major health problem, causing about 300,000 sudden cardiac deaths annually in the United States (Weiss J N et al., Circulation (1999) 99:2819-2826). Cardiac arrhythmias can occur when the electrical waves which stimulate the heart meander erratically through the heart muscle, creating disordered and ineffective contraction. The primary focus of literature and research has been on detecting when cardiac arrhythmias occur and reducing the occurrence of arrhythmias with medical therapies or lifestyle changes. Medical therapies include drugs which can reduce the occurrence of arrhythmias and implantable devices which can detect the onset of arrhythmias and apply electrical pulses to the heart to stop arrhythmias. However, oftentimes medical therapies are not employed until an individual first suffers and survives a sufficiently serious arrhythmia which signals the need for medical therapy. Consequently, there is a need for techniques and apparatus which can identify individuals at risk for developing cardiac arrhythmias prior to the onset of serious arrhythmia. The present invention provides methods, systems, and computer program products for evaluating a risk of the occurrence of cardiac arrhythmias in a heart. In some embodiments of the present invention the methods can include detecting electrical activity from the heart over a range of heart rates (i.e. restitution properties). Values of at least one restitution property of a heart are determined from the detected electrical activity over the range of heart rates. The risk of occurrence of cardiac arrhythmias is evaluated from the determined values of the at least one restitution property. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Arylated furan- and thiophenecarboxamides, processes for their preparation, their use as medicaments, and pharmaceutical preparations comprising them Inventor(s): Brendel, Joachim; (Bad Vilbel, DE), Hemmerle, Horst; (Bad Soden, DE), Kleemann, Heinz-Werner; (Bischofsheim, DE), Peukert, Stefan; (Frankfurt am Main, DE) Correspondence: Finnegan, Henderson, Farabow,; Garrett & Dunner, L.L.P.; 1300 I Street, N.W.; Washington; DC; 20005-3315; US Patent Application Number: 20040068120 Date filed: December 12, 2001 Abstract: Compounds of the formulae Ia and Ib 1in which X, R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(30) and R(31) have the meanings indicated in the claims, are very particularly suitable as novel antiarrhythmic active compounds, in particular for the treatment and prophylaxis of atrial arrhythmias, e.g. atrial fibrillation (AF) or atrial flutters. Excerpt(s): This application claims the benefit of priority under 35 U.S.C.sctn. 119(a) to German patent application no. 10061876.6-44, filed on Dec. 12, 2000, the contents of which are incorporated by reference herein. where phenyl, naphthyl, furyl, thienyl and

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the N-containing heteroaromatic are unsubstituted or substituted by 1, 2 or 3 substituents chosen from F, Cl, Br, I, CF.sub.3, OCF.sub.3, NO.sub.2, CN, COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino. independently of one another are F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, COOMe, CONH.sub.2, COMe, NH.sub.2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Bayesian discriminator for rapidly detecting arrhythmias Inventor(s): Chan, Francis Hy; (Pokfulam, HK), Fung, Peter Chin Wan; (Pokfulam, HK), Lau, Chu-pak; (Midlevel, HK), Tse, Hung-Fat; (Midlevel, HK), Xu, Weichao; (Shenzhen, CN) Correspondence: Pennie And Edmonds; 1155 Avenue OF The Americas; New York; NY; 100362711 Patent Application Number: 20030216654 Date filed: May 7, 2002 Abstract: A method for accurate and rapid automated detection of atrial fibrillation (AF), sinus rhythm (SF), and atrial flutter (AFL) is disclosed, which allows distinguishing of these cardiac signals with lowered risk of errors by implanted pacemakers and like devices. The method includes training episodes of intra-cardiac signals (called the closed data set CDS) to evaluate five feature parameters with a discriminator classifying the signal into AF, AFL or sinus rhythm (SR). Comparison with the independent decisions of experienced physicians for each episode reveals specificity, accuracy and sensitivity of greater than 97%. Each episode is a window of intracardiac signal of interval 1-2 seconds with the discriminator providing results in less than 0.25 s. In another aspect, the method is resistant to the presence of noise in the data. In yet another aspect, more feature parameters may be used in alternative implementations including for detecting signals other than AF, AFL & SR. Excerpt(s): The invention is directed to the generation and analysis of data with a multiple-index Bayesian discriminator. More specifically, the invention is directed to methods, systems, and devices for detecting and treating arrhythmias and heart diseases. Arrhythmias are caused by a disruption of the normal electrical conduction system of the heart, causing abnormal heart rhythms. Normally, the four chambers of the heart (2 atria and 2 ventricles) contract in a very specific, coordinated manner. The signal to contract is an electrical impulse that begins in the "sinoatrial node" (the SA node), which is the body's natural pacemaker. The signal then travels through the two atria and stimulates them to contract. The signal passes through the "atrioventricular note" node (the AV node), and finally travels through the ventricles and stimulates them to contract. Problems can occur anywhere along the electrical conduction system, causing various arrhythmias. There can be a problem in the heart muscle itself, causing it to respond differently to the signal, or causing the ventricles to contract out of step with the normal conduction system. Other causes of arrhythmias include abnormal rhythmicity of the body's natural pacemaker, a shift of the pacemaker from SA node to other parts, blocks at different transmission points, abnormal pathways of impulse conduction, and spontaneous general of abnormal impulses due to ischemia (low flow to coronary arteries), hypoxia (low oxygen), ANS imbalance, lactic acidosis, electrolyte

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abnormality, drug toxicity, and hemodynamic abnormalities. Atrial fibrillation (AF) is the most common form of supraventricular arrhythmia and is associated with a considerable risk of morbidity and mortality. (Benjamin E J, et al., 1998 Circulation 98:946-952; Ryder K M, et al., 1999 Am J Cardiol. 84:1311R-138R; Chugh S S, et al. 2001 J Am Coll Cardiol. 37:371-377). As many as 2 million Americans are living with atrial fibrillation according to the American Heart Association. Theoretical analyses and high-density mapping studies have suggested that the most common mechanism of AF is the presence of multiple wave fronts or "wavelets" circulating irregularly throughout the atrial tissue. (Moe G K, et al., 1964 Am Heart J. 67:2961-2967; Allessie M A, et al., "Experimental Evaluation of Moe s Multiple Wavelet Hypothesis of Atrial Fibrillation" in Zipes E P, Jalife J, eds. Cardiac Electrophysiology and Arrhyhtmias. Orlando, Fla: Grune & Stratton, Inc., 1985; pp 265-275; Konings KTS, et al., 1994 Circulation 89:16651680). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Cardiac system and method for treatment of cardiac arrhythmias and transmyocardial revascularization Inventor(s): Rastegar, Hassan; (Newton, MA), Wang, Paul J.; (Chestnut Hill, MA) Correspondence: Hoekendijk & Lynch, Llp; P.O. Box 4787; Burlingame; CA; 94011-4787; US Patent Application Number: 20040087941 Date filed: October 28, 2003 Abstract: A medical device, and related method, use epicardial ablators and detectors for intraoperative epicardial approaches to ablation therapy of cardiac conduction pathways. An epicardial gripper is sized to grasp the cardiac circumference or smaller structures on the epicardial surface of the heart. Ablators are disposed on the arms of the gripper for epicardial ablation of cardiac conduction tissue. In another embodiment of the invention, an electrode system includes a flexible, adjustable probe forming a loop for epicardial ablation. Ablators are provided on one or multiple surfaces of the probe for epicardial ablation of cardiac conduction tissue. In yet another embodiment of the invention, an endocardial ablator detection system provides an indicator adjacent an ablator on an endocardial catheter, and a detector on an epicardial probe. The epicardial probe detects signals transmitted by the indicator on the endocardial catheter to localize the position of the endocardial ablator relative to the epicardial surface. The surgeon uses this information for guidance in adjusting the position of the endocardial ablator according to therapeutic objectives of cardiac ablation. Excerpt(s): Tachycardia is a type of cardiac arrhythmia and is a serious, often-times, fatal condition characterized by rapid, uncontrolled, and ineffective beating of the heart. Most tachycardia is one of two broad categories: ventricular tachycardia (hereinafter VT) and supraventricular tachycardia (hereinafter SVT). VT occurs in the lower chambers of the heart, the ventricles, and frequently leads to serious complications, including sudden cardiac death. Atrial fibrillation and flutter, forms of SVT, originate in the upper chambers of the heart, the atria, and often result in chest pain, fatigue and dizziness and, while generally not life-threatening, is a leading cause of stroke in the United States. Currently, many cases of VT and SVT are treated by drugs that modify the electrical characteristics of the heart tissue. However, the drugs do not eliminate or may not completely control the arrhythmia In many cases of sustained VT, implantable cardiac defibrillators are used which deliver powerful shocks to the heart when

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fibrillation is detected. Concurrent treatment with drugs is standard therapy and each implantation of a cardiac defibrillator, of which there may be more than one per patient, is very expensive. In atrial fibrillation the regular pumping action of the atria is replaced by a disorganized, ineffective quivering caused by chaotic conduction of electrical signals through the upper chambers of the heart. Although not immediately life threatening, atrial fibrillation may cause up to a 30% reduction in cardiac output and can lead to more serious conditions, including the formation of blood clots in the atria that can dislodge and travel to the brain resulting in stroke. Currently, the only curative treatment for atrial fibrillation is the surgical "maze procedure", an open heart procedure in which the surgeon makes several incisions in the right and left atria creating scar tissue to electrically separate portions of the atria Despite clinical success of the maze procedure, it is time-consuming and demanding. The procedure requires open heart surgery and is very expensive. Accordingly, only a modest number of maze procedures are performed annually in a limited number of centers. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Cardiac treatment devices and methods Inventor(s): Bertolero, Art; (Danville, CA), Conley, Daniel J.; (Santa Rosa, CA), Ibrahim, Tamer; (Oakland, CA) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20040102771 Date filed: April 8, 2003 Abstract: Devices and methods provide for ablation of cardiac tissue for treating cardiac arrhythmias such as atrial fibrillation. Although the devices and methods are often be used to ablate epicardial tissue in the vicinity of at least one pulmonary vein, various embodiments may be used to ablate other cardiac tissues in other locations on a heart. Devices generally include at least one tissue contacting member for contacting epicardial tissue and securing the ablation device to the epicardial tissue, and at least one ablation member for ablating the tissue. Various embodiments include features, such as suction apertures, which enable the device to attach to the epicardial surface with sufficient strength to allow the tissue to be stabilized via the device. For example, some embodiments may be used to stabilize a beating heart to enable a beating heart ablation procedure. Many of the devices may be introduced into a patient via minimally invasive introducer devices and the like. Although devices and methods of the invention may be used to ablate epicardial tissue to treat atrial fibrillation, they may also be used in veterinary or research contexts, to treat various heart conditions other than atrial fibrillation and/or to ablate cardiac tissue other than the epicardium. Excerpt(s): The present application is a continuation-in-part application which claims priority to U.S. patent application Ser. No. 10/272,446, which was filed Oct. 15, 2002, which claims priority to U.S. Provisional Patent Application Serial No. 60/337,070, filed Dec. 4, 2001, entitled "Methods and Devices for the Least Invasive Cardiac Surgery of Atrial Fibrillation," and the entire contents of these applications are hereby incorporated by reference. The present invention relates generally to medical devices and methods. More specifically, the invention relates to devices and methods for ablating epicardial tissue to treat cardiac arrhythmias such as atrial fibrillation. Atrial fibrillation (AF) is a heart beat rhythm disorder (or "cardiac arrhythmia") in which the upper chambers of the heart known as the atria quiver rapidly instead of beating in a

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steady rhythm. This rapid quivering reduces the heart's ability to properly function as a pump. AF is characterized by circular waves of electrical impulses that travel across the atria in a continuous cycle. It is the most common clinical heart arrhythmia, affecting more than two million people in the United States and some six million people worldwide. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Coaxial catheter instruments for ablation with radiant energy Inventor(s): Arnold, Jeffrey M.; (Wellesley, MA), Baxter, Lincoln S.; (Centerville, MA), Farr, Norman E.; (Monument Beach, MA), Sinofsky, Edward L.; (Dennis, MA) Correspondence: Nutter Mcclennen & Fish Llp; World Trade Center West; 155 Seaport Boulevard; Boston; MA; 02210-2604; US Patent Application Number: 20040006333 Date filed: February 3, 2003 Abstract: Ablation methods and instruments are disclosed for creating lesions in tissue, especially cardiac tissue for treatment of arrhythmias and the like. Percutaneous ablation instruments in the form of coaxial catheter bodies are disclosed having at least one central lumen therein and having one or more balloon structures at the distal end region of the instrument. The instruments include an energy emitting element which is independently positionable within the lumen of the instrument and adapted to project radiant energy through a transmissive region of a projection balloon to a target tissue site. The instrument can optionally include at least one expandable anchor balloon disposed about, or incorporated into an inner catheter body designed to be slid over a guidewire. This anchor balloon can serve to position the device within a lumen, such as a pulmonary vein. A projection balloon structure is also disclosed that can be slid over the first (anchor balloon) catheter body and inflated within the heart, to define a staging from which to project radiant energy. An ablative fluid can also be employed outside of the instrument (e.g., between the balloon and the target region) to ensure efficient transmission of the radiant energy when the instrument is deployed. In another aspect of the invention, generally applicable to a wide range of cardiac ablation instruments, mechanisms are disclosed for determining whether the instrument has been properly seated within the heart, e.g., whether the device is in contact with a pulmonary vein and/or the atrial surface, in order to form a lesion by heating, cooling or projecting energy. This contact-sensing feature can be implemented by an illumination source situated within the instrument and an optical detector that monitors the level of reflected light. Measurements of the reflected light (or wavelengths of the reflected light) can thus be used to determine whether contact has been achieved and whether such contact is continuous over a desired ablation path. Excerpt(s): This application is a continuation-in part of U.S. patent application Ser. No. 09/924,393, filed on Aug. 7, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 09/390,964, filed Sep. 7, 1999, now U.S. Pat. No. 6,270,492 issued Aug. 7, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 08/991,130, filed Dec. 16, 1997, now U.S. Pat. No. 5,947,595 issued Sep. 7, 1999, which is a continuation-in-part of U.S. patent application Ser. No. 08/827,631, filed Apr. 10, 1997, now U.S. Pat. No. 5,908,415 issued Jun. 1, 1999, which is a continuation of U.S. patent application Ser. No. 08/303,605, filed Sep. 9, 1994, abandoned. This application is also a continuation-in-part of U.S. patent application Ser. No. 09/616,275 filed Jul. 14, 2000, which is a continuation-in-part of U.S. patent application Ser. No. 09/602,420 filed Jun.

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23, 2000, which is a continuation-in-part of U.S. patent application Ser. No. 09/357,355, filed on Jul. 14, 1999, now U.S. Pat. No. 6,423,055 issued Jul. 22, 2002. The teachings of all of these prior related applications are hereby expressly incorporated by reference. The present invention relates to ablation instruments for ablation of tissue for the treatment of diseases, and, in particular, to percutaneous instruments employing radiant energy. Methods of ablating tissue using radiant energy are also disclosed. The instruments can be used, for example, in the treatment of cardiac conditions such as cardiac arrhythmias. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Combined anti-tachycardia pacing (ATP) and high voltage therapy for treating ventricular arrhythmias Inventor(s): Degroot, Paul J.; (Brooklyn Park, MN), Kaszas, Cameron J.; (Minneapolis, MN), Krause, Paul G.; (St. Louis Park, MN), Olson, Walter H.; (North Oaks, MN), Ousdigian, Kevin T.; (Shoreview, MN), Padmanabhan, Vasant; (Maple Grove, MN), Sharma, Vinod; (Roseville, MN) Correspondence: Medtronic, INC.; 710 Medtronic Parkway NE; Ms-Lc340; Minneapolis; MN; 55432-5604; US Patent Application Number: 20030204210 Date filed: April 30, 2002 Abstract: The present invention provides a system and method for treating an arrhythmia of the heart. The system and method involves delivery of anti-tachy pacing (ATP) pulses to the heart, possibly followed by the delivery of a high-voltage shock. ATP delivery is controlled such that the time of delivery of any high-voltage shock is not affected by the prior delivery of the ATP pulses. System control may be accomplished using one or more programmable parameters, which may include a user-specified shock energy. Excerpt(s): The present invention relates generally to implantable cardioverters (ICDs); and more particularly, the present invention relates to a system and method for delivering appropriate therapies to treat various tachycardia conditions. Implantable cardioverter-defibrillator (ICD) art has long distinguished ventricular arrhythmias (VAs) by rate and type. Ventricular Tachycardias (VTs) generally are those arrhythmias with rates between 150 and 250 bpm. These rhythms can be further differentiated by their ECG configuration as either monomorphic or polymorphic. Arrhythmias with rates above the upper VT range are typically classified as Ventricular Fibrillation (VF). To treat each type of arrhythmia in the appropriate manner, some ICDs are equipped with "tiered therapies" for delivering therapy based on the type of arrhythmia detected by the device. Such devices, often referred to as Implantable Cardioverter-Defibrillators (ICDs), generally differentiate arrhythmias by rate. For example, less dangerous arrhythmias such as VTs may be treated by delivering a series of low-power, relatively high-rate, pacing pulses to the heart. This therapy is often referred to as antitachyarrhythmia pacing therapy (ATP). In contrast, more perilous arrhythmias such as VFs are often treated using a more aggressive shock therapy. For example, many ICDs may be programmed to first treat a VT with low-power ATP. If ATP fails to terminate the VT or the VT progresses to ventricular fibrillation, the device may then deliver one or more high-power cardioversion or defibrillation shocks. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Device and procedure to treat cardiac atrial arrhythmias Inventor(s): Lee, Claude K.; (Reno, NV), Schuler, Eleanor L.; (Rio Rancho, NM) Correspondence: William M. Lee, JR.; Barnes & Thornburg; Suite 410; 209 S. Lasalle Street; Chicago; IL; 60604; US Patent Application Number: 20030176818 Date filed: November 14, 2001 Abstract: A non-invasive vagal stimulation device and method. The device comprises a body having a vibration member. The stimulation is created by the vibration member which has a vibratory rate that can be adjusted from being off to a preferred operating range. The non-invasive stimulation method consists of placing the non-invasive stimulation device in the vicinity of the carotid artery bifrication where arises a carotid sinus and body which contain afferent sensory nerves that travel to medulla oblongata of brain, and either applying pressure in place, or moving the device along the target arm. The method can be accomplished either with the vibration feature of the device turned on or off. Excerpt(s): This invention relates to a device and method for non-invasively controlling human and animal hearts in a manner that treats emergency arrhythmias of the cardiac atrium. Atrial arrhythmias are abnormal electrical contraction (beating) of the two thinwalled atrial chambers. The two smaller atrial chambers of the heart sit atop the two thick-walled large ventricular chambers. Those powerful ventricular chambers pump blood both to the lungs (right ventricle) and to the entire body (left ventricle). Atrial chambers have the job of pumping blood downwardly to fill the two ventricles before they contract (pump). Arrhythmias (irregular beating or fibrillation) of atrial chambers can lead to serious performance deficit in the ventricles. Ventricles that receive less than adequate level of blood begin to contract (pump) at ever increasing rates per minute. Ventricles speed up because sensory information processed in the brain indicates that inadequate blood circulation is happening (i.e., inadequate oxygen being supplied). When heart beat cycles become too fast the heart can go into fibrillation which further cuts the oxygen supply and eventually leads to mortality. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Enhancing human ventricular contractility, perfusion, and rhythm by enhancing laminar coordination of ventricular myocardial repolarization by the His-Purkinje system Inventor(s): Craig, David Franklin; (Burnsville, NC), McGuinn, William David JR.; (Columbia, MD) Correspondence: David Franklin Craig; 838 J.R. Pate Road; Burnsville; NC; 28714; US Patent Application Number: 20040054380 Date filed: September 13, 2002 Abstract: New in the art of medicine in this invention is the ability to improve cardiac output and transmural ventricular perfusion and diminish ventricular arrhythmias in the human heart by correcting a common defect in electrical regulation of the systole of the ventricles, this being a defect in a previously unknown mechanism, namely laminar coordination of ventricular repolariation by the His-Purkinje system.

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Excerpt(s): There was no federal funding or sponsorship of this research and development. Not applicable. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Fluorinated cycloalkyl-derivatized benzoylguanidines, process for their preparation, their uses as medicament, and medicament containing them Inventor(s): Kleemann, Heinz-Wermer; (Bischofsheim, DE) Correspondence: Ross J. Oehler; Aventis Pharmaceuticals INC.; Route 202-206; Mail Code: D303a; Bridgewater; NJ; 08807; US Patent Application Number: 20040048930 Date filed: June 2, 2003 Abstract: Fluorinated cycloalkyl-derivatized benzoylguanidines of formula I 1are suitable as antiarrhythmic medicaments with a cardioprotective component for infarction prophylaxis and infarction treatment and for the treatment of angina pectoris.They also preventively inhibit the pathophysiological processes associated with the development of ischemia-induced damage, in particular in the triggering of ischemia-induced cardiac arrhythmias and of heart failure. Excerpt(s): This application claims priority from German Application No. 10226462.7, filed Jun. 13, 2002 as well as benefit from U.S. Provisional Application No. 60/418,409, filed Oct. 15, 2002. and the pharmacologically acceptable salts thereof. and their pharmaceutically acceptable salts. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Isoindolone derivatives, preparation process and intermediates of this process, their use as medicaments, and pharmaceutical compositions comprising them Inventor(s): Bigot, Antony; (Massy, FR), Carry, Jean-Christophe; (Saint Maur Des Fosses, FR), Hofmeister, Armin; (Nierstein, DE), Kleemann, Heinz-Werner; (Bischofsheim, DE), Mignani, Serge; (Chatenay-Malabry, FR), Ronan, Baptiste; (Clamart, FR) Correspondence: Ross J. Oehler; Aventis Pharmaceuticals INC.; Route 202-206; Mail Code: D303a; Bridgewater; NJ; 08807; US Patent Application Number: 20040048916 Date filed: May 27, 2003 Abstract: The present invention relates to the novel isoindolone derivatives of the formula I 1in which R1 to R6 have the meanings stated in the claims. The inventive compounds are suitable as antiarrhythmic medicaments with a cardioprotective component for infarction prophylaxis and infarction treatment and for the treatment of angina pectoris. They also inhibit in a preventive manner the pathophysiological processes associated with the development of ischemia-induced damage, in particular in the triggering of ischemia-induced cardiac arrhythmias and of heart failure. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/396,001, filed Jul. 16, 2002, and incorporated herein by reference. The inventive compounds are suitable as antiarrhythmic medicaments with a cardioprotective component for infarction prophylaxis and infarction treatment and for the treatment of

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angina pectoris. They also inhibit in a preventive manner the pathophysiological processes associated with the development of ischemia-induced damage, in particular in the triggering of ischemia-induced cardiac arrhythmias and of heart failure. and racemic mixtures, enantiomers and diastereomers thereof and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Isoquinolinone potassium channels inhibitors Inventor(s): Claremon, David A; (Maple Glen, PA), Liverton, Nigel J; (Harleysville, PA), McIntyre, Charles J; (Lansdale, PA) Correspondence: Merck And CO Inc; P O Box 2000; Rahway; NJ; 070650907 Patent Application Number: 20040044030 Date filed: February 25, 2003 Abstract: The present invention concerns certain isoquinolinone compounds and their utility as inhibitors of voltage-dependent potassium channels or currents, such as K.sub.v1.5 and I.sub.Kur, that could serve as targets for the treatment of cardiac arrhythmias especially atrial arrhythmias. The present invention also provide a method for treating or preventing conditions which respond to the inhibition of potassium channels or currents, such as cardiac arrhythmias and more especially atrial arrhythmias. The present invention further includes pharmaceutical formulations and a process of making a pharmaceutical composition comprising a compound of certain isoquinolinone or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and stereoisomers thereof, and a pharmaceutically acceptable carrier. Excerpt(s): The present invention is directed to class of isoquinolinone compounds that are useful as potassium channel inhibitors, which show antiarrhythmic properties. Mammalian cell membranes perform very important functions relating to the structural integrity and activity of various cells and tissues. Of particular interest in membrane physiology is the study of trans-membrane ion channels which act to directly control a variety of physiological, pharmacological and cellular processes. Numerous ion channels have been identified including calcium (Ca), sodium (Na) and potassium (K) channels, each of which have been analyzed in detail to determine their roles in physiological processes in vertebrate and insect cells. A great deal of attention has been focused on potassium channels because of their involvement in maintaining normal cellular homeostasis. A number of these potassium channels open in response to changes in the cell membrane potential. Many voltage-gated potassium channels have been identified and are distinguishable based on their electrophysiological and pharmacological properties. Potassium currents have been shown to be more diverse than sodium or calcium currents and also play a role in determining the way a cell responds to an external stimulus. The diversity of potassium channels and their important physiological role highlights their potential as targets for developing therapeutic agents for various diseases. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Methanocarba cycloakyl nucleoside analogues Inventor(s): Jacobson, kenneth A; (Silver Spring, MD), Marquez, Victor E; (Montgomery, MD) Correspondence: Leydig Voit & Mayer, Ltd; 700 Thirteenth ST. NW; Suite 300; Washington; DC; 20005-3960; US Patent Application Number: 20030216412 Date filed: July 12, 2002 Abstract: The present invention provides novel nucleoside and nucleotide derivatives that are useful agonists or antagonists of P1 or P2 receptors. For example, the present invention provides a compound of formula A-M, wherein A is modified adenine or uracil and M is a constrained cycloalkyl group. The adenine or uracil is bonded to the constrained cycloakyl group. The compounds of the present invention are useful in the treatment or prevention of various diseases including airway diseases (through A.sub.2B, A.sub.3, P2Y.sub.2 receptors), cancer (through A.sub.3, P2 receptors), cardiac arrhythmias (through A.sub.1 receptors), cardiac ischemia (through A.sub.1, A.sub.3 receptors), epilepsy (through A.sub.1, P2X receptors), and Huntington's Disease (through A.sub.2A receptors). Excerpt(s): This application claims the benefit of U.S. provisional application No. 60/176,373, filed Jan. 14, 2000, the disclosure of which is incorporated herein by reference. This invention pertains to a novel class of receptor ligands for P1 and P2 receptors and their therapeutic use. More specifically, the invention pertains to nucleoside derivatives in which the sugar moiety is replaced with a cycloalkyl group that is conformationally constrained by fusion to a second cycloalkyl group. Purines such as adenosine have been shown to play a wide array of roles in biological systems. For example, physiological roles played by adenosine include, inter alia, modulator of vasodilation and hypotension, muscle relaxant, central depressant, inhibitor of platelet aggregation, regulator of energy supply/demand, responder to oxygen availability, neurotransmitter, and neuromodulator. (Bruns, Nucleosides & Nucleotides, 10(5), 931934 (1991)). Because of its potent actions on many organs and systems, adenosine and its receptors have been the subject of considerable drug-development research (Daly, J. Med. Chem., 25, 197 (1982)). Potential therapeutic applications for agonists include, for instance, the prevention of reperfusion injury after cardiac ischemia or stroke, and treatment of hypertension and epilepsy (Jacobson, et al., J. Med. Chem., 35, 407-422 (1992)). Adenosine itself has recently been approved for the treatment of paroxysmal supra ventricular tachycardia (Pantely, et al., Circulation, 82, 1854 (1990)). Adenosine receptor agonists also find use as anti-arrhythmics, antinociceptives, anti-lipolytics, cerebroprotectives, and antipsychotics. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method and apparatus for classifying and localizing heart arrhythmias Inventor(s): Bhargava, Valmik; (San Diego, CA), Narayan, Sanjiv Mathur; (San Diego, CA) Correspondence: Kenton R. Mullins; Stout, Uxa, Buyan & Mullins, Llp; Suite 300; 4 Venture; Irvine; CA; 92618; US Patent Application Number: 20040059237 Date filed: December 18, 2002

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Abstract: Analyzes surface electrocardiographic and intracardiac signals to identify and separate electrical activity corresponding to distinct but superimposed events in the heart. Assesses the spatial phase, temporal phase, rate, spectrum and reproducibility of each event to determine uniformity of activation in all spatial dimensions. Uses numerical indices derived from these analyses to diagnose arrhythmias. Uses these indices to determine the location of an arrhythmia circuit, and to direct the movement of an electrode catheter to this location for ablation or permanent catheter positioning. Subsequently, uses these indices to determine whether ablation has successfully eliminated the circuit. Uses variability in these indices from the surface electrocardiogram to indicate subtle beat-to-beat fluctuations which reflect the tendency towards atrial and ventricular arrhythmias. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/412,148, filed Sep. 19, 2002, the entire contents of which are incorporated herein by reference. This invention relates generally to the field of heart rhythm disorders and more specifically to systems and methods for analyzing the electrocardiogram, pacing and mapping the heart for the diagnosis and treatment of cardiac conditions. A normal heartbeat consists of an organized sequence of conduction and orderly myocardial contraction. Normal (sinus) rhythm begins when the sinoatrial node (or "SA node") generates a depolarization wavefront in atrium. The impulse causes adjacent atrial cells to depolarize in a spreading wavefront, resulting in the "P-wave" on the Electrocardiogram (ECG), which causes the atria to contract and empty blood into the ventricles. Next, the impulse is delivered via the atrioventricular node (or "AV node") and the bundle of His to myocardial tissue cells of the ventricle. Depolarization propagates similarly across ventricular cells, resulting in the "QRS" complex on the ECG, causing the ventricles to contract and eject blood into the lungs and the systemic circulation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method and apparatus for predicting recurring ventricular arrhythmias Inventor(s): Olson, Walter H.; (North Oaks, MN), Sharma, Vinod; (Roseville, MN), Zhou, Xiaohong; (Plymouth, MN) Correspondence: Medtronic, INC.; 710 Medtronic Parkway NE; Ms-Lc340; Minneapolis; MN; 55432-5604; US Patent Application Number: 20030191403 Date filed: April 5, 2002 Abstract: An implantable medical device and method are provided for assessing autonomic tone and risk factors associated with arrhythmias and, based on this assessment, an early recurrence of ventricular tachycardia or ventricular fibrillation is predicted. Specifically, changes in R-R interval, heart rate variability, patient activity, and myocardial ischemia are measured prior to and after a detected an arrhythmia episode. A recurrence score is calculated as a weighted sum of measured parameters and compared to a prediction criterion. The prediction criterion may be a preset threshold score or an individualized episode template based on previously calculated recurrence scores associated with recurring episodes. Stored parameters and episoderelated data may be downloaded for offline analyses for optimizing prediction criteria and monitoring patient status.

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Excerpt(s): The present invention relates to a medical device and, more specifically, to a device and method for assessing cardiac autonomic tone and predicting the early recurrence of ventricular tachycardia or fibrillation and triggering an alert system for initiation of possible preventive measures. Nearly all of detected arrhythmias appropriately treated by an ICD do not result in death. However, some patients with ICDs do experience fatal arrhythmias. Compromised hemodynamic output during a VT or VF episode can render a patient unconscious resulting in related serious injuries or death. Patients may experience recurrent VT or VF and be subjected to repeated shock therapies, which cause great discomfort. Because of the serious consequences of VT and VF, it is desirable to predict the occurrence of VT and VF so that an ICD can be prepared to immediately deliver a therapy or take preventive measures to prevent the occurrence. Prediction of an imminent VT or VF episode also enables preventive medical treatments to be delivered. A number of parameters for predicting a discreet VT or VF episode have been proposed including, for example, left ventricular dysfunction, myocardial ischemia, frequency of ventricular ectopic beats, heart rate variability, heart rate turbulence, or other electrocardiographic changes (see Shusterman et al., J Am Coll Cardiol. 1998;32:1891-9, and Schmidt et al., Lancet. 1999;353:1390-96). Changes in the autonomic nervous system are known contributing factors to arrhythmogenesis. The heart rate is normally regulated by a balance between the sympathetic and parasympathetic (vagal) components of the autonomic nervous system. Increased sympathetic activity, referred to as sympathetic tone, increases the heart rate and decreases heart rate variability. Increased vagal tone decreases the heart rate and increases heart rate variability. Heart rate variability (HRV) is the variation in consecutive heart rate cycles, which may be measured as ventricular cycle intervals, known as "R-R intervals," or as atrial cycle intervals, known as "A-A intervals." Changes in autonomic tone, especially in conjunction with myocardial ischemia, however, can play an important role in the development of arrhythmias. Therefore, indicators of changes in autonomic tone may be useful in predicting arrhythmias. Reference is made to U.S. Pat. No. 5,042,497 issued to Shapland. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method and system for image improvement with ECG gating and dose reduction in CT imaging Inventor(s): Acharya, Kishore C.; (Brookfield, WI), Gopinath, Priya; (North Arlington, NJ), Li, Jianying; (New Berlin, WI), Reddy, Shankara Bonthu; (Cedarburg, WI) Correspondence: Cantor Colburn, Llp; 55 Griffin Road South; Bloomfield; CT; 06002 Patent Application Number: 20040077941 Date filed: October 21, 2002 Abstract: A method and system for associating ECG waveform data with medical imaging data using ECG gating for dose reduction and image improvement by generating the ECG waveform data using an electrocardiogram device. The ECG data is first validated and then QRS complexes are detected using a detection function. An underlying cardiac rhythm based on the detected QRS complexes is analyzed and an even number N of substantially normally shaped consecutive QRS complexes are selected. An RR interval between consecutive QRS complexes is computed to yield N-1 intervals. Duration of a representative cardiac cycle by averaging at least a plurality of the N-1 intervals is determined. Once a representative cardiac cycle is determined, a

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method to control power and improve image quality with the presence of patient's having arrhythmias is disclosed. Excerpt(s): The invention relates to cardiac imaging in computed tomography (CT), magnetic resonance (MR) imaging, nuclear imaging, ultrasound, and other imaging modalities, and more particularly, to an apparatus and a method for use in cardiac gating to improve image quality and for dose reduction in prospective ECG gating used in imaging modalities where dose to patient is a concern. Although the method is applicable to cardiac imaging by all modalities, the following description is given for cardiac imaging by a CT system. Cardiac imaging includes coronary artery imaging, imaging for determining the cardiac function and perfusion and identification of walls of the heart chambers and valvular structures. Common to all of the above applications of cardiac imaging and common to all imaging modalities (CT, MR, Ultrasound, Nuclear, etc.) is the need for proper gating of the images to certain phases of the cardiac cycle. When the heart rate is low, the intervals between the heart beats are nearly constant and each mechanical contraction of the heart is nearly the same (e.g., sinus rhythm with heart rate less than 65 beats), cardiac images taken by any modality will be of high diagnostic quality. However when the heart rate changes suddenly and intermittently due to arrhythmias, quality of the image degrades appreciably. Solutions to address these problems and thus improve the image quality are described here with reference to cardiac CT imaging. The invention described here, although described with reference to cardiac CT imaging, is equally applicable to other imaging modalities such as MR, Ultrasound, PET, Nuclear and thermal imaging. In current CT systems, in order to appropriately produce CT images of the heart's chambers (myocardium), interchamber valves and coronary vasculature, it is necessary to acquire CT radiograph data while the heart is at a certain position that is substantially spatially stationary. This requires that the heart rate of the patient be extremely slow, which is not clinically viable, or that the speed of the gantry be extremely high, which is not technically viable. In the past, a few different techniques have been employed in attempts to solve this problem. One technique, known as prospective gating, uses the ECG (electrocardiogram) signal of the heart to trigger data acquisition by the detector array at points in time when the heart is fairly stationary (typically during diastole) so that the radiographs used to reconstruct the image correspond to instants in time when the heart is fairly stationary. Another technique, known as retrospective gating, measures the ECG signal while acquiring CT radiograph data and then retrospectively selects the data that corresponds to a point in time of the ECG signal when the heart is fairly stationary. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for determining a metric of non-sustained arrhythmia occurrence for use in arrhythmia prediction and automatic adjustment of arrhythmia detection parameters Inventor(s): Gunderson, Bruce D.; (Plymouth, MN), Olson, Walter H.; (North Oaks, MN), Stadler, Robert W.; (Shoreview, MN), Zhou, Xiaohong; (Plymouth, MN) Correspondence: Medtronic, INC.; 710 Medtronic Parkway NE; Ms-Lc340; Minneapolis; MN; 55432-5604; US Patent Application Number: 20040064062 Date filed: September 30, 2002 Abstract: An implantable medical device and associated method are provided for detecting non-sustained arrhythmias and determining a metric of non-sustained arrhythmias. The metric may be used for predicting the occurrence of a sustained

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arrhythmia or for automatically adjusting the parameters used for detecting a sustained arrhythmia. Excerpt(s): The present invention relates to medical devices for detecting, predicting and treating arrhythmias and, more specifically, to a method for determining a metric of non-sustained cardiac arrhythmias for use in predicting the occurrence of sustained cardiac arrhythmias or automatically adjusting arrhythmia detection parameters. Detection of an arrhythmia by an ICD is generally determined by comparing the sensed heart rate to predetermined, programmable parameters. The intervals between sensed events in the atria, referred to P-waves, and/or sensed events in the ventricles, referred to as R-waves, may be used to determine a heart rate. Generally, the interval between two sensed cardiac events, an R-R interval in the ventricle or a P-P interval in the atrium, is compared to a set of programmable detection intervals. For example a sensed R-R interval may be compared to a specified VT detection interval, a fast VT detection interval and a VF detection interval. If the sensed R-R interval is less then any one of these intervals, it is classified as such. Arrhythmia detection is made when a specified number of intervals in a detection interval range is reached. For example, a nominal setting for detecting VT may be 16 consecutively sensed intervals less than 400 ms. A nominal setting to detect VF may be 18 of the last 24 sensed intervals must be less than 320 ms. These settings may be adjusted according to patient need, however, once programmed by a clinician, generally remain fixed until the next programming session. Nearly all of detected arrhythmias appropriately treated by an ICD do not result in death. However, ICD therapies can be very painful to the patient, and compromised hemodynamic output during a VT or VF episode can render a patient unconscious resulting in related serious injuries or death. Because of the serious consequences of cardiac arrhythmias, it is desirable to predict the occurrence of an arrhythmia so that preventive measures may be taken to avert the arrhythmia entirely. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for treating arrhythmias Inventor(s): Belardinelli, Luiz; (Menlo Park, CA), Dhalla, Arvinder; (Mountain View, CA) Correspondence: Brian Lewis; CV Therapeutics, INC.; 3172 Porter Drive; Palo Alto; CA; 94304; US Patent Application Number: 20030216349 Date filed: April 18, 2003 Abstract: Methods are provided for treating arrhythmia in a manner that minimizes undesirable side effects, comprising administration of a therapeutically effective minimal dose of an A.sub.1 adenosine receptor agonist with a therapeutically effective minimal dose of a beta blocker, calcium channel blocker, or a cardiac glycoside. Excerpt(s): Priority is claimed to U.S. Provisional Patent Application Serial No. 06/373,766, filed Apr. 19, 2002, the complete disclosure of which is hereby incorporated by reference. This invention relates to a method of treating arrhythmias and heart failure in a manner that minimizes undesirable side effects, comprising administration of a low dose of an adenosine Al receptor agonist in conjunction with a low dose of a beta blocker, or a calcium channel blocker, or a cardiac glycoside. Arrhythmias are abnormal heart rhythms that occur either in the atria or the ventricles. Arrhythmias arising in the atria are called atrial arrhythmias, and these disorders include atrial

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fibrillation, atrial flutter, and paroxysmal atrial tachycardia (PSVT). Arrhythmias arising in the ventricles, known as ventricular arrhythmias, are a group of disorders having diverse etiologies, including idiopathic ventricular tachycardia, ventricular fibrillation, and Torsade de Pointes (TdP). Arrhythmias can range from incidental, asymptomatic clinical findings to life-threatening abnormalities, and account for a significant percentage of the causes of death in humans. Thus, it is desirable to develop methods of mitigating the effects of arrhythmias. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel enantiomeric compounds for treatment of cardiac arrhythmias and methods of use Inventor(s): Druzgala, Pascal; (Santa Rosa, CA), Milner, Peter G.; (Los Altos Hills, CA) Correspondence: Saliwanchik Lloyd & Saliwanchik; A Professional Association; 2421 N.W. 41st Street; Suite A-1; Gainesville; FL; 326066669 Patent Application Number: 20040097743 Date filed: October 29, 2003 Abstract: The subject invention pertains to novel enantiomerically pure compounds, and compositions comprising the compounds, for the treatment of cardiac arrhythmias. The subject invention further concerns a method of making and purifying the compounds. The enantiomerically purified compounds, and compositions of these compounds, exhibit unexpectedly distinct and advantageous characteristics, such as a markedly superior ability to reduce or inhibit ventricular premature beats, as compared to racemic mixtures of the compounds. Excerpt(s): This application is a continuation of co-pending application Ser. No. 10/123,573, filed Apr. 15, 2002; which is a continuation-in-part of PCT/US00/28636, filed Oct. 13, 2000, which claims priority to U.S. Ser. No. 09/689,873, filed Oct. 6, 2000, pending, and 09/684,046, filed Oct. 6, 2000, now U.S. Pat. No. 6,362,223, both of which claim the benefit of provisional application serial No. 60/159,609, filed Oct. 15, 1999. This application also claims the benefit of U.S. Provisional Application No. 60/290,089, filed May 10, 2001. Congestive heart failure (CHF) is a disease affecting approximately 2% of the population of the United States (Sami, M. H. [1991] J. Clin. Pharmacol. 31:1081). Despite advances in the diagnosis and treatment of CHF, the prognosis remains poor with a 5-year mortality rate higher than 50% from the time of diagnosis (McFate Smith, W. [1985] Am. J. Cardiol. 55:3A; McKee, P. A., W. P. Castelli, P. M. McNamara, W. B. Kannel [1971] N. Engl. J. Med. 285:1441). In patients with CHF, the rate of survival is lowest in those patients with severe depression of left ventricular function and patients who have frequent ventricular arrhythmias. Patients with ventricular arrhythmias and ischemic cardiomyopathy have an increased risk of sudden death. The presence of ventricular tachycardia in patients with severe CHF results in a three-fold increase in sudden death compared to those without tachycardia (Bigger, J. T., Jr. [1987] Circulation 75(suppl.IV):28). Because of the high prevalence of sudden unexpected death in patients with CHF, there has been a growing interest in the prognostic significance of arrhythmias in these patients. Several compounds have been used in the management of cardiac arrhythmias in patients with congestive heart failure. Unfortunately, anti-arrhythmic drug therapy has been disappointing. The efficacy of anti-arrhythmic drugs markedly decreases as left ventricular function declines, such that only a small fraction of patients with CHF are responsive to antiarrhythmic therapy. No anti-arrhythmic drug has prevented sudden death in patients

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with CHF and there is even a question of increased mortality associated with certain anti-arrhythmic drugs (the CAST investigators [1989] N. Engl. J. Med. 321:406). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Oxabispidine compound useful in the treatment of cardiac arrhythmias Inventor(s): Bjorsne, Magnus; (Vastra Frolunda, SE), Cladingboel, David; (Loughborough, GB), Ponten, Fritiof; (Askim, SE), Strandlund, Gert; (Lindome, SE) Correspondence: Nixon & Vanderhye, PC; 1100 N Glebe Road; 8th Floor; Arlington; VA; 22201-4714; US Patent Application Number: 20040039199 Date filed: April 2, 2003 Abstract: There is provided 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3. 1]non-3-yl]propyl)}amino)benzonitrile, benzenesulfonic acid salt, which compound is useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias. Excerpt(s): This invention relates to a novel pharmaceutically useful compound, in particular a compound which is useful in the treatment of cardiac arrhythmias. Cardiac arrhythmias may be defined as abnormalities in the rate, regularity, or site of origin of the cardiac impulse or as disturbances in conduction which causes an abnormal sequence of activation. Arrhythmias may be classified clinically by means of the presumed site of origin (i.e. as supraventricular, including atrial and atrioventricular, arrhythmias and ventricular arrhythmias) and/or by means of rate (i.e. bradyarrhythmias (slow) and tachyarrhythmias (fast)). In the treatment of cardiac arrhythmias, the negative outcome in clinical trials (see, for example, the outcome of the Cardiac Arrhythmia Suppression Trial (CAST) reported in New England Journal of Medicine, 321, 406 (1989)) with "traditional" antiarrhythmic drugs, which act primarily by slowing the conduction velocity (class I antiarrhythmic drugs), has prompted drug development towards compounds which selectively delay cardiac repolarizadon, thus prolonging the QT interval. Class III antiarrhythmic drugs may be defined as drugs which prolong the trans-membrane action potential duration (which can be caused by a block of outward K.sup.+ currents or from an increase of inward ion currents) and refractoriness, without affecting cardiac conduction. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Potassium channel inhibitors Inventor(s): Beaudoin, Serge; (Morrisville, NC), Gross, Michael Francis; (Durham, NC), Reed, Aimee Dolores; (Durham, NC) Correspondence: Banner & Witcoff; 1001 G Street N W; Suite 1100; Washington; DC; 20001; US Patent Application Number: 20030236261 Date filed: March 19, 2003 Abstract: Compounds which are useful as potassium channel inhibitors and which because of their slow off-rates are especially useful for the treatment of cardiac arrhythmias are described.

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Excerpt(s): The present invention is broadly directed to a class of compounds useful as potassium channel inhibitors. The importance of potassium channels was first recognized almost fifty years ago when Hodgkin and Huxley discovered that potassium ions contributed to the current that excited the squid giant axon. Research in the area, however, was hampered by the lack of selective, high affinity ligands for potassium channels. But the advent of recombinant DNA techniques and single cell and whole cell voltage clamp techniques has changed the slow pace of the field. Indeed, potassium channels which exhibit functional, pharmacological and tissue distribution characteristics have been cloned. These cloned potassium channels are useful targets in assays for identifying candidate compounds for the treatment of various disease states. Potassium channels have turned out to be the most diverse family of ion channels discovered to date. They modulate a number of cellular events such as muscle contraction, neuro-endocrine secretion, frequency and duration of action potentials, electrolyte homeostasis, and resting membrane potential. Potassium channels are expressed in eukaryotic and procaryotic cells, and are elements in the control of electrical and nonelectrical cellular functions. Potassium channels have been classified according to their biophysical and pharmacological characteristics. Subclasses of these channels have been named based on amino acid sequence and functional properties. Salient among these are the voltage dependent potassium channels, for example voltage gated potassium channels (e.g., Kv1, Kv2, Kv3, Kv4). Subtypes within these subclasses have been characterized as to their putative function, pharmacology and distribution in cells and tissues (Chandy and Gutman, "Voltage-gated potassium channel genes" in Handbook of Receptors and Channels-Ligand and Voltage-gated Ion Channels, ed. R. A. North, 1995; Doupnik et al., Curr. Opin. Neurobiol. 5:268, 1995). For example, the Kv1 class of potassium channels is further subdivided depending on the molecular sequence of the channel, for example Kv 1.1, Kv 1.3, Kv 1.5. Functional voltage-gated K+ channels can exist as multimeric structures formed by the association of either identical or dissimilar subunits. This phenomena is thought to account for the wide diversity of K+ channels. However, subunit compositions of native K+ channels and the physiologic role that particular channels play are, in most cases, still unclear. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Stress reduction pacing mode for arrhythmia prevention Inventor(s): Girouard, Steven D.; (Woodbury, MN), Pastore, Joseph M.; ( Minneapolis, MN) Correspondence: Schwegman, Lundberg, Woessner & Kluth, P.A.; P.O. Box 2938; Minneapolis; MN; 55402; US Patent Application Number: 20040098057 Date filed: November 15, 2002 Abstract: An apparatus and method preventing cardiac arrhythmias with pacing therapy is disclosed. Upon detection of a pre-arrhythmic condition, an implantable cardiac rhythm management device is configured to deliver pacing therapy in a manner that pre-excites particular myocardial sites that have been identified as stressed sites and likely locations for the origination of arrhythmias. Such pacing results in a reduction in myocardial wall stress at those sites during systole and reduces the probability of an arrhythmia occurring. Excerpt(s): This invention pertains to apparatus and methods for the diagnosis and treatment of heart disease and to devices providing electrostimulation to the heart such

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as cardiac pacemakers. Tachyarrhythmias are abnormal heart rhythms characterized by a rapid heart rate, typically expressed in units of beats per minute (bpm). They can occur in either chamber of the heart (i.e., ventricles or atria) or both. Examples of tachyarrhythmias include sinus tachycardia, ventricular tachycardia, ventricular fibrillation (VF), atrial tachycardia, and atrial fibrillation (AF). Tachyarrhythmias can be due to abnormal excitation by normal pacemaker tissue, an ectopic excitatory focus, or a re-entry phenomenon. Tachycardia occurs when the heart contracts relatively normally but at a rapid rate, while fibrillation occurs when the chamber depolarizes in a chaotic fashion with abnormal depolarization waveforms as reflected by an EKG. An electrical defibrillation shock applied to a heart chamber can be used to terminate most tachyarrhythmias by depolarizing excitable myocardium and rendering it refractory. Implantable cardioverter/defibrillators (ICDs) provide this kind of therapy by delivering a shock pulse to the heart when fibrillation is detected by the device. ICDs can be designed to treat either atrial or ventricular tachyarrhythmias, or both, and may also incorporate cardiac pacing functionality. The most dangerous tachyarrhythmias are ventricular tachycardia and ventricular fibrillation, and ICDs have most commonly been applied in the treatment of those conditions. Another type of electrical therapy for tachycardia is anti-tachycardia pacing (ATP). In ATP, the heart is competitively paced with one or more pacing pulses in an effort to interrupt the reentrant circuit causing the tachycardia. Modern ICD's usually have ATP capability so that ATP therapy is delivered to the heart when a tachycardia is detected, while a shock pulse is delivered when fibrillation occurs. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

System and method for treating abnormal ventricular activation-recovery time Inventor(s): Levine, Paul A.; (Santa Clarita, CA), Weinberg, Lisa P.; (Moorpark, CA) Correspondence: Pacesetter, INC.; 15900 Valley View Court; Sylmar; CA; 91342-9221; US Patent Application Number: 20040044374 Date filed: August 30, 2002 Abstract: An implantable cardiac stimulation device provides long QT interval therapy for preventing abnormal ventricular activation-recovery time and ultimately ventricular arrhythmias. The device includes a sensing circuit that senses intracardiac activity of a heart and that generates electrical signals representing electrical activity of the heart. The device includes a physiologic sensor, such as body motion, or other diurnally varying sensor that reliably detects a diurnal state of the patient (i.e., not the QT interval itself). The device further includes a measuring circuit that measures a QT interval of the electrical signals, a control circuit that determines whether the QT interval is appropriate for the diurnal state, and a pulse generator that delivers pacing pulses to at least one chamber of the heart at a pacing rate when the QT Interval is pathologically too long. Furthermore, the pacing rate control circuit varies the pacing rate of the pulse generator responsive to the measured QT interval according to the measured diurnal state. Excerpt(s): The present invention generally relates to an implantable cardiac stimulation device, and more particularly relates to an implantable cardiac stimulation device capable of providing therapy to maintain a normal activation-recovery time, thereby preventing ventricular arrhythmias associated with Long QT Syndrome, Torsade de Pointe and ventricular fibrillation. Implantable cardiac stimulation devices are well known in the art. They may take the form of implantable defibrillators or cardioverters

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which treat accelerated rhythms of the heart, such as fibrillation, or implantable pacemakers which maintain the heart rate above a prescribed limit, such as, for example, to treat a bradycardia. Implantable cardiac devices are also known which incorporate both a pacemaker and a defibrillator. As seen on a standard electrocardiogram (EGG), one complete heartbeat includes a P-wave, a QRS complex, and a T-wave. In a normal cardiac cycle, the atria depolarize and contract (P-waves), delivering blood into the relaxed ventricles. The atria now repolarize and relax while the ventricles, now filled to capacity with blood, depolarize, contract and pump (QRS complex) blood into the systemic and pulmonary circulation systems. The ventricles then repolarize and relax (T-wave). The cycle begins again at the end of ventricular repolarization with the onset of passive ventricular filling. The "QT" interval is measured from the onset of the QRS complex to the end of the visible T-wave on the surface ECG. The QT interval is generally accepted as an indirect measure of patient myocardial depolarization and repolarization. The QT interval prolongation may occur naturally during sleep, or by a variety of drugs, electrolyte imbalance, central nervous system disorders, metabolic abnormalities, bradycardia, ischemia and other intrinsic disease states. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

System and method for treating cardiac arrhythmias with fibroblast cells Inventor(s): Lee, Randall J.; (Hillsborough, CA), Maciejewski, Mark J.; (Edina, MN) Correspondence: John P. O'banion; O'banion & Ritchey Llp; 400 Capitol Mall Suite 1550; Sacramento; CA; 95814; US Patent Application Number: 20040005295 Date filed: May 7, 2003 Abstract: A system delivers fibroblasts to a region of cardiac tissue at a location associated with a cardiac arrhythmia in a patient to form a conduction block in the region. A cardiac delivery system is coupled to a source the fibroblasts and delivers the fibroblasts to the location to form a conduction block. Substantial cardiac ablation is thus avoided. A contact member is shaped to correspond with a patterned region of tissue for delivering the fibroblasts along the pattern, such as linear, curvilinear, or circumferential patterns as required for treating particular arrhythmias. A pulmonary vein isolation assembly has an expandable or loop-shaped member cooperating with a needle array that delivers the fibroblast cells into a circumferential region of tissue engaged by the expandable member where a pulmonary vein extends from an atrium. Methods include providing the fibroblast cells as autologous cells in an injectable preparation. Excerpt(s): This application claims priority from U.S. provisional application serial No. 60/379,140 filed on May 8, 2002, and U.S. provisional application serial No. 60/426,058 filed on Nov. 13, 2002, and is a continuation-in-part of U.S. non-provisional patent application Ser. No. 10/329,295 filed on Dec. 23, 2002; the disclosures of these prior patent applications are herein incorporated in their entirety by reference thereto. This invention pertains generally to systems and methods for treating medical conditions associated with the heart, and more particularly to surgical devices and procedures for treating cardiac arrhythmias using fibroblast cell therapy. Cellular therapy for treating cardiac conditions has been the topic of significant research and development in recent years, generally for the purpose of increasing cardiac conduction or function. In fact, certain types of injected cells have been observed to couple poorly with indigenous cardiac cell tissues, and various prior disclosures have cited a related decrease in

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conduction transmission as a significant obstacle to the intended cellular therapy. Some disclosures have cited a desire to in fact modify the properties of injected cells to increase the cardiac tissue coupling-for enhanced conduction or contractility. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Treating arrhythmias by altering properties of tissue Inventor(s): Lafontaine, Daniel M.; (Plymouth, MN) Correspondence: Stephen R. Schaefer; Fish & Richardson P.C., P.A.; Suite 3300; 60 South Sixth Street; Minneapolis; MN; 55402; US Patent Application Number: 20040106952 Date filed: December 3, 2002 Abstract: A device for treating arrhythmia comprising an endoluminal member implantable within a region of a vascular lumen, wherein the member is configured to contact an inner wall of the lumen and alter the properties of tissue proximate the region. Methods of treating arrhythmias using the device are also disclosed. Excerpt(s): The invention relates generally to vascular medical devices and more particularly, to an implantable device and using the device to treat arrhythmias. Atrial fibrillation, identified as the most common arrhythmia, is a rapid and irregular rhythm in the heart's upper chambers. Atrial fibrillation is known to be the most common risk factor and cause of stroke as well as increased risk of death. The prevalence of atrial fibrillation increases with age, doubling in each decade of age after 50. Atrial fibrillation has for decades been understood to be maintained by the existence of multiple-reentrant wavelets occurring in random order in the atrium. The source, or sources, of atrial fibrillation have only recently begun to be understood. One source for atrial fibrillation is believed to be rapidly firing focus in or close to the pulmonary veins. Other sources of atrial fibrillation are believed to be similarly triggering foci, located in or near the superior vena cava with cardiac musculature extending from the right atrium, the ligament of Marshall, the insertion site of the vein of Marshall, the crista terminalis, the coronary sinus, and the left atrial posterior free wall. 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 arrhythmias, 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 “arrhythmias” (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 arrhythmias. You can also use this procedure to view pending patent applications concerning arrhythmias. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “arrhythmias” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on arrhythmias: •

Dental Management of the Medically Compromised Patient. 5th ed Source: St. Louis, MO: Mosby, Inc. 1997. 668 p. Contact: Available from Harcourt Health Sciences. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 325-4177. Fax (800) 874-6418. Website: www.harcourthealth.com. PRICE: $48.00 plus shipping and handling. ISBN: 0815156340. Summary: A working knowledge of the multitude of compromised health states is essential for dental professionals, as the majority of medically compromised patients need or want oral health care. This knowledge will support high standards for dental and oral health care delivery, which include recognizing and understanding conditions that reflect compromised states, preventing adverse side effects of procedures and drugs used in dentistry, and formulating treatment plans that are consistent with a patient's medical status. This text offers 28 chapters that provide the dental practitioner with an up to date reference work describing the dental management of patients with selected

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medical problems. After an introductory chapter on the interrelationships between medicine and dentistry, the text covers infective endocarditis, rheumatic fever and rheumatic heart disease, congenital heart disease, surgically corrected cardiac and vascular disease, hypertension, ischemic heart disease, cardiac arrhythmias, congestive heart failure, pulmonary disease, chronic renal failure and dialysis, liver disease, gastrointestinal disease, sexually transmitted diseases, AIDS and related conditions, arthritis, neurologic disorders, diabetes, adrenal insufficiency, thyroid disease, pregnancy and breastfeeding, allergy, bleeding disorders, blood dyscrasias, oral cancer, behavioral and psychiatric disorders, organ transplantation, and prosthetic implants. Two appendices offer an overview of infection control and a review of the therapeutic management of common oral lesions. Each chapter includes black and white photographs and concludes with references. A subject index concludes the volume. •

Cardiac Dysfunction in Chronic Uremia Source: Norwell, MA: Kluwer Academic Publishers. 1992. 231 p. Contact: Available from Kluwer Academic Publishers. P.O. Box 358, Accord Station, Hingham, MA 02018-0358. (617) 871-6600. PRICE: $145 plus shipping and handling. Summary: Cardiac disease is the major cause of death in dialysis patients, accounting for over one-third of deaths. This book focuses on myocardial function and dysfunction in chronic uremia. It is written for practicing and training nephrologists, cardiologists, and internists, and for research workers in the field. The first section comprises five chapters that provide an overview of the burden of illness associated with cardiac disease in endstage renal disease and a review of clinical epidemiological aspects of various cardiac diseases that occur in renal patients. The second section discusses abnormalities of left ventricular contractility and mass, and the factors that predispose to both systolic and diastolic disorders. The importance of hypertension, anemia, hyperparathyroidism, hyperlipidemia, and diabetes mellitus is reviewed. The final section concentrates on therapeutics. Data and opinion on management of congestive heart failure, cardiomyopathy, coronary artery disease, hypertension, and arrhythmias are provided. Each chapter includes numerous references and a subject index is appended to the volume. (AA-M).

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Dental Management of the Medically Compromised Patient. 4th ed Source: St. Louis, MO: Mosby-Year Book, Inc. 1993. 605 p. Contact: Available from Mosby-Year Book, Inc. 11830 Westline Industrial Drive, St. Louis, MO 63146-9934. (800) 426-4545 or (314) 872-8370; Fax (800) 535-9935 or (314) 4321380; E-mail: [email protected]; http://www.mosby.com. PRICE: $39.95 plus shipping and handling. ISBN: 0801668379. Summary: This book was written to provide the dental practitioner with an up-to-date, concise reference work describing the dental management of patients with selected medical problems. Twenty-seven chapters cover the interrelationships of medicine and dentistry; infective endocarditis; rheumatic fever, rheumatic heart disease, and murmurs; congenital heart disease; surgically-corrected cardiac and vascular disease; hypertension; ischemic heart disease; cardiac arrhythmias; congestive heart failure; pulmonary disease; chronic renal failure and dialysis; liver disease; sexually transmitted diseases; AIDS and related conditions; arthritis; neurologic disorders; diabetes; adrenal insufficiency; thyroid disease; pregnancy and breast-feeding; allergy; bleeding disorders; blood dyscrasias; oral cancer; behavioral and psychiatric disorders; organ transplantation; and prosthetic implants. Where appropriate, medical problems are

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organized to provide a brief overview of the basic disease process, pathophysiology, signs and symptoms, laboratory findings, and currently accepted medical therapy for each disorder. This is followed by a detailed explanation and recommendations for specific dental management. Two appendices cover infection control and the therapeutic management of common oral lesions. A detailed subject index concludes the text. •

Dental Management of the Medically Compromised Patient. 6th ed Source: St. Louis, MO: Elsevier Science. 2002. 735 p. Contact: Available from Elsevier Science. Customer Service Department, 11830 Westline Industrial Drive, St. Louis, MO 63146 (800) 545-2522. Fax (800) 535-9935. Email: [email protected]. Website: www.elsevierhealth.com. PRICE: $56.95. ISBN: 323011713. Summary: This resource guide helps dental professionals work with medically compromised patients. The book is not a comprehensive medical reference but rather a book containing enough core information about each of the medical conditions covered to enable the reader to recognize the basis for various dental management recommendations. After an introduction summary table of dental management and a discussion of common medical emergencies in the dental office, the text offers 26 chapters: physical evaluation and risk assessment, infective endocarditis, cardiac conditions associated with endocarditis, hypertension, ischemic heart disease, cardiac arrhythmias, congestive heart failure, pulmonary (lung) disease, chronic renal (kidney) failure and dialysis, liver disease, gastrointestinal disease, sexually transmitted diseases, AIDS and related conditions, diabetes, adrenal insufficiency, thyroid disease, pregnancy and breast-feeding, allergy, bleeding disorders, disorders of red and white blood cells, cancer, neurological disorders, behavioral and psychiatric disorders, arthritic diseases, organ transplantation, and the dental management of older adults. Each chapter provides a brief overview of the basic disease process, epidemiology, pathophysiology, signs and symptoms, laboratory findings, currently accepted medical therapy, and recommendations for specific dental management. The text concludes with 3 appendices: infection control, therapeutic management of common oral lesions, and drug interactions of significance to dentistry. A detailed subject index is also included.

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

A pocket atlas of arrhythmias for nurses by Neville Conway; ISBN: 0723405425; http://www.amazon.com/exec/obidos/ASIN/0723405425/icongroupinterna

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Adrenergic System and Ventricular Arrhythmias in Myocardial Infarction by J. Brachmann, A. Schomig; ISBN: 0387505938; http://www.amazon.com/exec/obidos/ASIN/0387505938/icongroupinterna

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Adrenergic System and Ventricular Arrhythmias in Myocardial Infarction; ISBN: 3540505938; http://www.amazon.com/exec/obidos/ASIN/3540505938/icongroupinterna

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Basic arrhythmia analysis by Sheryl Martz; ISBN: 0840377789; http://www.amazon.com/exec/obidos/ASIN/0840377789/icongroupinterna

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Basic Arrhythmias (5th Edition) by Gail Walraven; ISBN: 083595305X; http://www.amazon.com/exec/obidos/ASIN/083595305X/icongroupinterna

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Cardiac Arrhythmias 1995: Proceedings of the 4th International Workshop on Cardiac Arrhythmias, Venice, Italy, October 6-8, 1995 by Antonio Raviele (Other Contributor); ISBN: 3540750126; http://www.amazon.com/exec/obidos/ASIN/3540750126/icongroupinterna

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Cardiac Arrhythmias 2003: Proceedings of the 8th International Workshop on Cardiac Arrhythmias (Venice, 5-8 October 2003) by Antonio Raviele; ISBN: 8847002311; http://www.amazon.com/exec/obidos/ASIN/8847002311/icongroupinterna

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Cardiac Arrhythmias After Surgery for Congenital Heart Disease by Seshadri Balaji, et al; ISBN: 0340762071; http://www.amazon.com/exec/obidos/ASIN/0340762071/icongroupinterna

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Cardiac Arrhythmias and Device Therapy: Results and Perspectives for the New Century by I. Eli, Md, Phd, Fesc, Facc Ovsyshcher; ISBN: 0879934557; http://www.amazon.com/exec/obidos/ASIN/0879934557/icongroupinterna

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Cardiac arrhythmias for the clinical cardiologist: Proeedings of the Workshop on Cardiac Arrhythmias, Mallorca, 18-19 October 1985; ISBN: 0444808264; http://www.amazon.com/exec/obidos/ASIN/0444808264/icongroupinterna

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Cardiac Arrhythmias in Children and Young Adults With Congenital Heart Disease by Edward P., MD Walsh, et al; ISBN: 0397587449; http://www.amazon.com/exec/obidos/ASIN/0397587449/icongroupinterna

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Cardiac arrhythmias in the neonate, infant, and child by Nigel Keith Roberts (Other Contributor), Henry Gelband (Other Contributor); ISBN: 0838510388; http://www.amazon.com/exec/obidos/ASIN/0838510388/icongroupinterna

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Cardiac Arrhythmias, 1999, Volume 1: Proceedings of the 6th International Workshop on Cardiac Arrhythmias (Venice, October 5-8, 1999) by A. Raviele, et al; ISBN: 8847000718; http://www.amazon.com/exec/obidos/ASIN/8847000718/icongroupinterna

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Cardiology Today and Tomorrow: Current Preview of Cardiac Arrhythmia Pacemakers and Implantable Defibrillators: Mayo Clin Card Today Arrhythmia 1e by Mayo Clinic; ISBN: 0316551155; http://www.amazon.com/exec/obidos/ASIN/0316551155/icongroupinterna

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Common Mechanism for Teratogenicity of Antiepileptic Drugs: Drug-Induced Embryonic Arrhythmia and Hypoxia-Reoxygenation Damage by Faranak Azarbayjani; ISBN: 9155450652; http://www.amazon.com/exec/obidos/ASIN/9155450652/icongroupinterna

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Control of Cardiac Arrhythmias by Lengthening Repolarization by Bramah N. Singh; ISBN: 087993316X; http://www.amazon.com/exec/obidos/ASIN/087993316X/icongroupinterna

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Current Concepts in Diagnosis & Management of Arrhythmias in Infants & Children by Barbara J. Deal, et al; ISBN: 0879936878; http://www.amazon.com/exec/obidos/ASIN/0879936878/icongroupinterna

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Diagnosing & Treating Arrhythmias Made Easy by Glenn N. Levine; ISBN: 1576261069; http://www.amazon.com/exec/obidos/ASIN/1576261069/icongroupinterna

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Diagnosis and treatment of cardiac arrhythmias following open heart surgery: Emphasis on the use of atrial and ventricular epicardial wire electrodes by Albert L Waldo; ISBN: 0879931329; http://www.amazon.com/exec/obidos/ASIN/0879931329/icongroupinterna

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Ecg Arrhythmia Interpretation a Programmed Text for Health Personnel by Harold A. Braun; ISBN: 0835915506; http://www.amazon.com/exec/obidos/ASIN/0835915506/icongroupinterna

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ECG arrhythmia interpretation: A programmed text for health care personnel by Harold A Braun; ISBN: 0835915514; http://www.amazon.com/exec/obidos/ASIN/0835915514/icongroupinterna

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ECG bases; for arrhythmia management in coronary care by Harold A Braun; ISBN: 0878420193; http://www.amazon.com/exec/obidos/ASIN/0878420193/icongroupinterna

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ECG interpretation: Identifying arrhythmias : review and self-study guide by Sallie J Kelly; ISBN: 0397544502; http://www.amazon.com/exec/obidos/ASIN/0397544502/icongroupinterna

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Ecg Workout: Exercises in Arrhythmia Interpretation by Jane Huff; ISBN: 0397553714; http://www.amazon.com/exec/obidos/ASIN/0397553714/icongroupinterna

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ECG-Challenger: Blocks, Preexcitation Syndromes and Arrhythmias (ECG-Challenger Principles of Electrocardiography Series) by ECG-Challenger, et al; ISBN: 158016076X; http://www.amazon.com/exec/obidos/ASIN/158016076X/icongroupinterna

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How to Quickly and Accurately Master Arrhythmia Interpretation by Dale Davis, Patrick Turner; ISBN: 0397509472; http://www.amazon.com/exec/obidos/ASIN/0397509472/icongroupinterna

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Interpretation of Cardiac Arrhythmias - Self Assessment Approach (DEVELOPMENTS IN CARDIOVASCULAR MEDICINE Volume 220) by Zainul Abedin, Robert P. Conner; ISBN: 0792385764; http://www.amazon.com/exec/obidos/ASIN/0792385764/icongroupinterna

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Lethal Arrhythmias Resulting from Myocardial Ischemia and Infarction: Proceedings by Michael R. Rosen, Yoram Palti; ISBN: 089838401X; http://www.amazon.com/exec/obidos/ASIN/089838401X/icongroupinterna

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Management of Cardiac Arrhythmias - Update 1990 by L.S. Dreifus; ISBN: 3805553080; http://www.amazon.com/exec/obidos/ASIN/3805553080/icongroupinterna

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Nonpharmacological Therapy of Arrhythmias for the 21st Century: the State of the Art by Igor Singer (Editor), et al; ISBN: 0879936908; http://www.amazon.com/exec/obidos/ASIN/0879936908/icongroupinterna

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Pediatric Arrhythmias Electrophysiology and Pacing by Paul C. Gillette, Arthur Garson; ISBN: 0721632017; http://www.amazon.com/exec/obidos/ASIN/0721632017/icongroupinterna

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Recent Developments in the Management of Arrhythmia (International Congress and Symposium Series (ICSS)) by H. Hayakawa, et al; ISBN: 1853152161; http://www.amazon.com/exec/obidos/ASIN/1853152161/icongroupinterna

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Risk of Arrhythmia and Sudden Death by Marek Malik, Merek Malik; ISBN: 0727915819; http://www.amazon.com/exec/obidos/ASIN/0727915819/icongroupinterna

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The Ventricular Arrhythmias of Ischemia and Infarction: Electrophysiological Mechanisms by Andrew L. Wit, Michiel J. Janse; ISBN: 0879933763; http://www.amazon.com/exec/obidos/ASIN/0879933763/icongroupinterna

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Understanding electrocardiography: Arrhythmias and the 12-lead ECG by Mary Boudreau Conover; ISBN: 0801611385; http://www.amazon.com/exec/obidos/ASIN/0801611385/icongroupinterna

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Ventricular Arrhythmias Following Myocardial Infraction: Incidence and Prognostic Importance Studied by Repeated 24-Hour Electrocardiographic Monitoring by Mogens Moller; ISBN: 8774923315; http://www.amazon.com/exec/obidos/ASIN/8774923315/icongroupinterna

Chapters on Arrhythmias In order to find chapters that specifically relate to arrhythmias, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and arrhythmias using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “arrhythmias” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on arrhythmias: •

Cardiac Arrhythmias Source: in Little, J.W., et al. Dental Management of the Medically Compromised Patient. 6th ed. St. Louis, MO: Elsevier Science. 2002. p. 94-113. Contact: Available from Elsevier Science. Customer Service Department, 11830 Westline Industrial Drive, St. Louis, MO 63146 (800) 545-2522. Fax (800) 535-9935. Email: [email protected]. Website: www.elsevierhealth.com. PRICE: $56.95. ISBN: 323011713. Summary: A cardiac arrhythmia is any variation in the normal rhythm of the heartbeat. Various forms of cardiac arrhythmias are present in a significant percentage of the population seeking dental treatment. Some arrhythmias are of little concern to the patient or dentist; however, many can produce symptoms and a few can be life threatening. These include arrhythmias that occur because of anxiety associated with dental care. Therefore, patients with significant arrhythmias must be identified before undergoing dental treatment. This chapter on cardiac arrhythmias is from a resource text that helps dental professionals work with medically compromised patients. The chapter provides a brief overview of the basic disease process, epidemiology (incidence and prevalence), pathophysiology, signs and symptoms, laboratory findings, currentlyaccepted medical therapy, prevention of medical complications, and recommendations for specific dental treatment planning. 24 figures. 5 tables. 25 references.

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

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

Control strategy for persistent atrial fibrillation does not influence QOL Source: Reuters Medical News Date: January 30, 2004

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Azimilide reduces arrhythmias in patients with defibrillators Source: Reuters Industry Breifing Date: January 21, 2004

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Adjuvant enalapril helps curb atrial fibrillation after cardioversion Source: Reuters Industry Breifing Date: December 29, 2003

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Statin treatment lowers risk of recurrent atrial fibrillation after cardioversion Source: Reuters Industry Breifing Date: December 25, 2003

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Multiple factors tied to arrhythmias after CABG Source: Reuters Medical News Date: May 12, 2004

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Fixing leaky calcium channel protects against arrhythmias in mice Source: Reuters Industry Breifing Date: April 08, 2004

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Automatic arrhythmia recording aids syncope evaluation Source: Reuters Industry Breifing Date: November 06, 2003

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Propafenone SR safe and effective for preventing arrhythmia recurrence Source: Reuters Industry Breifing Date: November 04, 2003

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Scar tissue and low ejection fraction predict arrhythmia in sudden death survivors Source: Reuters Industry Breifing Date: October 06, 2003

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FDA advisors reject Cardima's atrial fibrillation device Source: Reuters Industry Breifing Date: May 29, 2003

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Criticare gets FDA okay for arrhythmia alert software Source: Reuters Industry Breifing Date: April 30, 2003 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.

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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 “arrhythmias” (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 “arrhythmias” (or synonyms). If you know the name of a company that is relevant to arrhythmias, 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 “arrhythmias” (or synonyms).

Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “arrhythmias” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on arrhythmias: •

Focus on Cisapride Source: Reflux Digest. 2(4): 1-6. Winter 1998. Contact: Available from Pediatric-Adolescent Gastroesophageal Reflux Association, Inc. (PAGER). P.O. Box 1153, Germantown, MD 20875-1153. (301) 601-9541 or (760) 747-5001. E-mail: [email protected]. Website: www.reflux.org. Summary: This issue of the Reflux Digest newsletter is devoted to information about the use of cisapride, one of the newer medications used to treat gastroesophageal reflux disease (GERD), especially in children. The authors provide an overview of current discussions and a background that can help readers understand why the use of

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cisapride has become so controversial. The issue begins with a brief editorial introduction explaining that some of the information presented in the issue is anecdotal and provided by parents with experience with the drug. The newsletter then offers an article outlining recent concerns about cisapride (Propulsid or Prepulsid). A number of people taking cisapride have experienced changes in their heart rhythms; 38 people taking cisapride have died. This has caused a lot of concern and some outright panic among parents of children with GERD and motility disorders. The article also reports on interactions with medications in several categories, including some very common prescription and nonprescription medications. High doses of cisapride alone can be dangerous; in children who are growing and changing, dosage must be recalculated carefully and regularly. Dehydration can also contribute to arrhythmias and can cause blood levels of cisapride to rise. The article also reports how the various news reports are affecting the use of cisapride and what professional societies recommend. The article notes that the safest approach is not to use cisapride. All motility medications have limitations and it may be more appropriate to address acid levels before treating any motility issues. The issue concludes with a list of recommendations for parents who choose to allow their children to use cisapride.

Academic Periodicals covering Arrhythmias Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to arrhythmias. In addition to these sources, you can search for articles covering arrhythmias 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 8. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

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

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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to arrhythmias: Amiodarone •

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

Anticonvulsants, Hydantoin •

Systemic - U.S. Brands: Cerebyx; Dilantin; Dilantin Infatabs; Dilantin Kapseals; Dilantin-125; Mesantoin; Peganone; Phenytek http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202052.html

Calcium Channel Blocking Agents •

Systemic - U.S. Brands: Adalat; Adalat CC; Calan; Calan SR; Cardene; Cardizem; Cardizem CD; Cardizem SR; Dilacor-XR; DynaCirc; Isoptin; Isoptin SR; Nimotop; Norvasc; Plendil; Procardia; Procardia XL; Vascor; Verelan http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202107.html

Disopyramide •

Systemic - U.S. Brands: Norpace; Norpace CR http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202204.html

Mexiletine •

Systemic - U.S. Brands: Mexitil http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202369.html

Moricizine •

Systemic - U.S. Brands: Ethmozine http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202381.html

Procainamide •

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

Propafenone •

Systemic - U.S. Brands: Rythmol http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202486.html

Quinidine •

Systemic - U.S. Brands: Cardioquin; Quinaglute Dura-tabs; Quinidex Extentabs; Quin-Release http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202498.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.

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Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.

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

Sotalol HCl (trade name: Betapace) http://www.rarediseases.org/nord/search/nodd_full?code=129

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•

Sotalol HCl (trade name: Betapace) http://www.rarediseases.org/nord/search/nodd_full?code=147

•

NAPA of the Bahamas http://www.rarediseases.org/nord/search/nodd_full?code=823

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

199

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

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

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/

10

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.11 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:12 •

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

11 Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 12 See http://www.nlm.nih.gov/databases/databases.html.

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•

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 Gateway13 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.14 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “arrhythmias” (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 114353 1326 385 51 1635 117750

HSTAT15 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.16 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.17 Simply search by “arrhythmias” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

13

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

14

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 15 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 16 17

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

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

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Coffee Break: Tutorials for Biologists18 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.19 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.20 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

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

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/.

18 Adapted 19

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

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 20 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.

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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on arrhythmias can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

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

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Arrhythmia http://www.nlm.nih.gov/medlineplus/arrhythmia.html Congenital Heart Disease http://www.nlm.nih.gov/medlineplus/congenitalheartdisease.html Heart Diseases http://www.nlm.nih.gov/medlineplus/heartdiseases.html Heart Failure http://www.nlm.nih.gov/medlineplus/heartfailure.html Pacemakers and Implantable Defibrillators http://www.nlm.nih.gov/medlineplus/pacemakersandimplantabledefibrillators.ht l

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

General/Overviews Arrhythmias http://www.nlm.nih.gov/medlineplus/tutorials/arrhythmiasloader.html Cardiac Arrhythmias Source: American College of Cardiology http://www.acc.org/media/patient/chd/cardiac%255Farrhythmias.htm Sudden Cardiac Death (Cardiac Arrest) Source: Heart Rhythm Society http://www.hrspatients.org/patients/heart_disorders/cardiac_arrest/default.asp What Are Arrhythmias? Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=560

•

Diagnosis/Symptoms Diagnosing Arrhythmias Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3 Echocardiogram Source: National Institutes of Health, Clinical Center http://www.cc.nih.gov/ccc/patient_education/procdiag/echocardiogram.pdf Electrophysiology (EP) Study Source: Heart Rhythm Society http://www.hrspatients.org/patients/heart_tests/electrophysiology_study.asp Fainting (Syncope) Source: Heart Rhythm Society http://www.hrspatients.org/patients/signs_symptoms/fainting/default.asp Other Symptoms of Heart Rhythm Disorders Source: Heart Rhythm Society http://www.hrspatients.org/patients/signs_symptoms/other.asp

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Rapid Heartbeat Source: Heart Rhythm Society http://www.hrspatients.org/patients/signs_symptoms/too_fast.asp Slow Heartbeat (Bradycardia) Source: Heart Rhythm Society http://www.hrspatients.org/patients/signs_symptoms/too_slow.asp Transesophageal Echocardiogram (TEE) Source: National Institutes of Health, Clinical Center http://www.cc.nih.gov/ccc/patient_education/procdiag/tee.pdf •

Treatment Arrthythmia Medications Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=18 Cardiac Ablation Source: Heart Rhythm Society http://www.hrspatients.org/patients/treatments/cardiac_ablation.asp Cardiac Ablation Catheter Source: Food and Drug Administration http://www.fda.gov/hearthealth/treatments/medicaldevices/cardiacablationcath eter.html Cardioversion Source: American Heart Association http://circ.ahajournals.org/cgi/reprint/106/22/e176.pdf Catheter Ablation of Arrhythmias Source: American Heart Association http://circ.ahajournals.org/cgi/reprint/106/25/e203.pdf Defibrillation Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=30 Implantable Cardioverter Defibrillators (ICDs) Source: Heart Rhythm Society http://www.hrspatients.org/patients/treatments/cardiac_defibrillators/default.as p Management of Newly Detected Atrial Fibrillation: Recommendations from the American College of Physicians and the American Academy of Family Physicians Source: American College of Physicians http://www.annals.org/cgi/content/full/139/12/I-32

•

Nutrition Caffeine, Diet and Heart Arrhythmias Source: Heart Rhythm Society http://www.hrspatients.org/patients/substances/diet.asp

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New Guidelines Focus on Fish, Fish Oil, Omega-3 Fatty Acids Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3006624 •

Specific Conditions/Aspects Arrhythmias Originating in the Atria Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=10 Arrhythmias Originating in the Ventricles Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=11 Atrial Fibrillation http://www.nlm.nih.gov/medlineplus/tutorials/atrialfibrillationloader.html Atrial Fibrillation Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DS00291 Bundle Branch Block Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=990 Heart Block Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=992 JAMA Patient Page: Atrial Fibrillation Source: American Medical Association http://www.medem.com/search/article_display.cfm?path=%5C%5CTANQUERA Y%5CM_ContentItem&mstr=/M_ContentItem/ZZZIX1IGUJD.html&soc=JAMA/A rchives&srch_typ=NAV_SERCH Long QT Syndrome Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DS00434 Long Q-T Syndrome Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=993 Postural Tachycardia Syndrome Source: National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/health_and_medical/disorders/postural_tachycardia_s yndrome.htm Sick Sinus Syndrome Source: American Heart Association http://circ.ahajournals.org/cgi/reprint/108/20/e143.pdf Sinus Dysrhythmia Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=AN00787

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Substances That Can Cause Heart Rhythm Disorders Source: Heart Rhythm Society http://www.hrspatients.org/patients/substances/default.asp Sudden Cardiac Death Source: Congenital Heart Information Network http://www.tchin.org/resource_room/c_art_21_.htm Wolff-Parkinson-White Syndrome Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=4785 •

Children Checklist for Parents of Children with Arrhythmias Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=20 Children and Arrhythmia Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=2 Diagnosing Arrhythmias in Children Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=4 Treating Arrhythmias in Children Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=26 Types of Arrhythmia in Children Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=7

•

From the National Institutes of Health Arrhythmias/Rhythm Disorders Source: National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/health/public/heart/other/arrhyth.htm

•

Latest News New Cardiac Arrhythmia Syndrome Identified Source: 06/02/2004, United Press International http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_18101 .html Surgery Cuts Cardiac Arrests among Those with Rare Heart Disorder Source: 03/29/2004, American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3020167

•

Organizations American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=1200000

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Heart Rhythm Society http://www.hrsonline.org/ National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/ •

Prevention/Screening Am I at Risk? Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=562 Risk Factors and Prevention Source: Heart Rhythm Society http://www.hrspatients.org/patients/risk_factors/default.asp

•

Research Atrial Fibrillation Hospitalizations Triple Since 1985, Will Continue Climb Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3014151 Blacks Less Likely to Benefit from High-Tech Treatments for Rapid Heartbeat Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3013010 Cardiac Imaging Can Be 'Gatekeeper' for Implantable Heart-Shocker Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3015775 Fish Oils in Heart Cells Can Block Dangerous Heart Rhythms Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3012101 Outcomes of Patients with Lone Atrial Flutter Source: American College of Physicians http://www.annals.org/cgi/content/full/140/4/I-55 Radiofrequency Treatment of Abnormal Heart Rhythm Can Damage the Vessels That Return Blood from the Lungs to the Heart Source: American College of Physicians http://www.annals.org/cgi/content/full/138/8/I-41

You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on arrhythmias. CHID offers summaries that

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describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •

Drug-Induced Lupus Source: Washington, DC: Lupus Foundation of America. 2003. 6 p. Contact: Available from Lupus Foundation of America. 2000 L. St., Suite 710, Washington, DC 20036-4916. (202) 349-1155 or (800) 558-0121. (800) 558-0231 (information in Spanish). Fax: (202) 349-1156. Website: www.lupus.org. Summary: This brochure discusses drug-induced lupus erythematosus (DILE), a sideeffect of long-term use of certain medications. Most cases of DILE are associated with the use of procainamide, hydralazine, and quinidine. These drugs are mainly used by men over 50 years of age for cardiac arrhythmias (procainamide and quinidine) and hypertension (hydralazine). The only well-defined genetic risk factor in DILE is the slow drug acetylation phenotype. Circumstantial evidence suggests that the metabolic change a drug undergoes in the body, as opposed to the drug itself, makes the drug able to react to the immune system. Individuals with DILE may experience flu-like symptoms. The symptoms of DILE are the same regardless of the medication. Tests that can help with diagnosis include the antinuclear antibody test and the histone-DNA complex test. The most important aspect of treating DILE is to identify the medication that is likely to be causing the problem and then discontinue it. Although most people recover once they stop using the medication, they may develop the syndrome if they take the medication again. The brochure explains the difference between DILE and systemic lupus erythematosus and lists drugs reported to induce lupus-like disease. 1 table.

•

Binswanger's Disease Source: Danbury, CT: National Organization for Rare Disorders. 2003. 7 p. Contact: National Organization for Rare Disorders. P.O. Box 1968, Danbury, CT 068131968. (800) 999-NORD; (203) 744-0100 or TDD (203) 797-9590. E-mail: [email protected]. Website: www.rarediseases.org. PRICE: Free for 1st request, $7.50 per copy thereafter. Summary: This fact sheet summarizes information on Binswanger's disease (BD), including a brief definition and synonyms for the disease, symptom progression, possible causes, the population affected, standard and investigational therapies, and related disorders. BD is a form of senile dementia usually brought on by deep whitematter lesions in the brain. Symptoms tend to begin after age 60 and include progressive loss of recent memory, difficulty in coping with unusual events, difficulty in walking, strokes and/or paralysis of one side of the body, and Parkinsonian type tremors and depression. Range and severity of symptoms of BD vary from case to case, but it slowly progresses during a period of 5 to 10 years in most affected individuals. BD affects males more often than females, and the cause is unknown. Therapies include antihypertensive drugs to control blood pressure, anti- depressive drugs, and medication for heart arrhythmias and low blood pressure. Other treatments are symptomatic and supportive. This fact sheet includes a list of resources on BD is provided.

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

Preventive health care, 2000 update. Use of ambulatory electrocardiography for the detection of paroxysmal atrial fibrillation in patients with stroke Source: Canadian Task Force on Preventive Health Care - National Government Agency [Non-U.S.]; 2000; 7 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2703&nbr=1929&a mp;string=arrhythmias 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 arrhythmias. 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

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

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

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

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

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

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

Associations and Arrhythmias The following is a list of associations that provide information on and resources relating to arrhythmias:

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Cardiac Arrhythmias Research and Education Foundation, Inc Telephone: (949) 752-2273 Toll-free: (800) 404-9500 Fax: (949) 752-9119 Email: [email protected] Web Site: http://www.longqt.org/ Background: The Cardiac Arrhythmias Research and Education Foundation, Inc. (CARE Foundation) is a national not-for-profit organization dedicated to promoting physician education and public awareness of the unexpected sudden death of children and young adults due to heart rhythm disorders. Cardiac arrhythmias are disturbances in the heart s natural rhythm. These disturbances are caused by disruptions in the normal conduction of electrical signals within the heart. Due to various reasons, electrical signals may be detoured, slowed, or blocked while traveling through certain parts of the heart. This may cause the heart s natural rhythm to speed up, slow down, or become irregular, affecting the flow of blood to the body s internal organs. The CARE Foundation was founded in 1995 by a group of electrophysiologists and individuals who have been affected by sudden cardiac death. The Foundation s primary goals are to raise funds for clinical research of cardiac arrhythmias and to educate the public and the medical community about the prevention and treatment of arrhythmias. The Foundation promotes screening for at-risk families and participation in ongoing genetic research studies. Foundation activities include providing physician referrals and conducting informational meetings and national seminars for affected families and physicians throughout the country. Publications produced by the CARE Foundation include brochures on various types of cardiac arrhythmias such as right ventricular dysplasia, mitral valve prolapse, hypertrophic cardiomyopathy, neurocardiogenic syncope, atrial fibrillation, and paroxysmal supraventricular tachycardia. The organization also publishes a regular newsletter entitled 'CARE'. Relevant area(s) of interest: Arrhythmias, Atrial Fibrillation

•

Sudden Arrhythmia Death Syndromes Foundation Telephone: (801) 531-0937 Toll-free: (800) 786-7723 Fax: (801) 531-0945 Email: [email protected] Web Site: http://www.sads.org Background: The Sudden Arrhythmia Death Syndromes (SADS) Foundation is a national not-for-profit organization that was established in 1991. The mission of the Foundation is to save the lives of children and young adults who are genetically predisposed to sudden death due to abnormal rhythym or rate of the heart beat (cardiac arrhythmias). The Foundation seeks to educate health care providers and the public about Sudden Arrhythmia Death Syndromes to promote early diagnosis and treatment. The Foundation encourages and funds ongoing medical research into Long QT Syndrome and other genetic cardiovascular diseases that predispose young people to sudden death. SADS serves as a physician referral resource center and provides advice to physicians who care for people with Long QT Syndrome. In addition, the Foundation is interested in the identification of individuals and families at risk for these diseases and to assisting families and friends affected by Long QT Syndrome. Educational materials distributed by the organization include a newsletter, reprints of medical

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articles, and an informational brochure on Long QT Syndrome. SADS also facilititates several family support groups and a person-to-person networking program.

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to arrhythmias. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with arrhythmias. 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 arrhythmias. 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 “arrhythmias” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “arrhythmias”. 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 “arrhythmias” (or synonyms) into the “For

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

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

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

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

21

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

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

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

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

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

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

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

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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

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California: Gateway Health Library (Sutter Gould Medical Foundation)

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

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

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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/

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

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

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

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

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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/

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

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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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

•

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 arrhythmias: •

Basic Guidelines for Arrhythmias Arrhythmias Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001101.htm Atrial fibrillation/flutter Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000184.htm Wolff-Parkinson-White syndrome Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000151.htm

•

Signs & Symptoms for Arrhythmias Absent pulse Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003078.htm Arrhythmia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003081.htm

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Breathing difficulty, lying down Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003076.htm Chest pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003079.htm Clammy skin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003216.htm Confusion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003205.htm Dizziness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003093.htm Fainting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003092.htm Fatigue Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Irregular pulse Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003081.htm Light headedness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003092.htm Lightheadedness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003092.htm Low blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003083.htm Paleness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003244.htm Palpitations Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003081.htm Shortness of breath Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003075.htm Weak or absent pulse Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003078.htm •

Diagnostics and Tests for Arrhythmias Angiography Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003327.htm Blood chemistries Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003468.htm

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Blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003398.htm Coronary angiography Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003875.htm Coronary angiography Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003876.htm ECG Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003868.htm Echocardiogram Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm Exercise treadmill ECG Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003878.htm Heart rate Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003399.htm Holter monitoring Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003877.htm Pulse Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003399.htm •

Nutrition for Arrhythmias Caffeine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002445.htm

•

Background Topics for Arrhythmias Alcohol use Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001944.htm Auscultation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002226.htm Chronic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002312.htm Emboli Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001124.htm Heart disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000147.htm Heart diseases Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000147.htm

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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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ARRHYTHMIAS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] 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] Ablate: In surgery, is to remove. [NIH] Ablation: The removal of an organ by surgery. [NIH] Ablation zone: The area of tissue that is removed during laser surgery. [NIH] Abscess: A localized, circumscribed collection of pus. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetaminophen: Analgesic antipyretic derivative of acetanilide. It has weak antiinflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Aconitine: A alkaloid from the root of Aconitum napellus L. and other aconites. Activates voltage-gated Na+ channels. Has been used to induce arrhythmia in experimental animals. Shows antiinflammatory and antineuralgic properties. [NIH] Acoustic: Having to do with sound or hearing. [NIH] Actin: Essential component of the cell skeleton. [NIH] Action Potentials: The electric response of a nerve or muscle to its stimulation. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the

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intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Triphosphate: Adenosine 5'-(tetrahydrogen triphosphate). An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenal insufficiency: The reduced secretion of adrenal glands. [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] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

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Agarose: A polysaccharide complex, free of nitrogen and prepared from agar-agar which is produced by certain seaweeds (red algae). It dissolves in warm water to form a viscid solution. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Akathisia: 1. A condition of motor restlessness in which there is a feeling of muscular quivering, an urge to move about constantly, and an inability to sit still, a common extrapyramidal side effect of neuroleptic drugs. 2. An inability to sit down because of intense anxiety at the thought of doing so. [EU] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] 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] 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] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]

Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allergic Rhinitis: Inflammation of the nasal mucous membrane associated with hay fever; fits may be provoked by substances in the working environment. [NIH] Allylamine: Possesses an unusual and selective cytotoxicity for vascular smooth muscle cells in dogs and rats. Useful for experiments dealing with arterial injury, myocardial fibrosis or cardiac decompensation. [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.

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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] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Aminophylline: A drug combination that contains theophylline and ethylenediamine. It is more soluble in water than theophylline but has similar pharmacologic actions. It's most common use is in bronchial asthma, but it has been investigated for several other applications. [NIH] Amiodarone: An antianginal and antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting Na,K-activated myocardial adenosine triphosphatase. There is a resulting decrease in heart rate and in vascular resistance. [NIH] Amlodipine: 2-((2-Aminoethoxy)methyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5pyridinedicarboxylic acid 3-ethyl 5-methyl ester. A long-acting dihydropyridine calcium channel blocker. It is effective in the treatment of angina pectoris and hypertension. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amnestic: Nominal aphasia; a difficulty in finding the right name for an object. [NIH] Amoxicillin: A broad-spectrum semisynthetic antibiotic similar to ampicillin except that its resistance to gastric acid permits higher serum levels with oral administration. [NIH] Ampicillin: Semi-synthetic derivative of penicillin that functions as an orally active broadspectrum antibiotic. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in

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the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] Anginal: Pertaining to or characteristic of angina. [EU] Angiography: Radiography of blood vessels after injection of a contrast medium. [NIH] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antianginal: Counteracting angina or anginal conditions. [EU] Antiarrhythmic: An agent that prevents or alleviates cardiac arrhythmia. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or

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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] Anticholinergic: An agent that blocks the parasympathetic nerves. Called also parasympatholytic. [EU] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Antidepressant: A drug used to treat depression. [NIH] Antidote: A remedy for counteracting a poison. [EU] Antiemetic: An agent that prevents or alleviates nausea and vomiting. Also antinauseant. [EU]

Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antihistamine: A drug that counteracts the action of histamine. The antihistamines are of two types. The conventional ones, as those used in allergies, block the H1 histamine receptors, whereas the others block the H2 receptors. Called also antihistaminic. [EU] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]

Antioxidants: Naturally occurring or synthetic substances that inhibit or retard the oxidation of a substance to which it is added. They counteract the harmful and damaging effects of oxidation in animal tissues. [NIH] Antipsychotic: Effective in the treatment of psychosis. Antipsychotic drugs (called also neuroleptic drugs and major tranquilizers) are a chemically diverse (including phenothiazines, thioxanthenes, butyrophenones, dibenzoxazepines, dibenzodiazepines, and

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diphenylbutylpiperidines) but pharmacologically similar class of drugs used to treat schizophrenic, paranoid, schizoaffective, and other psychotic disorders; acute delirium and dementia, and manic episodes (during induction of lithium therapy); to control the movement disorders associated with Huntington's chorea, Gilles de la Tourette's syndrome, and ballismus; and to treat intractable hiccups and severe nausea and vomiting. Antipsychotic agents bind to dopamine, histamine, muscarinic cholinergic, a-adrenergic, and serotonin receptors. Blockade of dopaminergic transmission in various areas is thought to be responsible for their major effects : antipsychotic action by blockade in the mesolimbic and mesocortical areas; extrapyramidal side effects (dystonia, akathisia, parkinsonism, and tardive dyskinesia) by blockade in the basal ganglia; and antiemetic effects by blockade in the chemoreceptor trigger zone of the medulla. Sedation and autonomic side effects (orthostatic hypotension, blurred vision, dry mouth, nasal congestion and constipation) are caused by blockade of histamine, cholinergic, and adrenergic receptors. [EU] Antipsychotic Agents: Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in schizophrenia, senile dementia, transient psychosis following surgery or myocardial infarction, etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus. [NIH] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antithrombotic: Preventing or interfering with the formation of thrombi; an agent that so acts. [EU] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Anxiolytic: An anxiolytic or antianxiety agent. [EU] Aorta: The main trunk of the systemic arteries. [NIH] Apamin: A highly neurotoxic polypeptide from the venom of the honey bee (Apis mellifera). It consists of 18 amino acids with two disulfide bridges and causes hyperexcitability resulting in convulsions and respiratory paralysis. [NIH] Apathy: Lack of feeling or emotion; indifference. [EU] Apnea: A transient absence of spontaneous respiration. [NIH] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arrhythmogenic: Producing or promoting arrhythmia. [EU] Arrhythmogenic Right Ventricular Dysplasia: A weakening of the right ventricle that results in the back up of blood in the venous system, liver, gastrointestinal tract, and extremities. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU]

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Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteritis: Inflammation of an artery. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Arthropathy: Any joint disease. [EU] Artifacts: Any visible result of a procedure which is caused by the procedure itself and not by the entity being analyzed. Common examples include histological structures introduced by tissue processing, radiographic images of structures that are not naturally present in living tissue, and products of chemical reactions that occur during analysis. [NIH] Ascites: Accumulation or retention of free fluid within the peritoneal cavity. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astemizole: A long-acting, non-sedative antihistaminic used in the treatment of seasonal allergic rhinitis, asthma, allergic conjunctivitis, and chronic idiopathic urticaria. The drug is well tolerated and has no anticholinergic side effects. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atrial: Pertaining to an atrium. [EU] Atrial Fibrillation: Disorder of cardiac rhythm characterized by rapid, irregular atrial impulses and ineffective atrial contractions. [NIH] Atrial Flutter: Rapid, irregular atrial contractions due to an abnormality of atrial excitation. [NIH]

Atrial Function: The hemodynamic and electrophysiological action of the atria. [NIH] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrioventricular Node: A small nodular mass of specialized muscle fibers located in the interatrial septum near the opening of the coronary sinus. It gives rise to the atrioventricular bundle of the conduction system of the heart. [NIH] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Auscultation: Act of listening for sounds within the body. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autologous bone marrow transplantation: A procedure in which bone marrow is removed from a person, stored, and then given back to the person after intensive treatment. [NIH]

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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] Autonomic Neuropathy: A disease of the nerves affecting mostly the internal organs such as the bladder muscles, the cardiovascular system, the digestive tract, and the genital organs. These nerves are not under a person's conscious control and function automatically. Also called visceral neuropathy. [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, 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] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Balloon Occlusion: Use of a balloon catheter to block the flow of blood through an artery or vein. [NIH] Barbiturates: A class of chemicals derived from barbituric acid or thiobarbituric acid. Many of these are medically important as sedatives and hypnotics (sedatives, barbiturate), as anesthetics, or as anticonvulsants. [NIH] 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] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Bepridil: Beta-((2-Methylpropoxy)methyl)-N-phenyl-N-(phenylmethyl)-1pyrrolidineethanamine. A long-acting calcium-blocking agent with significant anti-anginal activity. The drug produces significant coronary vasodilation and modest peripheral effects. It has antihypertensive and selective anti-arrhythmia activities and acts as a calmodulin antagonist. [NIH]

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Beta blocker: A drug used to slow the heart rate and reduce pressure inside blood vessels. It also can regulate heart rhythm. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Binding agent: A substance that makes a loose mixture stick together. For example, binding agents can be used to make solid pills from loose powders. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biophysics: The science of physical phenomena and processes in living organisms. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] 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 Glucose: Glucose in blood. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood transfusion: The administration of blood or blood products into a blood vessel. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood Volume: Volume of circulating blood. It is the sum of the plasma volume and erythrocyte volume. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body Fluids: Liquid components of living organisms. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists

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mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [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] Brachial: All the nerves from the arm are ripped from the spinal cord. [NIH] Brachial Plexus: The large network of nerve fibers which distributes the innervation of the upper extremity. The brachial plexus extends from the neck into the axilla. In humans, the nerves of the plexus usually originate from the lower cervical and the first thoracic spinal cord segments (C5-C8 and T1), but variations are not uncommon. [NIH] Brachiocephalic Veins: Large veins on either side of the root of the neck formed by the junction of the internal jugular and subclavian veins. They drain blood from the head, neck, and upper extremities, and unite to form the superior vena cava. [NIH] Bradycardia: Excessive slowness in the action of the heart, usually with a heart rate below 60 beats per minute. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bronchial: Pertaining to one or more bronchi. [EU] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] 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] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cell membranes or on the release and binding of calcium in intracellular pools. Since they are inducers of vascular and other smooth muscle relaxation, they are used in the

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drug therapy of hypertension and cerebrovascular spasms, as myocardial protective agents, and in the relaxation of uterine spasms. [NIH] Calcium Channels: Voltage-dependent cell membrane glycoproteins selectively permeable to calcium ions. They are categorized as L-, T-, N-, P-, Q-, and R-types based on the activation and inactivation kinetics, ion specificity, and sensitivity to drugs and toxins. The L- and T-types are present throughout the cardiovascular and central nervous systems and the N-, P-, Q-, & R-types are located in neuronal tissue. [NIH] Calcium Signaling: Signal transduction mechanisms whereby calcium mobilization (from outside the cell or from intracellular storage pools) to the cytoplasm is triggered by external stimuli. Calcium signals are often seen to propagate as waves, oscillations, spikes or puffs. The calcium acts as an intracellular messenger by activating calcium-responsive proteins. [NIH]

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] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardia: That part of the stomach surrounded by the esophagogastric junction, characterized by the lack of acid-forming cells. [NIH] 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 (volume per beat). [NIH] Cardiogenic: Originating in the heart; caused by abnormal function of the heart. [EU] Cardiology: The study of the heart, its physiology, and its functions. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiopulmonary Bypass: Diversion of the flow of blood from the entrance of the right atrium directly to the aorta (or femoral artery) via an oxygenator thus bypassing both the heart and lungs. [NIH] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardioselective: Having greater activity on heart tissue than on other tissue. [EU] Cardiotonic: 1. Having a tonic effect on the heart. 2. An agent that has a tonic effect on the heart. [EU] Cardiotoxic: Having a poisonous or deleterious effect upon the heart. [EU]

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Cardiotoxicity: Toxicity that affects the heart. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular Abnormalities: Congenital structural abnormalities of the cardiovascular system. [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] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Cardioversion: Electrical reversion of cardiac arrhythmias to normal sinus rhythm, formerly using alternatic current, but now employing direct current. [NIH] Carotid Sinus: The dilated portion of the common carotid artery at its bifurcation into external and internal carotids. It contains baroreceptors which, when stimulated, cause slowing of the heart, vasodilatation, and a fall in blood pressure. [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] Cataracts: In medicine, an opacity of the crystalline lens of the eye obstructing partially or totally its transmission of light. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catfish: Common name to express the order Siluriformes. This order contains many families and over 2,000 species, including venomous species. Heteropneustes and Plotosus genera have dangerous stings and are aggressive. Most species are passive stingers. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [NIH] Catheter Ablation: Removal of tissue with electrical current delivered via electrodes positioned at the distal end of a catheter. Energy sources are commonly direct current (DCshock) or alternating current at radiofrequencies (usually 750 kHz). The technique is used most often to ablate the AV junction and/or accessory pathways in order to interrupt AV conduction and produce AV block in the treatment of various tachyarrhythmias. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be

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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 Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Fusion: Fusion of somatic cells in vitro or in vivo, which results in somatic cell hybridization. [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 proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Aqueduct: Narrow channel in the mesencephalon that connects the third and fourth ventricles. [NIH] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Cesium: A member of the alkali metals. It has an atomic symbol Cs, atomic number 50, and atomic weight 132.91. Cesium has many industrial applications, including the construction of atomic clocks based on its atomic vibrational frequency. [NIH]

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Chaos: Complex behavior that seems random but actually has some hidden order. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] CHD: 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] Chemoreceptor: A receptor adapted for excitation by chemical substances, e.g., olfactory and gustatory receptors, or a sense organ, as the carotid body or the aortic (supracardial) bodies, which is sensitive to chemical changes in the blood stream, especially reduced oxygen content, and reflexly increases both respiration and blood pressure. [EU] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chest Pain: Pressure, burning, or numbness in the chest. [NIH] Chest wall: The ribs and muscles, bones, and joints that make up the area of the body between the neck and the abdomen. [NIH] 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] Chlorpromazine: The prototypical phenothiazine antipsychotic drug. Like the other drugs in this class chlorpromazine's antipsychotic actions are thought to be due to long-term adaptation by the brain to blocking dopamine receptors. Chlorpromazine has several other actions and therapeutic uses, including as an antiemetic and in the treatment of intractable hiccup. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chordae Tendineae: The tendinous cords that connect each cusp of the two atrioventricular valves to appropriate papillary muscles in the heart ventricles, preventing the valves from reversing themselves when the ventricles contract. [NIH] Chorea: Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Choroid Plexus: A villous structure of tangled masses of blood vessels contained within the third, lateral, and fourth ventricles of the brain. It regulates part of the production and composition of cerebrospinal fluid. [NIH]

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Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Circulatory system: The system that contains the heart and the blood vessels and moves blood throughout the body. This system helps tissues get enough oxygen and nutrients, and it helps them get rid of waste products. The lymph system, which connects with the blood system, is often considered part of the circulatory system. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clavulanic Acid: Clavulanic acid (C8H9O5N) and its salts and esters. The acid is a suicide inhibitor of bacterial beta-lactamase enzymes from Streptomyces clavuligerus. Administered alone, it has only weak antibacterial activity against most organisms, but given in combination with beta-lactam antibiotics prevents antibiotic inactivation by microbial lactamase. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [NIH] 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

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differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Combination chemotherapy: Treatment using more than one anticancer drug. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray

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machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjunctivitis: Inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connexins: A group of homologous proteins which form the intermembrane channels of gap junctions. The connexins are the products of an identified gene family which has both highly conserved and highly divergent regions. The variety contributes to the wide range of functional properties of gap junctions. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Contractility: Capacity for becoming short in response to a suitable stimulus. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contralateral: Having to do with the opposite side of the body. [NIH] Contrast medium: A substance that is introduced into or around a structure and, because of the difference in absorption of x-rays by the contrast medium and the surrounding tissues, allows radiographic visualization of the structure. [EU] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH]

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Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary Artery Bypass: Surgical therapy of ischemic coronary artery disease achieved by grafting a section of saphenous vein, internal mammary artery, or other substitute between the aorta and the obstructed coronary artery distal to the obstructive lesion. [NIH] Coronary Circulation: The circulation of blood through the coronary vessels of the heart. [NIH]

Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or 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] Corpus: The body of the uterus. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Coumarin: A fluorescent dye. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Criterion: A standard by which something may be judged. [EU] Critical Care: Health care provided to a critically ill patient during a medical emergency or crisis. [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curare: Plant extracts from several species, including Strychnos toxifera, S. castelnaei, S. crevauxii, and Chondodendron tomentosum, that produce paralysis of skeletal muscle and are used adjunctively with general anesthesia. These extracts are toxic and must be used with the administration of artificial respiration. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] 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]

Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the

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hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokines: Non-antibody proteins secreted by inflammatory leukocytes and some nonleukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. [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] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [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] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Decongestant: An agent that reduces congestion or swelling. [EU] Defibrillation: The act to arrest the fibrillation of (heart muscle) by applying electric shock across the chest, thus depolarizing the heart cells and allowing normal rhythm to return. [EU] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydration: The condition that results from excessive loss of body water. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delirium: (DSM III-R) an acute, reversible organic mental disorder characterized by reduced ability to maintain attention to external stimuli and disorganized thinking as manifested by rambling, irrelevant, or incoherent speech; there are also a reduced level of consciousness, sensory misperceptions, disturbance of the sleep-wakefulness cycle and level of psychomotor activity, disorientation to time, place, or person, and memory impairment. Delirium may be caused by a large number of conditions resulting in derangement of cerebral metabolism, including systemic infection, poisoning, drug intoxication or withdrawal, seizures or head trauma, and metabolic disturbances such as hypoxia, hypoglycaemia, fluid, electrolyte, or acid-base imbalances, or hepatic or renal failure. Called also acute confusional state and acute brain syndrome. [EU] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dental Care: The total of dental diagnostic, preventive, and restorative services provided to

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meet the needs of a patient (from Illustrated Dictionary of Dentistry, 1982). [NIH] Dental Hygienists: Persons trained in an accredited school or dental college and licensed by the state in which they reside to provide dental prophylaxis under the direction of a licensed dentist. [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] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Detergents: Purifying or cleansing agents, usually salts of long-chain aliphatic bases or acids, that exert cleansing (oil-dissolving) and antimicrobial effects through a surface action that depends on possessing both hydrophilic and hydrophobic properties. [NIH] Developmental Biology: The field of biology which deals with the process of the growth and differentiation of an organism. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialysate: A cleansing liquid used in the two major forms of dialysis--hemodialysis and peritoneal dialysis. [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] Diastole: Period of relaxation of the heart, especially the ventricles. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Digitalis: A genus of toxic herbaceous Eurasian plants of the Scrophulaceae which yield cardiotonic glycosides. The most useful are Digitalis lanata and D. purpurea. [NIH] Dihydropyridines: Pyridine moieties which are partially saturated by the addition of two hydrogen atoms in any position. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilated cardiomyopathy: Heart muscle disease that leads to enlargement of the heart's chambers, robbing the heart of its pumping ability. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilator: A device used to stretch or enlarge an opening. [NIH] Diltiazem: A benzothiazepine derivative with vasodilating action due to its antagonism of the actions of the calcium ion in membrane functions. It is also teratogenic. [NIH] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU]

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Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Disposition: A tendency either physical or mental toward certain diseases. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Diuretic: A drug that increases the production of urine. [NIH] Diurnal: Occurring during the day. [EU] Dizziness: An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. [NIH] Dobutamine: A beta-2 agonist catecholamine that has cardiac stimulant action without evoking vasoconstriction or tachycardia. It is proposed as a cardiotonic after myocardial infarction or open heart surgery. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] 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

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of another drug. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Drug Toxicity: Manifestations of the adverse effects of drugs administered therapeutically or in the course of diagnostic techniques. It does not include accidental or intentional poisoning for which specific headings are available. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dyslipidemia: Disorders in the lipoprotein metabolism; classified as hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and low levels of high-density lipoprotein (HDL) cholesterol. All of the dyslipidemias can be primary or secondary. Both elevated levels of low-density lipoprotein (LDL) cholesterol and low levels of HDL cholesterol predispose to premature atherosclerosis. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystonia: Disordered tonicity of muscle. [EU] Dystrophic: Pertaining to toxic habitats low in nutrients. [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] Ectopic: Pertaining to or characterized by ectopia. [EU] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] 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] Eicosanoids: A class of oxygenated, endogenous, unsaturated fatty acids derived from arachidonic acid. They include prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acid compounds (HETE). They are hormone-like substances that act near the site of synthesis without altering functions throughout the body. [NIH] Ejection fraction: A measure of ventricular contractility, equal to normally 65 8 per cent; lower values indicate ventricular dysfunction. [EU] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electric shock: A dangerous patho-physiological effect resulting from an electric current

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passing through the body of a human or animal. [NIH] Electrocardiogram: Measurement of electrical activity during heartbeats. [NIH] Electrocardiography: Recording of the moment-to-moment electromotive forces of the heart as projected onto various sites on the body's surface, delineated as a scalar function of time. [NIH]

Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electroporation: A technique in which electric pulses of intensity in kilovolts per centimeter and of microsecond-to-millisecond duration cause a temporary loss of the semipermeability of cell membranes, thus leading to ion leakage, escape of metabolites, and increased uptake by cells of drugs, molecular probes, and DNA. Some applications of electroporation include introduction of plasmids or foreign DNA into living cells for transfection, fusion of cells to prepare hybridomas, and insertion of proteins into cell membranes. [NIH] Emboli: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embolism: Blocking of a blood vessel by a blood clot or foreign matter that has been transported from a distant site by the blood stream. [NIH] Embolization: The blocking of an artery by a clot or foreign material. Embolization can be done as treatment to block the flow of blood to a tumor. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emesis: Vomiting; an act of vomiting. Also used as a word termination, as in haematemesis. [EU]

Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Enalapril: An angiotensin-converting enzyme inhibitor that is used to treat hypertension. [NIH]

Endarterectomy: Surgical excision, performed under general anesthesia, of the atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [NIH] Endocarditis: Exudative and proliferative inflammatory alterations of the endocardium, characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a

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primary disorder or as a complication of or in association with another disease. [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] Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enkephalins: One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. [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] Epidemiological: Relating to, or involving epidemiology. [EU] Epidural: The space between the wall of the spinal canal and the covering of the spinal cord. An epidural injection is given into this space. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most

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species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Erythrocyte Volume: Volume of circulating erythrocytes. It is usually measured by radioisotope dilution technique. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Esophagitis: Inflammation, acute or chronic, of the esophagus caused by bacteria, chemicals, or trauma. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]

Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] 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] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] 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

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severity, and to evaluate therapy. Data may also be used in prescribing exercise by determining a person's exercise capacity. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Expiration: The act of breathing out, or expelling air from the lungs. [EU] Expressed Sequence Tags: Sequence tags derived from cDNAs. Expressed sequence tags (ESTs) are partial DNA sequences from clones. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extracorporeal: Situated or occurring outside the body. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [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]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Felodipine: A dihydropyridine calcium antagonist with positive inotropic effects. It lowers blood pressure by reducing peripheral vascular resistance through a highly selective action on smooth muscle in arteriolar resistance vessels. [NIH] Femoral: Pertaining to the femur, or to the thigh. [EU] Femoral Artery: The main artery of the thigh, a continuation of the external iliac artery. [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] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH]

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Fish Oils: Oils high in unsaturated fats extracted from the bodies of fish or fish parts, especially the livers. Those from the liver are usually high in vitamin A. The oils are used as dietary supplements, in soaps and detergents, as protective coatings, and as a base for other food products such as vegetable shortenings. [NIH] 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] Fluphenazine: A phenothiazine used in the treatment of psychoses. Its properties and uses are generally similar to those of chlorpromazine. [NIH] Flutter: A rapid vibration or pulsation. [EU] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fourth Ventricle: An irregularly shaped cavity in the rhombencephalon, between the medulla oblongata, the pons, and the isthmus in front, and the cerebellum behind. It is continuous with the central canal of the cord below and with the cerebral aqueduct above, and through its lateral and median apertures it communicates with the subarachnoid space. [NIH]

Fractals: Patterns (real or mathematical) which look similar at different scales, for example the network of airways in the lung which shows similar branching patterns at progressively higher magnifications. Natural fractals are self-similar across a finite range of scales while mathematical fractals are the same across an infinite range. Many natural, including biological, structures are fractal (or fractal-like). Fractals are related to "chaos" (see nonlinear dynamics) in that chaotic processes can produce fractal structures in nature, and appropriate representations of chaotic processes usually reveal self-similarity over time. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has calories. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gangrene: Death and putrefaction of tissue usually due to a loss of blood supply. [NIH] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close

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apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Acid: Hydrochloric acid present in gastric juice. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastroesophageal Reflux: Reflux of gastric juice and/or duodenal contents (bile acids, pancreatic juice) into the distal esophagus, commonly due to incompetence of the lower esophageal sphincter. Gastric regurgitation is an extension of this process with entry of fluid into the pharynx or mouth. [NIH] Gastroesophageal Reflux Disease: Flow of the stomach's contents back up into the esophagus. Happens when the muscle between the esophagus and the stomach (the lower esophageal sphincter) is weak or relaxes when it shouldn't. May cause esophagitis. Also called esophageal reflux or reflux esophagitis. [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Generator: Any system incorporating a fixed parent radionuclide from which is produced a daughter radionuclide which is to be removed by elution or by any other method and used in a radiopharmaceutical. [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

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]

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Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycoproteins: Conjugated protein-carbohydrate compounds including mucins, mucoid, and amyloid glycoproteins. [NIH] Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] 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] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Granule: A small pill made from sucrose. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Guanidine: A strong organic base existing primarily as guanidium ions at physiological pH.

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It is found in the urine as a normal product of protein metabolism. It is also used in laboratory research as a protein denaturant. (From Martindale, the Extra Pharmacopoeia, 30th ed and Merck Index, 12th ed) It is also used in the treatment of myasthenia and as a fluorescent probe in HPLC. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Haloperidol: Butyrophenone derivative. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heart Murmurs: Abnormal heart sounds heard during auscultation caused by alterations in the flow of blood into a chamber, through a valve, or by a valve opening or closing abnormally. They are classified by the time of occurrence during the cardiac cycle, the duration, and the intensity of the sound on a scale of I to V. [NIH] Heart Sounds: The sounds heard over the cardiac region produced by the functioning of the heart. There are four distinct sounds: the first occurs at the beginning of systole and is heard as a "lubb" sound; the second is produced by the closing of the aortic and pulmonary valves and is heard as a "dupp" sound; the third is produced by vibrations of the ventricular walls when suddenly distended by the rush of blood from the atria; and the fourth is produced by atrial contraction and ventricular filling but is rarely audible in the normal heart. The physiological concept of heart sounds is differentiated from the pathological heart murmurs. [NIH]

Heart Transplantation: The transference of a heart from one human or animal to another. [NIH]

Heartbeat: One complete contraction of the heart. [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] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH]

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Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoperfusion: Removal of toxins or metabolites from the circulation by the passing of blood, within a suitable extracorporeal circuit, over semipermeable microcapsules containing adsorbents (e.g., activated charcoal) or enzymes, other enzyme preparations (e.g., gel-entrapped microsomes, membrane-free enzymes bound to artificial carriers), or other adsorbents (e.g., various resins, albumin-conjugated agarose). [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hepatic: Refers to the liver. [NIH] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] Hepatotoxicity: How much damage a medicine or other substance does to the liver. [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. [NIH]

Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homotypic: Adhesion between neutrophils. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH]

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Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydralazine: A direct-acting vasodilator that is used as an antihypertensive agent. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercapnia: A clinical manifestation of abnormal increase in the amount of carbon dioxide in arterial blood. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [NIH] Hyperthyroidism: Excessive functional activity of the thyroid gland. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] 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] Hypnotic: A drug that acts to induce sleep. [EU] Hypoglycaemia: An abnormally diminished concentration of glucose in the blood, which may lead to tremulousness, cold sweat, piloerection, hypothermia, and headache, accompanied by irritability, confusion, hallucinations, bizarre behaviour, and ultimately, convulsions and coma. [EU] Hypoglycemic: An orally active drug that produces a fall in blood glucose concentration.

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[NIH]

Hypoglycemic Agents: Agents which lower the blood glucose level. [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypothermia: Lower than normal body temperature, especially in warm-blooded animals; in man usually accidental or unintentional. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Idiopathic: Describes a disease of unknown cause. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunomodulator: New type of drugs mainly using biotechnological methods. Treatment of cancer. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within

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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] Incidental: 1. Small and relatively unimportant, minor; 2. Accompanying, but not a major part of something; 3. (To something) Liable to occur because of something or in connection with something (said of risks, responsibilities, .) [EU] Incision: A cut made in the body during surgery. [NIH] Incisional: The removal of a sample of tissue for examination under a microscope. [NIH] Incompetence: Physical or mental inadequacy or insufficiency. [EU] Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infection Control: Programs of disease surveillance, generally within health care facilities, designed to investigate, prevent, and control the spread of infections and their causative microorganisms. [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] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] 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] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH]

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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] Insomnia: Difficulty in going to sleep or getting enough sleep. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]

Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Interneurons: Most generally any neurons which are not motor or sensory. Interneurons may also refer to neurons whose axons remain within a particular brain region as contrasted with projection neurons which have axons projecting to other brain regions. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestinal Mucosa: The surface lining of the intestines where the cells absorb nutrients. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] 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 Channel Gating: The opening and closing of ion channels due to a stimulus. The stimulus can be a change in membrane potential (voltage-gated), drugs or chemical transmitters (ligand-gated), or a mechanical deformation. Gating is thought to involve conformational changes of the ion channel which alters selective permeability. [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] Ions: An atom or group of atoms that have a positive or negative electric charge due to a

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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] Isoleucine: An essential branched-chain amino acid found in many proteins. It is an isomer of LEUCINE. It is important in hemoglobin synthesis and regulation of blood sugar and energy levels. [NIH] Isradipine: 4-(4-Benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methyl ethyl ester. A potent calcium channel antagonist that is highly selective for vascular smooth muscle. It is effective in the treatment of chronic stable angina pectoris, hypertension, and congestive cardiac failure. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an osseous and a membranous portion. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Laser Surgery: The use of a laser either to vaporize surface lesions or to make bloodless cuts in tissue. It does not include the coagulation of tissue by laser. [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] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Libido: The psychic drive or energy associated with sexual instinct in the broad sense

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(pleasure and love-object seeking). It may also connote the psychic energy associated with instincts in general that motivate behavior. [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] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Limbic: Pertaining to a limbus, or margin; forming a border around. [EU] 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] Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipopolysaccharides: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposomes: Artificial, single or multilaminar vesicles (made from lecithins or other lipids) that are used for the delivery of a variety of biological molecules or molecular complexes to cells, for example, drug delivery and gene transfer. They are also used to study membranes and membrane proteins. [NIH] Lipoxygenase Inhibitors: Compounds or agents that combine with lipoxygenase and thereby prevent its substrate-enzyme combination with arachidonic acid and the formation of the eicosanoid products hydroxyeicosatetraenoic acid and various leukotrienes. [NIH] Lithium: An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH]

Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver cancer: A disease in which malignant (cancer) cells are found in the tissues of the liver. [NIH]

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

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diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lower Esophageal Sphincter: The muscle between the esophagus and stomach. When a person swallows, this muscle relaxes to let food pass from the esophagus to the stomach. It stays closed at other times to keep stomach contents from flowing back into the esophagus. [NIH]

Loxapine: An antipsychotic agent used in schizophrenia. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammary: Pertaining to the mamma, or breast. [EU] Manic: Affected with mania. [EU] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Median Nerve: A major nerve of the upper extremity. In humans, the fibers of the median nerve originate in the lower cervical and upper thoracic spinal cord (usually C6 to T1), travel via the brachial plexus, and supply sensory and motor innervation to parts of the forearm and hand. [NIH]

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Mediastinitis: Inflammation of the mediastinum, the area between the pleural sacs. [NIH] Mediastinum: The area between the lungs. The organs in this area include the heart and its large blood vessels, the trachea, the esophagus, the bronchi, and lymph nodes. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [NIH] Mesolimbic: Inner brain region governing emotion and drives. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microdialysis: A technique for measuring extracellular concentrations of substances in tissues, usually in vivo, by means of a small probe equipped with a semipermeable membrane. Substances may also be introduced into the extracellular space through the membrane. [NIH]

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Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microsomal: Of or pertaining to microsomes : vesicular fragments of endoplasmic reticulum formed after disruption and centrifugation of cells. [EU] Midazolam: A short-acting compound, water-soluble at pH less than 4 and lipid-soluble at physiological pH. It is a hypnotic-sedative drug with anxiolytic and amnestic properties. It is used for sedation in dentistry, cardiac surgery, endoscopic procedures, as preanesthetic medication, and as an adjunct to local anesthesia. Because of its short duration and cardiorespiratory stability, it is particularly useful in poor-risk, elderly, and cardiac patients. [NIH]

Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitral Valve: The valve between the left atrium and left ventricle of the heart. [NIH] Mitral Valve Prolapse: Abnormal protrusion of one or both of the leaflets of the mitral valve into the left atrium during systole. This may be accompanied by mitral regurgitation, systolic murmur, nonejection click, or cardiac arrhythmia. [NIH] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Probes: A group of atoms or molecules attached to other molecules or cellular structures and used in studying the properties of these molecules and structures. Radioactive DNA or RNA sequences are used in molecular genetics to detect the presence of a complementary sequence by molecular hybridization. [NIH] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH]

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Mood Disorders: Those disorders that have a disturbance in mood as their predominant feature. [NIH] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Motor nerve: An efferent nerve conveying an impulse that excites muscular contraction. [NIH]

Movement Disorders: Syndromes which feature dyskinesias as a cardinal manifestation of the disease process. Included in this category are degenerative, hereditary, post-infectious, medication-induced, post-inflammatory, and post-traumatic conditions. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Multivariate Analysis: A set of techniques used when variation in several variables has to be studied simultaneously. In statistics, multivariate analysis is interpreted as any analytic method that allows simultaneous study of two or more dependent variables. [NIH] Muscle Contraction: A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscle relaxant: An agent that specifically aids in reducing muscle tension, as those acting at the polysynaptic neurons of motor nerves (e.g. meprobamate) or at the myoneural junction (curare and related compounds). [EU] Muscle Relaxation: That phase of a muscle twitch during which a muscle returns to a resting position. [NIH] Muscle Spindles: Mechanoreceptors found between skeletal muscle fibers. Muscle spindles are arranged in parallel with muscle fibers and respond to the passive stretch of the muscle, but cease to discharge if the muscle contracts isotonically, thus signaling muscle length. The muscle spindles are the receptors responsible for the stretch or myotactic reflex. [NIH] Muscle tension: A force in a material tending to produce extension; the state of being stretched. [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] Myasthenia: Muscular debility; any constitutional anomaly of muscle. [EU] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myenteric: On stimulation of an intestinal segment, the segment above contracts and that below relaxes. [NIH] Myocardial Contraction: Contractile activity of the heart. [NIH]

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Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]

Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myopathy: Any disease of a muscle. [EU] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonia: Prolonged failure of muscle relaxation after contraction. This may occur after voluntary contractions, muscle percussion, or electrical stimulation of the muscle. Myotonia is a characteristic feature of myotonic disorders. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Naloxone: A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] 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

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swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Nephropathy: Disease of the kidneys. [EU] Nerve Endings: Specialized terminations of peripheral neurons. Nerve endings include neuroeffector junction(s) by which neurons activate target organs and sensory receptors which transduce information from the various sensory modalities and send it centrally in the nervous system. Presynaptic nerve endings are presynaptic terminals. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuroeffector Junction: The synapse between a neuron (presynaptic) and an effector cell other than another neuron (postsynaptic). Neuroeffector junctions include synapses onto muscles and onto secretory cells. [NIH] Neurogenic: Loss of bladder control caused by damage to the nerves controlling the bladder. [NIH] Neuroleptic: A term coined to refer to the effects on cognition and behaviour of antipsychotic drugs, which produce a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients cause a reduction in confusion and agitation and normalization of psychomotor activity. [EU] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptides: Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] 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] Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. [NIH] Niacinamide: An important compound functioning as a component of the coenzyme NAD.

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Its primary significance is in the prevention and/or cure of blacktongue and pellagra. Most animals cannot manufacture this compound in amounts sufficient to prevent nutritional deficiency and it therefore must be supplemented through dietary intake. [NIH] Nicardipine: 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl) methyl 2(methyl(phenylmethyl)amino)-3,5-pyridinecarboxylic acid ethyl ester. A potent calcium channel blockader with marked vasodilator action. It has antihypertensive properties and is effective in the treatment of angina and coronary spasms without showing cardiodepressant effects. It has also been used in the treatment of asthma and enhances the action of specific antineoplastic agents. [NIH] Nicorandil: A derivative of the niacinamide that is structurally combined with an organic nitrate. It is a potassium-channel opener that causes vasodilatation of arterioles and large coronary arteries. Its nitrate-like properties produce venous vasodilation through stimulation of guanylate cyclase. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nifedipine: A potent vasodilator agent with calcium antagonistic action. It is a useful antianginal agent that also lowers blood pressure. The use of nifedipine as a tocolytic is being investigated. [NIH] Nimodipine: A calcium channel blockader with preferential cerebrovascular activity. It has marked cerebrovascular dilating effects and lowers blood pressure. [NIH] Nisoldipine: 1,4-Dihydro-2,6-dimethyl-4 (2-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-methylpropyl ester. Nisoldipine is a dihydropyridine calcium channel antagonist that acts as a potent arterial vasodilator and antihypertensive agent. It is also effective in patients with cardiac failure and angina. [NIH] Nitrates: Inorganic or organic salts and esters of nitric acid. These compounds contain the NO3- radical. [NIH] Nitric acid: A toxic, corrosive, colorless liquid used to make fertilizers, dyes, explosives, and other chemicals. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nociceptors: Peripheral receptors for pain. Nociceptors include receptors which are sensitive to painful mechanical stimuli, extreme heat or cold, and chemical stimuli. All nociceptors are free nerve endings. [NIH] Nonlinear Dynamics: The study of systems which respond disproportionately (nonlinearly) to initial conditions or perturbing stimuli. Nonlinear systems may exhibit "chaos" which is classically characterized as sensitive dependence on initial conditions. Chaotic systems, while distinguished from more ordered periodic systems, are not random. When their

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behavior over time is appropriately displayed (in "phase space"), constraints are evident which are described by "strange attractors". Phase space representations of chaotic systems, or strange attractors, usually reveal fractal (fractals) self-similarity across time scales. Natural, including biological, systems often display nonlinear dynamics and chaos. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Normotensive: 1. Characterized by normal tone, tension, or pressure, as by normal blood pressure. 2. A person with normal blood pressure. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Occupational Exposure: The exposure to potentially harmful chemical, physical, or biological agents that occurs as a result of one's occupation. [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] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] Opioid Peptides: The endogenous peptides with opiate-like activity. The three major classes currently recognized are the enkephalins, the dynorphins, and the endorphins. Each of these families derives from different precursors, proenkephalin, prodynorphin, and proopiomelanocortin, respectively. There are also at least three classes of opioid receptors, but the peptide families do not map to the receptors in a simple way. [NIH] Opium: The air-dried exudate from the unripe seed capsule of the opium poppy, Papaver somniferum, or its variant, P. album. It contains a number of alkaloids, but only a few morphine, codeine, and papaverine - have clinical significance. Opium has been used as an analgesic, antitussive, antidiarrheal, and antispasmodic. [NIH] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Oral Hygiene: The practice of personal hygiene of the mouth. It includes the maintenance of oral cleanliness, tissue tone, and general preservation of oral health. [NIH] Orderly: A male hospital attendant. [NIH] Organ Transplantation: Transference of an organ between individuals of the same species

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or between individuals of different species. [NIH] Orthostatic: Pertaining to or caused by standing erect. [EU] Ouabain: A cardioactive glycoside consisting of rhamnose and ouabagenin, obtained from the seeds of Strophanthus gratus and other plants of the Apocynaceae; used like digitalis. It is commonly used in cell biological studies as an inhibitor of the NA(+)-K(+)-exchanging atpase. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidative metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, cell respiration, or aerobic metabolism. [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenator: An apparatus by which oxygen is introduced into the blood during circulation outside the body, as during open heart surgery. [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] Pacer: Device that delivers battery-supplied electrical stimuli over leads with electrodes in contact with the heart. Virtually all leads are inserted transvenously. Electronic circuitry regulates the timing and characteristics of the stimuli. [NIH] Paclitaxel: Antineoplastic agent isolated from the bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel stabilizes microtubules in their polymerized form and thus mimics the action of the proto-oncogene proteins c-mos. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] 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] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH] Panic: A state of extreme acute, intense anxiety and unreasoning fear accompanied by disorganization of personality function. [NIH]

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Papilla: A small nipple-shaped elevation. [NIH] Papillary: Pertaining to or resembling papilla, or nipple. [EU] Papillary Muscles: Conical muscular projections from the walls of the cardiac ventricles, attached to the cusps of the atrioventricular valves by the chordae tendineae. [NIH] Paraesthesia: Morbid or perverted sensation; an abnormal sensation, as burning, prickling, formication, etc. [EU] Paralysis: Loss of ability to move all or part of the body. [NIH] Parasympathetic Nervous System: The craniosacral division of the autonomic nervous system. The cell bodies of the parasympathetic preganglionic fibers are in brain stem nuclei and in the sacral spinal cord. They synapse in cranial autonomic ganglia or in terminal ganglia near target organs. The parasympathetic nervous system generally acts to conserve resources and restore homeostasis, often with effects reciprocal to the sympathetic nervous system. [NIH] Paresthesia: Subjective cutaneous sensations (e.g., cold, warmth, tingling, pressure, etc.) that are experienced spontaneously in the absence of stimulation. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Parotid: The space that contains the parotid gland, the facial nerve, the external carotid artery, and the retromandibular vein. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] 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] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Advocacy: Promotion and protection of the rights of patients, frequently through a legal process. [NIH] Patient Compliance: Voluntary cooperation of the patient in following a prescribed regimen. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Patient Selection: Criteria and standards used for the determination of the appropriateness of the inclusion of patients with specific conditions in proposed treatment plans and the criteria used for the inclusion of subjects in various clinical trials and other research protocols. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU]

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Perforation: 1. The act of boring or piercing through a part. 2. A hole made through a part or substance. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Periaqueductal Gray: Central gray matter surrounding the cerebral aqueduct in the mesencephalon. Physiologically it is probably involved in rage reactions, the lordosis reflex, feeding responses, bladder tonus, and pain. [NIH] Pericardial Effusion: Presence of fluid within the pericardium. [NIH] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Periodicity: The tendency of a phenomenon to recur at regular intervals; in biological systems, the recurrence of certain activities (including hormonal, cellular, neural) may be annual, seasonal, monthly, daily, or more frequently (ultradian). [NIH] Perioperative: Around the time of surgery; usually lasts from the time of going into the hospital or doctor's office for surgery until the time the patient goes home. [NIH] Perioperative Care: Interventions to provide care prior to, during, and immediately after surgery. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneal Dialysis: Dialysis fluid being introduced into and removed from the peritoneal cavity as either a continuous or an intermittent procedure. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [NIH] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer

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phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phenylephrine: An alpha-adrenergic agonist used as a mydriatic, nasal decongestant, and cardiotonic agent. [NIH] Phenytoin: An anticonvulsant that is used in a wide variety of seizures. It is also an antiarrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. [NIH] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phorbol Esters: Tumor-promoting compounds obtained from croton oil (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylates: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] 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] Picrotoxin: A noncompetitive antagonist at GABA-A receptors and thus a convulsant. Picrotoxin blocks the GABA-activated chloride ionophore. Although it is most often used as a research tool, it has been used as a CNS stimulant and an antidote in poisoning by CNS depressants, especially the barbiturates. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pigmentation: Coloration or discoloration of a part by a pigment. [NIH] Piloerection: Involuntary erection or bristling of hairs. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH]

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Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma Volume: Volume of plasma in the circulation. It is usually measured by indicator dilution techniques. [NIH] Plasmids: Any extrachromosomal hereditary determinant. Plasmids are self-replicating circular molecules of DNA that are found in a variety of bacterial, archaeal, fungal, algal, and plant species. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Pleural: A circumscribed area of hyaline whorled fibrous tissue which appears on the surface of the parietal pleura, on the fibrous part of the diaphragm or on the pleura in the interlobar fissures. [NIH] Plexus: A network or tangle; a general term for a network of lymphatic vessels, nerves, or veins. [EU] 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] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] 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] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [NIH] 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

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ventralis. [NIH] Port: An implanted device through which blood may be withdrawn and drugs may be infused without repeated needle sticks. Also called a port-a-cath. [NIH] Port-a-cath: An implanted device through which blood may be withdrawn and drugs may be infused without repeated needle sticks. Also called a port. [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] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-synaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Postural: Pertaining to posture or position. [EU] 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] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precordial: Pertaining to the precordium (= region over the heart and lower part of the thorax). [EU] 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] Preoperative: Preceding an operation. [EU] Pressoreceptors: Receptors in the vascular system, particularly the aorta and carotid sinus, which are sensitive to stretch of the vessel walls. [NIH] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Presynaptic Terminals: The distal terminations of axons which are specialized for the release of neurotransmitters. Also included are varicosities along the course of axons which have similar specializations and also release transmitters. Presynaptic terminals in both the central and peripheral nervous systems are included. [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] Primary Prevention: Prevention of disease or mental disorders in susceptible individuals or populations through promotion of health, including mental health, and specific protection,

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as in immunization, as distinguished from the prevention of complications or after-effects of existing disease. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Procainamide: A derivative of procaine with less CNS action. [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] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Propafenone: An antiarrhythmia agent that is particularly effective in ventricular arrhythmias. It also has weak beta-blocking activity. The drug is generally well tolerated. [NIH]

Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Propranolol: A widely used non-cardioselective beta-adrenergic antagonist. Propranolol is used in the treatment or prevention of many disorders including acute myocardial infarction, arrhythmias, angina pectoris, hypertension, hypertensive emergencies, hyperthyroidism, migraine, pheochromocytoma, menopause, and anxiety. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane).

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The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostaglandins D: Physiologically active prostaglandins found in many tissues and organs. They show pressor activity, are mediators of inflammation, and have potential antithrombotic effects. [NIH] Prostaglandins F: (9 alpha,11 alpha,13E,15S)-9,11,15-Trihydroxyprost-13-en-1-oic acid (PGF(1 alpha)); (5Z,9 alpha,11,alpha,13E,15S)-9,11,15-trihydroxyprosta-5,13-dien-1-oic acid (PGF(2 alpha)); (5Z,9 alpha,11 alpha,13E,15S,17Z)-9,11,15-trihydroxyprosta-5,13,17-trien-1oic acid (PGF(3 alpha)). A family of prostaglandins that includes three of the six naturally occurring prostaglandins. All naturally occurring PGF have an alpha configuration at the 9carbon position. They stimulate uterine and bronchial smooth muscle and are often used as oxytocics. [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] Protective Agents: Synthetic or natural substances which are given to prevent a disease or disorder or are used in the process of treating a disease or injury due to a poisonous agent. [NIH]

Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Kinase C: An enzyme that phosphorylates proteins on serine or threonine residues in the presence of physiological concentrations of calcium and membrane phospholipids. The additional presence of diacylglycerols markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by phorbol esters and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters. EC 2.7.1.-. [NIH] Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [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

Dictionary 281

recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Pruritus: An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychosis: A mental disorder characterized by gross impairment in reality testing as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behaviour without apparent awareness on the part of the patient of the incomprehensibility of his behaviour; the term is also used in a more general sense to refer to mental disorders in which mental functioning is sufficiently impaired as to interfere grossly with the patient's capacity to meet the ordinary demands of life. Historically, the term has been applied to many conditions, e.g. manic-depressive psychosis, that were first described in psychotic patients, although many patients with the disorder are not judged psychotic. [EU] Psychotropic: Exerting an effect upon the mind; capable of modifying mental activity; usually applied to drugs that effect the mental state. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Circulation: The circulation of blood through the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary Embolism: Embolism in the pulmonary artery or one of its branches. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH]

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Pulmonary Veins: The veins that return the oxygenated blood from the lungs to the left atrium of the heart. [NIH] Pulsation: A throb or rhythmical beat, as of the heart. [EU] 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]

Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Putrefaction: The process of decomposition of animal and vegetable matter by living organisms. [NIH] Pyloric Sphincter: The muscle between the stomach and the small intestine. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Quinidine: An optical isomer of quinine, extracted from the bark of the Cinchona tree and similar plant species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. It prolongs cellular action potential, and decreases automaticity. Quinidine also blocks muscarinic and alphaadrenergic neurotransmission. [NIH] Quinine: An alkaloid derived from the bark of the cinchona tree. It is used as an antimalarial drug, and is the active ingredient in extracts of the cinchona that have been used for that purpose since before 1633. Quinine is also a mild antipyretic and analgesic and has been used in common cold preparations for that purpose. It was used commonly and as a bitter and flavoring agent, and is still useful for the treatment of babesiosis. Quinine is also useful in some muscular disorders, especially nocturnal leg cramps and myotonia congenita, because of its direct effects on muscle membrane and sodium channels. The mechanisms of its antimalarial effects are not well understood. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Racemic: Optically inactive but resolvable in the way of all racemic compounds. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radioactive: Giving off radiation. [NIH] Radiofrequency ablation: The use of electrical current to destroy tissue. [NIH] Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and

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interventional radiology or other planning and guiding medical radiology. [NIH] Radiopharmaceutical: Any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose. [NIH] Rage: Fury; violent, intense anger. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] 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] Recombinant Proteins: Proteins prepared by recombinant DNA technology. [NIH] 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] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] 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] Reflux: The term used when liquid backs up into the esophagus from the stomach. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regurgitation: A backward flowing, as the casting up of undigested food, or the backward flowing of blood into the heart, or between the chambers of the heart when a valve is incompetent. [EU]

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Relaxant: 1. Lessening or reducing tension. 2. An agent that lessens tension. [EU] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]

Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Renin-Angiotensin System: A system consisting of renin, angiotensin-converting enzyme, and angiotensin II. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. The converting enzyme contained in the lung acts on angiotensin I in the plasma converting it to angiotensin II, the most powerful directly pressor substance known. It causes contraction of the arteriolar smooth muscle and has other indirect actions mediated through the adrenal cortex. [NIH] Renovascular: Of or pertaining to the blood vessels of the kidneys. [EU] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory Paralysis: Complete or severe weakness of the muscles of respiration. This condition may be associated with motor neuron diseases; peripheral nerve disorders; neuromuscular junction diseases; spinal cord diseases; injury to the phrenic nerve; and other disorders. [NIH] Respiratory System: The tubular and cavernous organs and structures, by means of which pulmonary ventilation and gas exchange between ambient air and the blood are brought about. [NIH] Restitution: The restoration to a normal state. [NIH] Resuscitation: The restoration to life or consciousness of one apparently dead; it includes such measures as artificial respiration and cardiac massage. [EU] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The

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outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retrograde: 1. Moving backward or against the usual direction of flow. 2. Degenerating, deteriorating, or catabolic. [EU] Retrospective: Looking back at events that have already taken place. [NIH] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] Rhamnose: A methylpentose whose L- isomer is found naturally in many plant glycosides and some gram-negative bacterial lipopolysaccharides. [NIH] Rheumatic Heart Disease: Disease of the heart resulting from rheumatic fever and characterized by inflammatory changes in the myocardium or scarring of the valves. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rhythmicity: Regular periodicity. [NIH] Ribonuclease: RNA-digesting enzyme. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rubber: A high-molecular-weight polymeric elastomer derived from the milk juice (latex) of Hevea brasiliensis and other trees. It is a substance that can be stretched at room temperature to atleast twice its original length and after releasing the stress, retractrapidly, and recover its original dimensions fully. Synthetic rubber is made from many different chemicals, including styrene, acrylonitrile, ethylene, propylene, and isoprene. [NIH] Ryanodine: Insecticidal alkaloid isolated from Ryania speciosa; proposed as a myocardial depressant. [NIH] Saccule: The smaller of the 2 sacs within the vestibule of the ear. [NIH] Saline: A solution of salt and water. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Saphenous: Applied to certain structures in the leg, e. g. nerve vein. [NIH] Saphenous Vein: The vein which drains the foot and leg. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sarcoidosis: An idiopathic systemic inflammatory granulomatous disorder comprised of epithelioid and multinucleated giant cells with little necrosis. It usually invades the lungs with fibrosis and may also involve lymph nodes, skin, liver, spleen, eyes, phalangeal bones, and parotid glands. [NIH]

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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] Scalpel: A small pointed knife with a convex edge. [NIH] Scatter: The extent to which relative success and failure are divergently manifested in qualitatively different tests. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Screening: Checking for disease when there are no symptoms. [NIH] Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [EU] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] 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] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH]

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Septum: A dividing wall or partition; a general term for such a structure. The term is often used alone to refer to the septal area or to the septum pellucidum. [EU] Septum Pellucidum: A triangular double membrane separating the anterior horns of the lateral ventricles of the brain. It is situated in the median plane and bounded by the corpus callosum and the body and columns of the fornix. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Sequester: A portion of dead bone which has become detached from the healthy bone tissue, as occurs in necrosis. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sexually Transmitted Diseases: Diseases due to or propagated by sexual contact. [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]

Sibutramine: A drug used for the management of obesity that helps reduce food intake and is indicated for weight loss and maintenance of weight loss when used in conjunction with a reduced-calorie diet. It works to suppress the appetite primarily by inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin. Side effects include dry mouth, headache, constipation, insomnia, and a slight increase in average blood pressure. In some patients it causes a higher blood pressure increase. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of

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protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] 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] Skin Pigmentation: Coloration of the skin. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sleep apnea: A serious, potentially life-threatening breathing disorder characterized by repeated cessation of breathing due to either collapse of the upper airway during sleep or absence of respiratory effort. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Soaps: Sodium or potassium salts of long chain fatty acids. These detergent substances are obtained by boiling natural oils or fats with caustic alkali. Sodium soaps are harder and are used as topical anti-infectives and vehicles in pills and liniments; potassium soaps are soft, used as vehicles for ointments and also as topical antimicrobials. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] 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] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH]

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Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH] Somnolence: Sleepiness; also unnatural drowsiness. [EU] Sotalol: An adrenergic beta-antagonist that is used in the treatment of life-threatening arrhythmias. [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] Soybean Oil: Oil from soybean or soybean plant. [NIH] Spatial disorientation: Loss of orientation in space where person does not know which way is up. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinal Nerves: The 31 paired peripheral nerves formed by the union of the dorsal and ventral spinal roots from each spinal cord segment. The spinal nerve plexuses and the spinal roots are also included. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Stabilization: The creation of a stable state. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. [NIH] Steady state: Dynamic equilibrium. [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] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the

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ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stenosis: Narrowing or stricture of a duct or canal. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stethoscope: An instrument used for the detection and study of sounds within the body that conveyed to the ears of the observer through rubber tubing. [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 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] Strangulation: Extreme compression or constriction of the trachea or of any part. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroke Volume: The amount of blood pumped out of the heart per beat not to be confused with cardiac output (volume/time). [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. [NIH] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH]

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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] Sulfamoyl: AMPA/Kainate antagonist. [NIH] Superior vena cava: Vein which returns blood from the head and neck, upper limbs, and thorax. It is formed by the union of the two brachiocephalic veins. [NIH] Supine: Having the front portion of the body upwards. [NIH] Supine Position: The posture of an individual lying face up. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Supraventricular: Situated or occurring above the ventricles, especially in an atrium or atrioventricular node. [EU] Surgical Instruments: Hand-held tools or implements used by health professionals for the performance of surgical tasks. [NIH] Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [NIH] Sympathectomy: The removal or interruption of some part of the sympathetic nervous system for therapeutic or research purposes. [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] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU]

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Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Syncope: A temporary suspension of consciousness due to generalized cerebral schemia, a faint or swoon. [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systole: Period of contraction of the heart, especially of the ventricles. [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] Tachycardia, Ventricular: An abnormally rapid ventricular rhythm with wide QRS complexes, usually in excess of 150 per minute. It is generated within the ventricle, below the Bundle of His, and is most commonly associated with atrioventricular dissociation. [NIH] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU] Taxus: Genus of coniferous yew trees or shrubs, several species of which have medicinal uses. Notable is the Pacific yew, Taxus brevifolia, which is used to make the anti-neoplastic drug taxol (paclitaxel). [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Terfenadine: A selective histamine H1-receptor antagonist devoid of central nervous system depressant activity. The drug is used in the treatment of seasonal allergic rhinitis, asthma, allergic conjunctivitis, and chronic idiopathic urticaria. [NIH] Terminalis: A groove on the lateral surface of the right atrium. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Tetralogy of Fallot: A combination of congenital cardiac defects consisting of pulmonary stenosis, interventricular septal defects, dextroposition of the aorta so that it overrides the interventricular septum and receives venous as well as arterial blood, and right ventricular hypertrophy. [NIH]

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Tetrodotoxin: Octahydro-12-(hydroxymethyl)-2-imino-5,9:7,10a-dimethano10aH(1,3)dioxocino(6,5-a)pyrimidine-4,7,10,11,12-pentol. An aminoperhydroquinazoline poison found mainly in the liver and ovaries of fishes in the order Tetradontiformes (pufferfish, globefish, toadfish), which are eaten. The toxin causes paresthesia and paralysis through interference with neuromuscular conduction. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Theophylline: Alkaloid obtained from Thea sinensis (tea) and others. It stimulates the heart and central nervous system, dilates bronchi and blood vessels, and causes diuresis. The drug is used mainly in bronchial asthma and for myocardial stimulation. Among its more prominent cellular effects are inhibition of cyclic nucleotide phosphodiesterases and antagonism of adenosine receptors. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thermal ablation: A procedure using heat to remove tissue or a part of the body, or destroy its function. For example, to remove the lining of the uterus, a catheter is inserted through the cervix into the uterus, a balloon at the end of the catheter is inflated, and fluid inside the balloon is heated to destroy the lining of the uterus. [NIH] Thoracic: Having to do with the chest. [NIH] Thoracic Surgery: A surgical specialty concerned with diagnosis and treatment of disorders of the heart, lungs, and esophagus. Two major types of thoracic surgery are classified as pulmonary and cardiovascular. [NIH] Thoracotomy: Surgical incision into the chest wall. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thromboembolism: Obstruction of a vessel by a blood clot that has been transported from a distant site by the blood stream. [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] Thromboxanes: Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation,

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contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [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 Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] 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] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] 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] Transduction: The transfer of genes from one cell to another by means of a viral (in the case

Dictionary 295

of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]

Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Trees: Woody, usually tall, perennial higher plants (Angiosperms, Gymnosperms, and some Pterophyta) having usually a main stem and numerous branches. [NIH] Triad: Trivalent. [NIH] Tricuspid Valve: The valve consisting of three cusps situated between the right atrium and right ventricle of the heart. [NIH] Trigger zone: Dolorogenic zone (= producing or causing pain). [EU] Trophic: Of or pertaining to nutrition. [EU] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [NIH]

Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Unsaturated Fats: A type of fat. [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the

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deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urokinase: A drug that dissolves blood clots or prevents them from forming. [NIH] Urticaria: A vascular reaction of the skin characterized by erythema and wheal formation due to localized increase of vascular permeability. The causative mechanism may be allergy, infection, or stress. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccines: Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa, or rickettsiae), antigenic proteins derived from them, or synthetic constructs, administered for the prevention, amelioration, or treatment of infectious and other diseases. [NIH]

Vagal: Pertaining to the vagus nerve. [EU] Vagotomy: The interruption or removal of any part of the vagus (10th cranial) nerve. Vagotomy may be performed for research or for therapeutic purposes. [NIH] Vagus Nerve: The 10th cranial nerve. The vagus is a mixed nerve which contains somatic 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] Valves: Flap-like structures that control the direction of blood flow through the heart. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasoactive Intestinal Peptide: A highly basic, single-chain polypeptide isolated from the intestinal mucosa. It has a wide range of biological actions affecting the cardiovascular, gastrointestinal, and respiratory systems. It is also found in several parts of the central and peripheral nervous systems and is a neurotransmitter. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilatation: A state of increased calibre of the blood vessels. [EU] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in

Dictionary 297

nature or in recombinant DNA technology. [NIH] Vectorcardiography: Recording of the moment-to-moment electromotive forces of the heart on a plane of the body surface delineated as a vector function of time. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Vena: A vessel conducting blood from the capillary bed to the heart. [NIH] Venom: That produced by the poison glands of the mouth and injected by the fangs of poisonous snakes. [NIH] Venous: Of or pertaining to the veins. [EU] Venous Thrombosis: The formation or presence of a thrombus within a vein. [NIH] Venter: Belly. [NIH] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [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] Ventricular Function: The hemodynamic and electrophysiological action of the ventricles. [NIH]

Ventricular Remodeling: The geometric and structural changes that the ventricle undergoes, usually following myocardial infarction. It comprises expansion of the infarct and dilatation of the healthy ventricle segments. While most prevalent in the left ventricle, it can also occur in the right ventricle. [NIH] Verapamil: A calcium channel blocker that is a class IV anti-arrhythmia agent. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] 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] Villous: Of a surface, covered with villi. [NIH] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] 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]

298

Arrhythmias

Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral Afferents: The sensory fibers innervating the viscera. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Voltage-gated: It is opened by the altered charge distribution across the cell membrane. [NIH]

Warfarin: An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Xenograft: The cells of one species transplanted to another species. [NIH] Xerostomia: Decreased salivary flow. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] 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]

299

INDEX A Abdomen, 227, 237, 241, 262, 264, 275, 289, 290, 296, 298 Abdominal, 8, 227, 266, 273, 275 Abdominal Pain, 8, 227 Abducens, 227, 229 Aberrant, 55, 158, 227 Ablate, 65, 140, 158, 166, 227, 239, 250 Ablation zone, 31, 227 Abscess, 227, 286 Acceptor, 227, 264, 273, 295 Acetaminophen, 10, 227 Acetylcholine, 227, 241, 270, 271 Acidosis, 164, 227 Aconitine, 125, 227 Acoustic, 31, 227 Actin, 227, 268, 269 Action Potentials, 24, 43, 46, 50, 53, 55, 179, 227 Acute renal, 4, 227 Adaptability, 227, 240 Adaptation, 47, 227, 241, 277 Adenine, 172, 228, 282 Adenocarcinoma, 228, 258 Adenosine, 6, 18, 84, 102, 119, 134, 150, 172, 176, 228, 230, 276, 293 Adenosine Triphosphate, 6, 84, 228, 276 Adjustment, 175, 227, 228 Adrenal Cortex, 228, 229, 279, 284 Adrenal Glands, 228 Adrenal insufficiency, 184, 185, 228 Adrenal Medulla, 228, 239, 251, 272 Adverse Effect, 6, 14, 228, 249, 276, 287 Aerobic, 228, 252, 273 Afferent, 21, 169, 228 Affinity, 46, 48, 50, 179, 228, 229, 288 Agar, 228, 229, 277 Agarose, 229, 258 Agonist, 35, 150, 176, 229, 248, 269, 271, 276 Airway, 12, 172, 229, 288 Akathisia, 229, 233 Albumin, 229, 258 Aldosterone, 39, 229 Algorithms, 47, 141, 160, 229, 236 Alkaline, 227, 229, 230, 237 Alkaloid, 227, 229, 242, 268, 271, 282, 285, 293

Alkylating Agents, 229, 295 Alleles, 229, 264 Allergen, 229, 247 Allergic Rhinitis, 229, 234, 292 Allylamine, 229, 230 Alternans, 54, 77, 229 Alternative medicine, 191, 229 Amine, 54, 230, 258 Amino Acid Sequence, 179, 230, 232 Amino Acids, 19, 230, 231, 233, 274, 277, 281, 287, 296 Aminophylline, 119, 230 Amiodarone, 10, 72, 102, 103, 130, 134, 145, 194, 230 Amlodipine, 7, 230 Ammonia, 230, 291, 295 Amnestic, 230, 267 Amoxicillin, 10, 230 Ampicillin, 230 Amplification, 34, 230 Amputation, 9, 230 Anaesthesia, 113, 230, 261 Anal, 230, 268 Analgesic, 10, 227, 230, 268, 272, 282 Analogous, 230, 248, 295 Anaphylatoxins, 230, 243 Anatomical, 51, 231, 234, 241, 247, 260 Androgens, 13, 228, 231 Anemia, 5, 184, 231, 254 Anesthesia, 19, 21, 40, 73, 75, 110, 111, 130, 229, 231, 245, 250, 267, 279 Anesthetics, 46, 231, 235, 252 Aneurysm, 231, 296 Angina, 4, 6, 7, 8, 21, 40, 86, 170, 171, 230, 231, 263, 271, 279 Angina Pectoris, 6, 8, 40, 86, 170, 171, 230, 231, 263, 279 Anginal, 231, 235, 271 Angiography, 224, 225, 231 Angioplasty, 107, 231, 269 Angiotensinogen, 231, 284 Animal model, 10, 15, 19, 22, 28, 29, 40, 49, 50, 59, 61, 64, 65, 231 Anions, 229, 231, 263 Antagonism, 231, 247, 293 Antianginal, 230, 231 Antibacterial, 231, 242, 289 Antibiotic, 230, 231, 232, 237, 242, 289

300

Arrhythmias

Antibodies, 19, 42, 81, 232, 257, 259, 277 Antibody, 11, 211, 228, 232, 243, 246, 257, 258, 260, 261, 289 Anticholinergic, 232, 234 Anticoagulant, 6, 92, 232, 280, 298 Anticonvulsant, 232, 276 Antidepressant, 50, 232 Antidote, 232, 276 Antiemetic, 232, 233, 241 Antigen, 228, 232, 243, 258, 259, 260, 261 Antigen-Antibody Complex, 232, 243 Antihistamine, 102, 232 Antihypertensive, 52, 232, 235, 259, 271 Anti-inflammatory, 10, 227, 232, 234 Anti-Inflammatory Agents, 10, 232, 234 Antineoplastic, 229, 232, 271, 273 Antineoplastic Agents, 229, 232, 271 Antioxidants, 122, 232 Antipsychotic, 41, 67, 232, 233, 241, 265, 270 Antipsychotic Agents, 42, 233 Antipyretic, 227, 233, 282 Antithrombotic, 233, 280 Anxiety, 188, 229, 233, 273, 279 Anxiolytic, 233, 267 Aorta, 233, 238, 245, 278, 292, 297 Apamin, 20, 233 Apathy, 233, 270 Apnea, 12, 233 Applicability, 65, 233 Aqueous, 233, 235, 246, 259, 263 Arachidonic Acid, 233, 249, 263, 264, 279 Arginine, 230, 233, 271 Arrhythmogenic, 13, 15, 16, 22, 34, 43, 47, 59, 61, 86, 158, 233 Arrhythmogenic Right Ventricular Dysplasia, 47, 233 Arterial, 21, 51, 69, 126, 229, 233, 259, 271, 281, 292 Arteries, 8, 30, 83, 164, 233, 234, 236, 241, 245, 265, 269, 271, 281, 294 Arteriolar, 233, 237, 253, 284 Arterioles, 233, 234, 236, 269, 271, 296 Arteritis, 113, 234 Artery, 5, 6, 19, 25, 38, 40, 81, 88, 91, 92, 94, 103, 107, 120, 133, 157, 169, 175, 184, 231, 233, 234, 235, 239, 245, 250, 253, 269, 274, 282, 284 Arthropathy, 8, 234 Artifacts, 73, 79, 150, 234 Ascites, 8, 234 Aspirin, 69, 234

Assay, 11, 234 Astemizole, 6, 234 Asymptomatic, 8, 9, 12, 75, 108, 177, 234, 254 Ataxia, 49, 234, 293 Atrial Flutter, 64, 94, 151, 156, 160, 161, 163, 164, 177, 210, 234 Atrial Function, 65, 234 Atrioventricular, 96, 156, 160, 164, 173, 178, 234, 241, 274, 288, 291, 292 Atrioventricular Node, 96, 173, 234, 291 Atrophy, 8, 234 Auscultation, 225, 234, 257 Autologous, 127, 181, 234 Autologous bone marrow transplantation, 127, 234 Autonomic Nervous System, 39, 41, 174, 235, 274, 275, 288, 291 Autonomic Neuropathy, 9, 235 Axons, 235, 262, 278 B Bacteria, 231, 232, 235, 250, 251, 252, 266, 267, 283, 289, 294, 295, 296 Bacterial Physiology, 228, 235 Bactericidal, 235, 252 Balloon Occlusion, 91, 235 Barbiturates, 235, 276, 282 Baroreflex, 39, 74, 235 Basal Ganglia, 233, 234, 235, 241 Basal Ganglia Diseases, 234, 235, 241 Base, 3, 15, 228, 235, 246, 254, 256, 263, 277, 292 Benign, 156, 235, 257 Bepridil, 7, 235 Beta blocker, 7, 8, 176, 236 Bile, 236, 254, 255, 263, 264, 290 Bile Acids, 236, 255, 290 Bile Pigments, 236, 263 Binding agent, 131, 236 Binding Sites, 46, 236 Bioavailability, 145, 236 Biochemical, 13, 16, 33, 36, 44, 57, 58, 59, 81, 96, 229, 236, 256, 263, 287 Biophysics, 13, 29, 38, 44, 236 Biopsy, 8, 236, 274 Biosynthesis, 233, 236, 280, 287 Biotechnology, 23, 67, 70, 191, 201, 236 Bladder, 235, 236, 270, 275, 296 Blood Coagulation, 236, 237, 293 Blood Glucose, 236, 258, 259, 260, 262 Blood transfusion, 3, 236 Blood Volume, 7, 236

Index 301

Blot, 29, 37, 236 Body Fluids, 236, 237, 249, 288 Bone Marrow, 234, 236, 237, 260, 265, 267 Bone Marrow Transplantation, 237 Bowel, 5, 14, 230, 237, 262 Brachial, 237, 265 Brachial Plexus, 237, 265 Brachiocephalic Veins, 237, 291 Bradycardia, 20, 68, 96, 149, 150, 152, 159, 181, 207, 237 Bradykinin, 237, 271 Brain Stem, 237, 274 Breeding, 51, 237 Broad-spectrum, 230, 237 Bronchial, 230, 237, 258, 280, 293 Buccal, 237, 265 Buffers, 235, 237 Bupivacaine, 237, 264 Bypass, 64, 237, 269 C Calcium Channel Blockers, 7, 8, 237 Calcium Channels, 12, 22, 49, 54, 238 Calcium Signaling, 15, 45, 238 Calmodulin, 16, 77, 159, 235, 238 Carbohydrate, 238, 256 Carbon Dioxide, 238, 246, 259, 284 Carcinogenic, 229, 238, 261, 279, 290 Carcinoma, 238 Cardia, 92, 238 Cardiac arrest, 25, 37, 38, 39, 67, 77, 103, 238, 291 Cardiac Output, 23, 142, 166, 169, 235, 238, 290 Cardiogenic, 5, 238 Cardiomyopathy, 5, 12, 15, 30, 54, 57, 86, 108, 145, 157, 177, 184, 238 Cardiopulmonary, 77, 107, 129, 238 Cardiopulmonary Bypass, 107, 129, 238 Cardiorespiratory, 238, 267 Cardioselective, 238, 279 Cardiotonic, 238, 247, 248, 276 Cardiotoxic, 42, 238 Cardiotoxicity, 41, 239 Cardiovascular Abnormalities, 12, 239 Cardiovascular disease, 6, 7, 18, 34, 60, 84, 157, 213, 239 Cardiovascular System, 12, 33, 47, 235, 239 Cardioversion, 68, 72, 84, 93, 94, 103, 108, 141, 162, 168, 190, 207, 239 Carotid Sinus, 169, 239, 278 Case report, 111, 127, 239, 242

Case series, 239, 242 Cataracts, 20, 32, 239 Catecholamine, 239, 248, 275 Catfish, 28, 239 Catheter Ablation, 79, 87, 94, 101, 107, 108, 140, 144, 207, 239 Catheterization, 231, 239, 269 Cations, 239, 263 Caudal, 239, 260, 278 Causal, 22, 126, 239 Cause of Death, 15, 16, 184, 239 Cell Death, 35, 240, 270 Cell Differentiation, 33, 240, 287 Cell Fusion, 61, 240 Cell membrane, 129, 143, 159, 171, 237, 238, 240, 247, 250, 255, 276, 278, 288, 298 Cell proliferation, 240, 287 Cell Respiration, 240, 273, 284 Centrifugation, 240, 267 Cerebellar, 234, 240, 283 Cerebral, 147, 234, 235, 237, 240, 244, 246, 252, 253, 254, 257, 275, 292 Cerebral Aqueduct, 240, 254, 275 Cerebral Cortex, 234, 240, 252, 253 Cerebrospinal, 240, 241 Cerebrospinal fluid, 240, 241 Cerebrovascular, 235, 238, 239, 240, 271, 293 Cerebrum, 240 Cervical, 237, 240, 257, 265 Cervix, 240, 293 Cesium, 119, 240 Chaos, 26, 110, 241, 254, 271 Character, 10, 231, 241, 246 CHD, 97, 206, 241, 245, 265 Chemoreceptor, 233, 241 Chemotactic Factors, 241, 243 Chemotherapy, 241 Chest Pain, 8, 40, 142, 165, 241 Chest wall, 241, 293 Chin, 164, 241, 266 Chlorpromazine, 241, 254 Cholesterol, 236, 241, 245, 249, 259, 264, 265, 290 Cholinergic, 233, 241, 271 Chordae Tendineae, 241, 274 Chorea, 233, 241 Choroid, 19, 241, 284 Choroid Plexus, 19, 241 Chromosomal, 47, 230, 242 Chromosome, 20, 30, 86, 242, 264 Chronic renal, 4, 184, 185, 242

302

Arrhythmias

Circulatory system, 143, 242 Cirrhosis, 8, 242, 257 Clamp, 12, 15, 29, 32, 35, 36, 41, 43, 46, 49, 51, 179, 242 Clavulanic Acid, 10, 242 Clinical Medicine, 62, 242, 278 Clinical study, 60, 242, 244 Clinical trial, 11, 37, 49, 50, 74, 127, 178, 201, 242, 274, 283 Cloning, 14, 30, 57, 236, 242 Coagulation, 140, 157, 236, 242, 263, 298 Cofactor, 242, 280, 293 Cognition, 242, 270 Colchicine, 242, 295 Collagen, 242, 253, 277 Collapse, 12, 243, 288 Combination chemotherapy, 118, 243 Complement, 45, 62, 231, 243, 255 Complementary and alternative medicine, 125, 136, 243 Complementary medicine, 125, 243 Computational Biology, 201, 243 Computed tomography, 175, 243, 244 Computerized axial tomography, 243, 244 Computerized tomography, 243, 244 Conception, 244, 253 Confounding, 19, 244 Confusion, 224, 244, 259, 270, 296 Congestion, 233, 244, 246 Congestive heart failure, 4, 5, 6, 9, 30, 58, 70, 85, 91, 101, 144, 157, 177, 184, 185, 244 Conjugated, 244, 245, 256, 258 Conjunctivitis, 234, 244, 292 Connective Tissue, 237, 242, 244, 253, 254, 265, 292 Connexins, 29, 33, 244, 255 Consciousness, 37, 230, 244, 246, 248, 281, 284, 292 Constipation, 233, 244, 287 Constriction, 244, 263, 290, 296 Contractility, 12, 83, 169, 182, 184, 244, 249 Contraindications, ii, 4, 244 Contralateral, 229, 244, 283 Contrast medium, 231, 244 Controlled clinical trial, 5, 130, 244 Convulsions, 232, 233, 244, 259 Coordination, 46, 98, 169, 244 Coronary Arteriosclerosis, 245, 269 Coronary Artery Bypass, 4, 73, 104, 129, 245 Coronary Circulation, 231, 245

Coronary heart disease, 97, 239, 241, 245 Coronary Thrombosis, 245, 269 Corpus, 28, 245, 279, 287 Cortex, 245, 283 Cortical, 245, 252, 286, 293 Coumarin, 69, 245 Cranial, 245, 257, 274, 275, 296 Criterion, 26, 141, 173, 245 Critical Care, 13, 73, 88, 108, 245 Cultured cells, 32, 245 Curare, 245, 268 Curative, 37, 142, 166, 245, 293 Cutaneous, 14, 245, 265, 274 Cyclic, 238, 245, 257, 271, 280, 286, 293 Cysteine, 29, 63, 245 Cystine, 245 Cytochrome, 42, 245 Cytokines, 58, 59, 246 Cytoplasm, 238, 240, 246, 251, 256, 265, 267, 270, 286 Cytosine, 18, 246, 282 Cytoskeleton, 33, 246 Cytotoxic, 10, 246, 287 D Data Collection, 147, 246 Decarboxylation, 246, 258 Decongestant, 246, 276 Defibrillation, 25, 39, 42, 66, 71, 99, 141, 148, 157, 162, 168, 180, 207, 246 Degenerative, 246, 268, 285 Dehydration, 63, 192, 246 Deletion, 44, 56, 246 Delirium, 233, 246 Dementia, 211, 233, 246 Dendrites, 246, 270 Dental Care, 188, 246 Dental Hygienists, 6, 7, 247 Depolarization, 41, 42, 145, 160, 173, 180, 181, 247, 287 Desensitization, 12, 247 Detergents, 247, 254 Developmental Biology, 13, 17, 247 Diabetes Mellitus, 8, 184, 247, 256, 258 Diagnostic procedure, 139, 191, 247 Dialysate, 3, 247 Dialyzer, 247, 257 Diastole, 175, 247 Diastolic, 5, 36, 58, 184, 247, 259 Digestion, 236, 237, 247, 262, 264, 290 Digestive tract, 235, 247, 288 Digitalis, 118, 119, 121, 131, 247, 273 Dihydropyridines, 7, 12, 247

Index 303

Dilatation, Pathologic, 247, 296 Dilated cardiomyopathy, 30, 74, 75, 85, 112, 114, 247 Dilation, 237, 247, 296 Dilator, 13, 247 Diltiazem, 7, 134, 247 Dimethyl, 178, 247, 263, 271 Discrete, 55, 156, 248 Discrimination, 19, 145, 146, 160, 248 Disinfectant, 248, 252 Disposition, 19, 248 Dissociation, 143, 228, 248, 292 Dissociative Disorders, 248 Distal, 20, 28, 167, 239, 245, 248, 250, 255, 278, 281 Diuretic, 7, 248 Diurnal, 52, 180, 248 Dizziness, 37, 142, 165, 224, 248 Dobutamine, 95, 99, 248 Dopamine, 233, 241, 248, 270, 276 Dorsal, 248, 278, 289 Drive, ii, vi, 5, 8, 40, 41, 74, 117, 183, 184, 185, 188, 248, 263 Drug Design, 19, 195, 248 Drug Interactions, 7, 11, 44, 185, 195, 248 Drug Tolerance, 249, 294 Drug Toxicity, 165, 249 Duct, 239, 249, 285, 290 Duodenum, 236, 249, 251, 273, 290 Dyes, 43, 249, 270, 271 Dyskinesia, 233, 249 Dyslipidemia, 6, 249 Dysplasia, 47, 213, 249 Dystonia, 233, 249 Dystrophic, 49, 249 Dystrophy, 11, 20, 30, 32, 49, 249 E Echocardiography, 5, 95, 99, 101, 249 Ectopic, 28, 51, 140, 143, 144, 155, 156, 174, 180, 249 Edema, 159, 249, 269 Effector, 227, 243, 249, 270 Efficacy, 25, 42, 49, 50, 64, 69, 80, 84, 94, 103, 145, 177, 248, 249 Eicosanoids, 127, 249 Ejection fraction, 190, 249 Elective, 249 Electric shock, 246, 249 Electrocardiogram, 106, 115, 151, 155, 156, 162, 173, 174, 175, 181, 250 Electrocardiography, 66, 69, 99, 161, 187, 188, 212, 250

Electrocoagulation, 242, 250 Electrode, 14, 141, 152, 162, 163, 165, 173, 250 Electrolyte, 119, 164, 179, 181, 229, 246, 250, 278, 288 Electrons, 235, 250, 263, 273, 282 Electroporation, 42, 250 Emboli, 14, 225, 250, 298 Embolism, 250, 281, 298 Embolization, 250, 298 Embolus, 5, 250, 261 Embryo, 240, 250, 261 Emesis, 233, 250 Empirical, 16, 250 Enalapril, 190, 250 Endarterectomy, 231, 250 Endocarditis, 5, 133, 184, 185, 250 Endocardium, 37, 250, 251 Endogenous, 12, 21, 119, 131, 248, 249, 251, 272, 280, 294 Endorphins, 251, 270, 272 Endoscopic, 251, 267 Endothelial cell, 251, 293 Endothelium, 29, 251, 271 Endothelium, Lymphatic, 251 Endothelium, Vascular, 251 Endothelium-derived, 251, 271 Endotoxic, 251, 264 Endotoxins, 243, 251 End-stage renal, 3, 4, 5, 9, 113, 184, 242, 251 Enkephalins, 36, 251, 270, 272 Environmental Health, 200, 202, 251 Enzymatic, 6, 237, 243, 251, 258 Epidemiological, 52, 103, 184, 251 Epidural, 75, 251 Epinephrine, 4, 119, 228, 248, 251, 270, 272, 295 Epithelial, 228, 252 Epithelial Cells, 252 Epithelium, 19, 251, 252 Erectile, 84, 252 Erection, 252, 276 Erythrocyte Volume, 236, 252 Erythrocytes, 231, 237, 252 Esophageal, 4, 252, 255 Esophagitis, 252, 255 Esophagus, 247, 252, 255, 265, 266, 275, 283, 290, 293 Estrogen, 60, 252 Estrogen receptor, 60, 252 Ethanol, 12, 252

304

Arrhythmias

Eukaryotic Cells, 252, 261 Evoke, 252, 290 Excitability, 27, 34, 44, 46, 52, 61, 252, 282 Excitation, 12, 16, 30, 35, 51, 149, 180, 234, 241, 252, 270 Excitatory, 21, 52, 53, 180, 252, 256 Exercise Test, 78, 84, 252 Exogenous, 251, 253, 280 Expiration, 253, 284 Expressed Sequence Tags, 65, 253 Extracellular, 21, 27, 58, 62, 244, 253, 266, 288 Extracellular Matrix, 244, 253 Extracellular Space, 253, 266 Extracorporeal, 253, 258 Extrapyramidal, 229, 233, 248, 253 Extremity, 237, 253, 265 F Facial, 229, 253, 274, 288 Facial Paralysis, 229, 253 Family Planning, 201, 253 Fat, 14, 164, 233, 237, 241, 245, 250, 253, 264, 277, 295 Fatigue, 8, 142, 165, 224, 253, 257 Fatty acids, 127, 129, 130, 229, 249, 253, 279, 288 Felodipine, 7, 253 Femoral, 238, 253 Femoral Artery, 238, 253 Fetus, 28, 253, 296 Fibroblasts, 181, 253, 262 Fibrosis, 8, 11, 229, 253, 285 Fish Oils, 127, 210, 254 Flecainide, 91, 100, 254 Fluphenazine, 42, 254 Flutter, 142, 156, 158, 161, 165, 223, 254 Folate, 254 Fold, 56, 63, 145, 177, 254, 266 Folic Acid, 8, 254 Forearm, 236, 254, 265 Fourth Ventricle, 240, 241, 254 Fractals, 254, 272 Free Radicals, 128, 248, 254, 269 Fructose, 254, 256 G Gallbladder, 21, 227, 254 Ganglia, 227, 235, 254, 270, 274, 275, 291 Gangrene, 9, 254 Gap Junctions, 24, 35, 48, 56, 244, 254, 292 Gas, 230, 238, 255, 259, 271, 284, 290 Gastric, 28, 230, 255, 258 Gastric Acid, 230, 255

Gastrin, 255, 258 Gastroesophageal Reflux, 4, 191, 255 Gastroesophageal Reflux Disease, 4, 191, 255 Gastrointestinal, 5, 9, 14, 184, 185, 233, 237, 252, 255, 263, 287, 288, 290, 296 Gastrointestinal tract, 233, 252, 255, 263, 287 Gene Expression, 23, 55, 58, 61, 65, 255 Generator, 145, 148, 162, 180, 255 Genetic Engineering, 236, 242, 255 Genetic Markers, 30, 255 Genetics, 18, 20, 27, 44, 60, 62, 89, 90, 97, 255, 267 Genital, 235, 255 Genotype, 38, 44, 47, 90, 255, 275 Germ Cells, 255, 266, 272, 288, 292 Gland, 228, 255, 259, 265, 273, 274, 286, 290, 294 Glomerular, 255, 284 Glucose, 70, 94, 236, 247, 255, 256, 258, 259, 261, 262, 285 Glucose Intolerance, 247, 256 Glucose tolerance, 94, 256 Glucose Tolerance Test, 256 Glutamic Acid, 254, 256, 270 Glutathione Peroxidase, 131, 256, 286 Glycine, 256, 270, 287 Glycogen, 70, 256 Glycoproteins, 238, 256, 262, 266, 278, 288 Glycoside, 176, 256, 273, 285 Glycosylation, 56, 81, 256 Gonad, 256 Gonadal, 128, 256, 290 Governing Board, 256, 278 Graft, 129, 256, 260, 269 Grafting, 73, 104, 245, 256, 260 Granule, 50, 256 Granulocytes, 256, 287, 298 Grasses, 254, 256 Guanidine, 54, 256 Guanylate Cyclase, 257, 271 H Habitual, 241, 257 Haloperidol, 42, 257 Haptens, 228, 257 Headache, 257, 259, 287 Heart attack, 239, 257 Heart Murmurs, 7, 8, 257 Heart Sounds, 257 Heart Transplantation, 6, 99, 257

Index 305

Heartbeat, 17, 140, 156, 173, 181, 188, 207, 210, 257, 291, 297 Hemiplegia, 229, 257 Hemochromatosis, 8, 257 Hemodialysis, 3, 4, 5, 9, 113, 247, 257, 263 Hemodynamics, 83, 113, 258 Hemoglobin, 8, 231, 252, 258, 263 Hemoperfusion, 125, 258 Hemorrhage, 250, 257, 258, 269, 290 Hepatic, 8, 10, 42, 229, 246, 256, 258 Hepatocellular, 8, 258 Hepatocellular carcinoma, 8, 258 Hepatotoxicity, 10, 258 Hereditary, 8, 60, 70, 258, 268, 277 Heredity, 255, 258 Heterogeneity, 30, 35, 38, 43, 228, 258 Histamine, 10, 96, 120, 231, 232, 233, 258, 292 Histidine, 258 Histology, 31, 48, 61, 258 Homeostasis, 3, 9, 16, 22, 35, 45, 48, 171, 179, 258, 274, 288 Homologous, 229, 244, 258, 291 Homotypic, 29, 258 Hormonal, 4, 39, 58, 234, 258, 275 Hormone, 102, 229, 249, 251, 255, 258, 262, 266, 279, 285, 286, 287, 294 Hybrid, 93, 107, 258, 259 Hybridization, 23, 240, 259, 267 Hybridomas, 250, 259, 262 Hydralazine, 211, 259 Hydrogen, 227, 230, 235, 237, 238, 247, 256, 259, 264, 267, 272, 273 Hydrogen Peroxide, 256, 259, 264 Hyperbilirubinemia, 259, 263 Hypercapnia, 12, 259 Hypercholesterolemia, 249, 259 Hyperlipidemia, 184, 249, 259 Hyperplasia, 7, 259 Hypersensitivity, 229, 247, 259, 263, 285 Hyperthermia, 140, 259 Hyperthyroidism, 259, 279 Hypertriglyceridemia, 249, 259 Hypertrophic cardiomyopathy, 6, 94, 101, 213, 259 Hypertrophy, 4, 5, 18, 32, 36, 55, 58, 65, 77, 95, 114, 120, 157, 259, 292 Hypnotic, 259, 267 Hypoglycaemia, 113, 246, 259 Hypoglycemic, 9, 84, 94, 259, 260 Hypoglycemic Agents, 84, 260

Hypotension, 5, 9, 20, 21, 147, 172, 233, 244, 260 Hypothalamus, 235, 260 Hypothermia, 259, 260 Hypoxia, 12, 28, 57, 120, 164, 186, 246, 260, 293 I Idiopathic, 30, 34, 60, 86, 112, 177, 234, 260, 285, 292 Immune response, 232, 257, 260, 290, 298 Immune system, 211, 260, 263, 298 Immunity, 149, 260 Immunization, 260, 279 Immunofluorescence, 39, 260 Immunogenic, 260, 264 Immunologic, 30, 241, 260 Immunology, 24, 228, 260 Immunomodulator, 54, 260 Immunosuppressive, 10, 260 Immunosuppressive therapy, 10, 260 Immunotherapy, 247, 260 Impairment, 234, 246, 249, 260, 266, 281 Implantation, 55, 82, 142, 166, 244, 260 Impotence, 9, 252, 260 In situ, 13, 34, 260 In Situ Hybridization, 34, 260 In vitro, 13, 14, 23, 34, 41, 50, 51, 54, 56, 58, 83, 240, 261 In vivo, 13, 27, 33, 34, 51, 52, 54, 56, 58, 120, 128, 240, 261, 266, 293 Incidental, 177, 261 Incision, 261, 262, 293 Incisional, 156, 261 Incompetence, 255, 261 Incubated, 59, 261 Induction, 61, 66, 120, 231, 233, 261 Infarction, 4, 5, 6, 7, 8, 9, 12, 16, 25, 26, 39, 43, 55, 58, 59, 60, 85, 88, 95, 97, 98, 107, 112, 119, 140, 170, 185, 186, 187, 188, 233, 245, 248, 261, 269, 279, 284, 297, 298 Infection, 36, 184, 185, 241, 246, 261, 265, 270, 285, 290, 296, 298 Infection Control, 184, 185, 261 Inflammation, 229, 232, 234, 244, 252, 253, 261, 263, 266, 269, 277, 280, 285, 292 Infusion, 99, 107, 261, 269, 295 Ingestion, 12, 120, 256, 261, 277 Inhalation, 52, 70, 261, 277 Initiation, 24, 25, 34, 42, 43, 51, 55, 174, 261, 294 Innervation, 36, 48, 58, 237, 261, 265 Inositol, 129, 261, 286

306

Arrhythmias

Inotropic, 248, 253, 262 Insight, 13, 18, 28, 65, 262 Insomnia, 262, 287 Insulin, 6, 53, 70, 256, 262 Insulin-dependent diabetes mellitus, 262 Intensive Care, 73, 107, 113, 262 Interleukin-6, 58, 262 Intermittent, 28, 147, 262, 275 Interneurons, 52, 262 Interstitial, 28, 40, 253, 262, 284 Intestinal, 14, 42, 256, 262, 268, 296 Intestinal Mucosa, 262, 296 Intestine, 5, 237, 262, 263 Intoxication, 12, 120, 246, 262, 298 Intracellular, 14, 15, 16, 22, 23, 28, 32, 45, 58, 59, 60, 62, 237, 238, 261, 262, 266, 271, 278, 280, 286, 287 Intracellular Membranes, 262, 266 Intravenous, 261, 262 Intrinsic, 28, 30, 46, 52, 57, 140, 143, 152, 181, 228, 262 Invasive, 14, 44, 65, 93, 115, 166, 169, 260, 262, 265 Involuntary, 235, 241, 253, 262, 269, 276, 283 Ion Channel Gating, 46, 262 Ion Channels, 11, 14, 15, 16, 22, 27, 34, 35, 37, 45, 55, 62, 171, 179, 262, 276, 292 Ions, 62, 63, 179, 235, 237, 238, 248, 250, 256, 259, 262, 267, 278, 286, 288 Ischemia, 5, 14, 19, 21, 24, 25, 35, 36, 39, 40, 43, 55, 57, 59, 68, 73, 97, 119, 121, 128, 130, 137, 140, 164, 170, 171, 172, 174, 181, 188, 234, 263, 269, 284 Isoleucine, 98, 263 Isradipine, 7, 263 J Jaundice, 8, 259, 263 K Kb, 200, 263 Kidney Failure, 251, 263 Kinetic, 11, 16, 263 L Labile, 243, 263 Labyrinth, 263, 297 Large Intestine, 247, 262, 263, 288 Laser Surgery, 227, 263 Lectin, 263, 266 Lens, 239, 263 Lesion, 31, 37, 140, 167, 229, 245, 263, 264, 292, 295

Lethal, 22, 26, 41, 50, 63, 81, 97, 98, 120, 154, 159, 187, 235, 263 Leukotrienes, 121, 233, 249, 263, 264 Libido, 8, 231, 263 Lidocaine, 46, 264 Ligament, 182, 264 Ligands, 172, 179, 264 Ligation, 21, 264 Limbic, 34, 264 Linkage, 20, 30, 255, 264 Linkage Disequilibrium, 20, 264 Lipid, 57, 59, 122, 129, 262, 264, 267 Lipid A, 57, 264 Lipid Peroxidation, 122, 264 Lipopolysaccharides, 264, 285 Lipoprotein, 249, 264, 265 Liposomes, 34, 264 Lipoxygenase Inhibitors, 119, 264 Lithium, 233, 264 Liver, 8, 10, 184, 185, 227, 229, 233, 236, 242, 254, 256, 257, 258, 264, 284, 285, 293, 295 Liver cancer, 8, 264 Localization, 13, 31, 56, 99, 143, 149, 156, 264 Localized, 34, 227, 257, 261, 264, 277, 295, 296 Loop, 7, 111, 141, 149, 165, 181, 264 Low-density lipoprotein, 249, 264, 265 Lower Esophageal Sphincter, 255, 265 Loxapine, 42, 265 Lupus, 133, 211, 265, 292 Lymph, 240, 242, 251, 265, 266, 285 Lymph node, 240, 265, 266, 285 Lymphatic, 251, 261, 265, 277, 289 Lymphatic system, 265, 289 Lymphocytes, 232, 259, 260, 265, 289, 298 Lymphoid, 232, 265 M Magnetic Resonance Imaging, 149, 265 Malignant, 27, 36, 38, 48, 54, 57, 68, 78, 80, 82, 85, 102, 104, 109, 129, 228, 232, 264, 265 Malnutrition, 5, 9, 229, 234, 265 Mammary, 245, 265 Manic, 233, 264, 265, 281 Manifest, 57, 257, 265 Median Nerve, 21, 265 Mediastinitis, 4, 266 Mediastinum, 266 Mediate, 21, 44, 60, 248, 266 Medicament, 170, 266

Index 307

MEDLINE, 201, 266 Megaloblastic, 254, 266 Meiosis, 266, 291 Melanin, 266, 276, 295 Membrane Glycoproteins, 266 Membrane Proteins, 27, 62, 264, 266 Memory, 27, 211, 246, 266 Meninges, 240, 266 Menopause, 266, 279 Mental, iv, 10, 11, 80, 200, 202, 240, 241, 242, 244, 246, 248, 253, 261, 266, 278, 281, 286, 296 Mental Disorders, 11, 266, 278, 281 Mental Health, iv, 10, 200, 202, 266, 278, 281 Mental Processes, 248, 266, 281 Mesenteric, 5, 14, 266 Mesentery, 266 Mesolimbic, 233, 266 Metabolite, 10, 41, 247, 266 Microbe, 266, 294 Microbiology, 228, 266 Microdialysis, 40, 266 Microorganism, 242, 267, 298 Microscopy, 28, 267 Microsomal, 42, 267 Midazolam, 119, 267 Mitochondrial Swelling, 267, 270 Mitral Valve, 82, 213, 267 Mitral Valve Prolapse, 213, 267 Mobilization, 238, 267 Modeling, 19, 43, 47, 62, 68, 248, 267 Modification, 14, 21, 96, 140, 255, 267, 282 Modulator, 17, 61, 172, 267 Molecular, 13, 14, 15, 16, 17, 19, 20, 22, 23, 24, 30, 33, 35, 36, 38, 39, 41, 43, 44, 45, 46, 47, 49, 53, 56, 57, 60, 61, 62, 63, 68, 90, 96, 109, 179, 201, 203, 236, 238, 243, 248, 250, 264, 267, 285, 294, 295 Molecular Probes, 250, 267 Molecular Structure, 63, 267 Monitor, 11, 29, 32, 37, 38, 42, 141, 147, 150, 153, 267, 272 Monocytes, 262, 267 Mood Disorders, 26, 268 Morphine, 122, 268, 269, 272 Morphological, 16, 250, 268 Morphology, 17, 101, 156, 268 Motility, 4, 28, 192, 268, 287 Motor nerve, 268 Movement Disorders, 233, 268, 293 Mucosa, 265, 268

Multivariate Analysis, 114, 268 Muscle Contraction, 53, 179, 268, 286 Muscle Fibers, 160, 234, 268, 269, 288 Muscle relaxant, 172, 268, 276 Muscle Relaxation, 268, 269 Muscle Spindles, 268, 276 Muscle tension, 268 Musculature, 182, 268 Mutagenesis, 19, 45, 46, 268 Mutagens, 268 Myasthenia, 257, 268 Mydriatic, 247, 268, 276 Myenteric, 28, 268 Myocardial Contraction, 173, 268 Myocardial Ischemia, 21, 24, 35, 40, 70, 97, 118, 173, 174, 187, 231, 269 Myocardial Reperfusion, 269, 284 Myocardial Reperfusion Injury, 269, 284 Myocarditis, 9, 91, 269 Myocardium, 8, 16, 20, 22, 42, 55, 57, 61, 65, 140, 157, 159, 175, 180, 231, 269, 285 Myopathy, 32, 269 Myosin, 268, 269 Myotonia, 20, 269, 282 Myotonic Dystrophy, 20, 32, 99, 269 N Naloxone, 118, 269 Narcotic, 268, 269 Nausea, 232, 233, 269, 296 Necrosis, 9, 157, 261, 269, 284, 285, 287 Neonatal, 24, 86, 127, 270 Nephropathy, 9, 270 Nerve Endings, 21, 270, 271 Nervous System, 12, 19, 32, 41, 51, 53, 62, 174, 181, 227, 228, 235, 238, 240, 254, 256, 257, 263, 268, 270, 274, 275, 277, 287, 291, 292, 293 Networks, 33, 47, 67, 270 Neural, 21, 28, 47, 51, 119, 228, 270, 275, 288 Neuroeffector Junction, 270 Neurogenic, 33, 110, 270 Neuroleptic, 42, 229, 232, 270 Neurologic, 184, 270 Neuromuscular, 227, 253, 270, 284, 293 Neuronal, 21, 27, 34, 47, 51, 58, 238, 270 Neurons, 21, 36, 39, 49, 51, 52, 58, 246, 252, 254, 262, 268, 270, 271, 291 Neuropathy, 9, 235, 270 Neuropeptides, 52, 58, 110, 270 Neurophysiology, 247, 270 Neurotoxic, 233, 270

308

Arrhythmias

Neutrophils, 256, 258, 270 Niacinamide, 270, 271 Nicardipine, 7, 271 Nicorandil, 122, 271 Nicotine, 52, 271 Nifedipine, 7, 12, 271 Nimodipine, 7, 271 Nisoldipine, 7, 271 Nitrates, 7, 271 Nitric acid, 271 Nitric Oxide, 128, 271 Nitrogen, 53, 229, 230, 231, 271 Nociceptors, 40, 271 Nonlinear Dynamics, 26, 254, 271 Norepinephrine, 36, 57, 119, 228, 248, 270, 272, 287 Normotensive, 105, 272 Nuclear, 175, 229, 235, 250, 252, 270, 272 Nuclei, 31, 250, 253, 255, 265, 272, 274 Nucleic acid, 246, 259, 260, 268, 271, 272, 282 Nucleic Acid Hybridization, 259, 272 Nucleus, 52, 235, 245, 246, 252, 265, 266, 267, 270, 272, 279, 288, 290, 293 O Occupational Exposure, 6, 272 Oocytes, 18, 34, 272 Opacity, 239, 272 Opiate, 21, 268, 269, 272 Opioid Peptides, 251, 272 Opium, 268, 272 Oral Health, 6, 183, 272 Oral Hygiene, 7, 272 Orderly, 173, 272 Organ Transplantation, 184, 185, 272 Orthostatic, 233, 273 Ouabain, 118, 119, 121, 273 Ovaries, 273, 287, 293 Overdose, 69, 75, 273 Overexpress, 59, 273 Oxidation, 227, 232, 245, 256, 264, 273 Oxidative metabolism, 263, 273 Oxygen Consumption, 252, 273, 284 Oxygenator, 238, 273 P Pacer, 153, 273 Paclitaxel, 273, 292 Palliative, 273, 293 Palsy, 229, 273 Pancreas, 227, 257, 262, 273 Pancreatic, 255, 273 Pancreatic Juice, 255, 273

Panic, 192, 273 Papilla, 274 Papillary, 120, 241, 274 Papillary Muscles, 120, 241, 274 Paraesthesia, 6, 274 Paralysis, 49, 62, 211, 245, 253, 274, 293 Parasympathetic Nervous System, 122, 274 Paresthesia, 274, 293 Parkinsonism, 233, 274 Parotid, 274, 285 Paroxysmal, 151, 158, 172, 177, 212, 213, 231, 274 Particle, 274, 289, 295 Patch, 12, 15, 29, 32, 35, 36, 41, 46, 49, 51, 96, 274 Pathologic, 10, 36, 227, 236, 245, 259, 274, 296 Pathologies, 28, 274 Pathophysiology, 12, 15, 39, 47, 49, 59, 62, 78, 185, 188, 274 Patient Advocacy, 49, 274 Patient Compliance, 147, 274 Patient Education, 4, 210, 218, 220, 226, 274 Patient Selection, 107, 274 Peptide, 23, 272, 274, 277, 280, 281 Perception, 40, 274, 286 Percutaneous, 140, 167, 168, 274 Perforation, 140, 275 Perfusion, 5, 48, 59, 99, 148, 149, 169, 175, 260, 275, 294 Periaqueductal Gray, 21, 275 Pericardial Effusion, 104, 275 Pericardium, 275, 292 Periodicity, 275, 285 Perioperative, 4, 101, 118, 275 Perioperative Care, 4, 275 Peripheral Nervous System, 9, 251, 257, 270, 273, 275, 278, 290, 296 Peritoneal, 234, 247, 275 Peritoneal Cavity, 234, 275 Peritoneal Dialysis, 247, 275 Pharmaceutical Preparations, 161, 163, 252, 275 Pharmacodynamic, 41, 275 Pharmacokinetic, 41, 275 Pharmacologic, 21, 36, 44, 60, 72, 86, 104, 140, 230, 231, 275, 294 Pharmacotherapy, 22, 94, 97, 130, 275 Pharynx, 255, 275, 296

Index 309

Phenotype, 16, 23, 24, 34, 44, 47, 49, 52, 90, 211, 275 Phenyl, 163, 235, 276 Phenylalanine, 276, 295 Phenylephrine, 56, 276 Phenytoin, 118, 131, 276 Phorbol, 276, 280 Phorbol Esters, 276, 280 Phospholipases, 276, 287 Phospholipids, 253, 261, 264, 276, 280 Phosphorus, 237, 276 Phosphorylates, 276, 280 Phosphorylation, 49, 56, 59, 276 Photocoagulation, 242, 276 Physiologic, 56, 62, 65, 147, 150, 179, 180, 229, 236, 276, 279, 283 Picrotoxin, 118, 276 Pigment, 276 Pigmentation, 8, 276 Piloerection, 259, 276 Pilot study, 36, 67, 276 Plants, 229, 237, 238, 247, 255, 256, 263, 268, 272, 273, 277, 285, 294, 295 Plaque, 7, 231, 277 Plasma, 56, 229, 232, 236, 240, 251, 256, 258, 263, 277, 284, 294 Plasma cells, 232, 277 Plasma Volume, 236, 277 Plasmids, 250, 277 Plasticity, 32, 277 Platelet Activation, 277, 288 Platelet Aggregation, 172, 231, 271, 277, 293 Platelets, 121, 271, 277, 287, 293 Pleural, 266, 277 Plexus, 19, 237, 277 Pneumonia, 244, 277 Point Mutation, 63, 277 Poisoning, 77, 246, 249, 262, 269, 276, 277 Polymorphic, 33, 43, 55, 86, 89, 108, 168, 277 Polypeptide, 230, 233, 242, 259, 277, 280, 296, 298 Polyunsaturated fat, 105, 127, 129, 130, 277, 294 Pons, 229, 237, 253, 254, 277 Port, 157, 278 Port-a-cath, 278 Posterior, 104, 182, 230, 234, 241, 248, 273, 278, 286 Postnatal, 48, 58, 278, 290 Postoperative, 64, 65, 82, 103, 129, 278

Postsynaptic, 53, 270, 278, 287, 292 Post-synaptic, 21, 278 Post-translational, 14, 55, 278 Postural, 208, 278 Potassium Channels, 27, 37, 53, 62, 63, 145, 171, 179, 278 Potentiation, 50, 278, 287 Practice Guidelines, 71, 72, 202, 212, 278 Precordial, 68, 278 Precursor, 231, 233, 248, 249, 251, 272, 276, 278, 295 Preoperative, 82, 278 Pressoreceptors, 235, 278 Presynaptic, 49, 52, 119, 270, 278, 292 Presynaptic Terminals, 270, 278 Prevalence, 5, 33, 93, 104, 105, 145, 177, 182, 188, 278 Primary Prevention, 54, 278 Probe, 42, 61, 141, 165, 257, 266, 279 Procainamide, 194, 211, 279 Procaine, 70, 264, 279 Progesterone, 279, 290 Progression, 8, 211, 231, 279 Progressive, 30, 47, 68, 91, 211, 240, 242, 246, 249, 269, 277, 279, 284 Projection, 167, 262, 272, 279, 283 Promoter, 31, 279 Prone, 34, 65, 279 Propafenone, 112, 135, 190, 194, 279 Prophase, 272, 279, 291 Prophylaxis, 161, 163, 170, 178, 247, 279, 298 Propranolol, 69, 279 Prospective study, 71, 279 Prostaglandin, 119, 279, 293 Prostaglandins A, 40, 279, 280 Prostaglandins D, 40, 280 Prostaglandins F, 280 Protease, 6, 280 Protease Inhibitors, 6, 280 Protective Agents, 238, 280 Protein Binding, 53, 280, 294 Protein C, 20, 44, 46, 229, 230, 264, 280, 296 Protein Conformation, 230, 280 Protein Kinase C, 70, 280 Protein Kinases, 33, 280 Protein S, 57, 58, 236, 280 Proteolytic, 243, 281 Proximal, 20, 28, 248, 278, 281, 286 Pruritus, 233, 281 Psychiatric, 184, 185, 266, 281 Psychiatry, 38, 40, 281

310

Arrhythmias

Psychic, 263, 266, 281, 286 Psychoactive, 281, 298 Psychology, 121, 248, 281 Psychosis, 232, 233, 281 Psychotropic, 69, 281 Public Health, 14, 202, 281 Public Policy, 201, 281 Publishing, 5, 9, 67, 281 Pulmonary Artery, 236, 281, 297 Pulmonary Circulation, 181, 281 Pulmonary Edema, 58, 72, 263, 281 Pulmonary Embolism, 281, 298 Pulmonary hypertension, 113, 281 Pulmonary Veins, 87, 156, 158, 182, 282 Pulsation, 254, 282 Pulse, 144, 145, 148, 149, 157, 162, 180, 223, 224, 225, 267, 282 Purifying, 144, 177, 247, 282 Purines, 172, 282, 287 Putrefaction, 254, 282 Pyloric Sphincter, 28, 282 Pyrimidines, 282, 287 Q Quality of Life, 5, 9, 12, 49, 64, 147, 282 Quaternary, 62, 280, 282 Quinidine, 135, 194, 211, 282 Quinine, 282 R Race, 131, 144, 171, 177, 282 Racemic, 144, 171, 177, 282 Radiation, 231, 254, 259, 282, 298 Radioactive, 50, 259, 260, 267, 272, 282, 283 Radiofrequency ablation, 94, 282 Radiography, 66, 231, 282 Radiological, 274, 282 Radiopharmaceutical, 255, 283 Rage, 275, 283 Randomized, 69, 71, 157, 249, 283 Randomized clinical trial, 69, 283 Reactive Oxygen Species, 83, 283 Recombinant, 33, 42, 46, 179, 283, 297 Recombinant Proteins, 33, 283 Recombination, 255, 283 Recurrence, 25, 87, 173, 174, 190, 275, 283 Red Nucleus, 234, 283 Reentry, 39, 51, 55, 64, 283 Refer, 1, 237, 243, 248, 251, 262, 264, 270, 281, 283, 287, 294 Reflex, 20, 21, 147, 268, 275, 283 Reflux, 191, 255, 283 Refraction, 283, 289

Refractory, 4, 43, 84, 103, 145, 153, 180, 250, 283 Regeneration, 29, 283 Regimen, 249, 274, 275, 283 Regurgitation, 83, 255, 267, 283 Relaxant, 276, 284 Reliability, 23, 284 Remission, 283, 284 Renal failure, 4, 246, 284 Renin, 32, 231, 284 Renin-Angiotensin System, 32, 284 Renovascular, 55, 284 Reperfusion Injury, 128, 140, 172, 284 Respiration, 51, 233, 238, 241, 245, 267, 273, 284 Respiratory Paralysis, 233, 284 Respiratory System, 284, 296 Restitution, 43, 162, 163, 284 Resuscitation, 25, 39, 77, 103, 284 Retina, 241, 263, 284, 285 Retinopathy, 6, 276, 285 Retrograde, 156, 285 Retrospective, 38, 114, 175, 285 Reversion, 68, 239, 285 Rhamnose, 273, 285 Rheumatic Heart Disease, 157, 184, 285 Rheumatoid, 10, 285 Rheumatoid arthritis, 10, 285 Rhythmicity, 12, 164, 285 Ribonuclease, 36, 285 Ribose, 228, 285 Risk factor, 5, 10, 26, 86, 97, 103, 114, 173, 182, 211, 279, 285 Rod, 242, 285 Rubber, 285, 290 Ryanodine, 22, 45, 108, 285 S Saccule, 285, 297 Saline, 37, 285 Salivary, 285, 298 Saphenous, 83, 245, 285 Saphenous Vein, 83, 245, 285 Saponins, 285, 290 Sarcoidosis, 10, 285 Sarcoplasmic Reticulum, 22, 23, 286 Scalpel, 157, 286 Scatter, 160, 286 Schizoid, 286, 298 Schizophrenia, 233, 265, 286, 298 Schizotypal Personality Disorder, 286, 298 Sclera, 241, 286

Index 311

Screening, 11, 26, 68, 108, 210, 213, 242, 286 Second Messenger Systems, 12, 286 Secretion, 53, 179, 228, 258, 262, 286 Sedative, 234, 267, 286 Sedimentation, 240, 286, 295 Seizures, 6, 34, 75, 246, 274, 276, 286 Selenium, 124, 131, 286 Semisynthetic, 230, 286 Senile, 211, 233, 286 Sensor, 13, 149, 150, 151, 154, 180, 286 Septal, 70, 82, 286, 287, 292 Septum, 160, 234, 287, 292 Septum Pellucidum, 287 Sequencing, 34, 287 Sequester, 32, 287 Serine, 33, 280, 287 Serotonin, 233, 270, 275, 287 Serous, 251, 287 Serum, 42, 229, 230, 231, 243, 265, 287 Sex Characteristics, 231, 287 Sexually Transmitted Diseases, 184, 185, 287 Shock, 5, 25, 42, 66, 68, 148, 168, 174, 180, 239, 287, 295 Sibutramine, 102, 108, 287 Side effect, 7, 8, 11, 42, 64, 128, 158, 161, 176, 183, 193, 195, 228, 229, 233, 234, 287, 294 Signal Transduction, 12, 32, 48, 59, 81, 261, 287 Signs and Symptoms, 8, 185, 188, 284, 288 Sinoatrial Node, 164, 173, 288 Skeletal, 32, 46, 231, 242, 245, 268, 282, 286, 288 Skeleton, 227, 279, 288 Skin Pigmentation, 8, 288 Skull, 31, 288, 292 Sleep apnea, 12, 97, 288 Small intestine, 249, 258, 262, 282, 288 Smooth muscle, 8, 14, 61, 229, 231, 237, 253, 258, 263, 268, 280, 284, 288, 290 Soaps, 254, 288 Social Environment, 282, 288 Sodium, 7, 22, 35, 46, 49, 60, 171, 229, 282, 288, 291 Sodium Channels, 46, 282, 288 Solitary Nucleus, 235, 288 Solvent, 252, 288 Soma, 288, 289 Somatic, 18, 21, 130, 240, 266, 275, 289, 296 Somatic cells, 240, 266, 289

Somnolence, 12, 289 Sotalol, 83, 112, 135, 195, 196, 289 Sound wave, 244, 289 Soybean Oil, 277, 289 Spatial disorientation, 248, 289 Specialist, 214, 247, 289 Specificity, 20, 47, 164, 228, 238, 289, 294 Spectrum, 20, 23, 173, 289 Sperm, 231, 242, 289, 295 Spinal cord, 51, 86, 237, 240, 241, 251, 257, 265, 266, 270, 274, 275, 283, 284, 289, 291 Spinal Nerves, 275, 289 Spleen, 4, 8, 265, 285, 289 Stabilization, 276, 289 Staging, 167, 289 Standard therapy, 142, 166, 289 Steady state, 159, 289 Steel, 242, 289 Stem Cells, 18, 289 Stenosis, 5, 94, 158, 290, 292 Steroid, 10, 83, 143, 285, 290 Stethoscope, 66, 290 Stimulant, 248, 258, 276, 290 Stimulus, 48, 66, 171, 244, 248, 250, 252, 261, 262, 283, 290, 293 Stomach, 28, 227, 238, 247, 252, 255, 256, 258, 265, 269, 275, 282, 283, 288, 289, 290 Strand, 63, 290 Strangulation, 14, 290 Stress, 58, 80, 95, 99, 125, 179, 235, 239, 269, 285, 290, 296 Stricture, 290 Stroke Volume, 155, 162, 238, 290 Subacute, 261, 290 Subclinical, 261, 286, 290 Subcutaneous, 162, 249, 290 Subspecies, 289, 290 Substance P, 266, 286, 290 Substrate, 19, 21, 57, 65, 66, 101, 158, 264, 290 Substrate Specificity, 57, 290 Suction, 166, 290 Sulfamoyl, 164, 291 Superior vena cava, 182, 237, 288, 291 Supine, 9, 291 Supine Position, 9, 291 Supplementation, 127, 128, 129, 130, 131, 291 Support group, 214, 291 Suppression, 39, 44, 58, 69, 86, 96, 114, 118, 149, 178, 291 Surgical Instruments, 157, 291

312

Arrhythmias

Survival Rate, 25, 291 Sweat, 259, 291 Sympathectomy, 75, 291 Sympathetic Nervous System, 36, 48, 235, 274, 291 Sympathomimetic, 248, 251, 272, 291 Symptomatic, 38, 103, 211, 254, 291 Synapse, 228, 270, 274, 278, 291, 292, 295 Synapsis, 291 Synaptic, 32, 52, 270, 271, 287, 291, 292 Synaptic Transmission, 271, 292 Syncope, 38, 71, 94, 95, 109, 111, 133, 147, 190, 206, 213, 292 Synergistic, 57, 62, 292 Systemic disease, 9, 292 Systemic lupus erythematosus, 211, 292 Systole, 169, 179, 257, 267, 292 Systolic, 5, 36, 54, 184, 259, 267, 292 T Tachyarrhythmia, 128, 141, 152, 153, 155, 162, 168, 292 Tachycardia, 9, 19, 37, 43, 55, 61, 72, 76, 92, 108, 140, 141, 142, 145, 146, 151, 152, 153, 154, 155, 156, 158, 165, 168, 172, 173, 174, 177, 180, 208, 213, 248, 292 Tachycardia, Ventricular, 177, 180, 292 Tardive, 233, 292 Taxus, 120, 273, 292 Temporal, 26, 42, 43, 56, 62, 65, 156, 173, 292 Teratogenic, 229, 247, 292 Terfenadine, 6, 292 Terminalis, 182, 292 Testicular, 8, 118, 292 Testis, 292 Tetralogy of Fallot, 96, 292 Tetrodotoxin, 46, 293 Thalamic, 234, 293 Thalamic Diseases, 234, 293 Theophylline, 230, 282, 293 Therapeutics, 33, 49, 106, 109, 114, 144, 150, 184, 195, 293 Thermal, 31, 37, 175, 248, 293 Thermal ablation, 31, 293 Thoracic, 76, 82, 84, 103, 104, 110, 114, 150, 237, 265, 293, 298 Thoracic Surgery, 76, 82, 84, 103, 104, 110, 293 Thoracotomy, 19, 293 Threonine, 33, 280, 287, 293 Threshold, 10, 41, 146, 148, 173, 252, 259, 293

Thrombin, 277, 280, 293 Thrombocytes, 277, 293 Thromboembolism, 69, 158, 293 Thrombomodulin, 280, 293 Thrombosis, 10, 14, 26, 159, 281, 290, 293 Thromboxanes, 233, 249, 293 Thyroid, 102, 184, 185, 259, 294, 295 Tissue Distribution, 179, 294 Tolerance, 47, 145, 149, 227, 256, 294 Tomography, 294 Tone, 32, 51, 74, 86, 87, 173, 174, 272, 294 Tonic, 53, 238, 294 Tonus, 275, 294 Tooth Preparation, 228, 294 Topical, 252, 259, 288, 294 Torsion, 261, 294 Toxic, iv, 30, 54, 158, 229, 245, 247, 249, 256, 260, 270, 271, 286, 294 Toxicity, 6, 10, 145, 239, 248, 294 Toxicology, 52, 75, 202, 294 Toxin, 46, 251, 293, 294 Trachea, 266, 275, 290, 294 Traction, 242, 294 Transcription Factors, 31, 294 Transduction, 32, 59, 238, 287, 294 Transfection, 236, 250, 295 Transferases, 256, 295 Transfusion, 295 Transgenes, 33, 295 Translational, 41, 295 Transmitter, 227, 248, 262, 272, 295 Transplantation, 10, 99, 242, 260, 295 Trauma, 235, 246, 252, 257, 269, 293, 295 Trees, 285, 292, 295 Triad, 66, 295 Tricuspid Valve, 103, 295 Trigger zone, 233, 295 Trophic, 36, 295 Tuberculosis, 265, 295 Tubulin, 131, 295 Tunica, 28, 250, 268, 295 Tyrosine, 32, 56, 248, 295 U Ulcer, 295 Ulceration, 9, 295 Unconscious, 174, 176, 231, 295 Unsaturated Fats, 254, 295 Uracil, 172, 282, 295 Urea, 291, 295, 296 Uremia, 5, 184, 263, 284, 296 Urethra, 296 Urine, 7, 236, 248, 257, 296

Index 313

Urokinase, 118, 296 Urticaria, 234, 292, 296 Uterus, 240, 245, 273, 279, 293, 296 V Vaccines, 296, 298 Vagal, 19, 38, 52, 147, 169, 174, 296 Vagotomy, 118, 296 Vagus Nerve, 288, 296 Valves, 175, 241, 257, 274, 285, 296 Vascular endothelial growth factor, 56, 296 Vascular Resistance, 36, 230, 235, 253, 296 Vasoactive, 32, 58, 296 Vasoactive Intestinal Peptide, 58, 296 Vasoconstriction, 248, 252, 296 Vasodilatation, 239, 271, 296 Vasodilation, 8, 172, 235, 271, 296 Vasodilator, 237, 248, 258, 259, 269, 271, 296 Vector, 295, 296, 297 Vectorcardiography, 161, 297 Vein, 94, 111, 155, 158, 166, 167, 181, 182, 231, 235, 262, 272, 274, 285, 291, 297 Vena, 297 Venom, 233, 297 Venous, 8, 160, 233, 271, 281, 292, 297, 298 Venous Thrombosis, 297, 298 Venter, 297 Ventral, 21, 260, 277, 289, 297 Ventricular Dysfunction, 82, 109, 174, 249, 297 Ventricular fibrillation, 25, 37, 42, 51, 60, 86, 141, 145, 146, 148, 155, 158, 168, 173, 180, 297

Ventricular Function, 47, 112, 144, 177, 297 Ventricular Remodeling, 61, 98, 297 Verapamil, 7, 122, 136, 297 Vertebrae, 289, 297 Vesicular, 267, 297 Vestibule, 44, 63, 285, 297 Veterinary Medicine, 118, 201, 297 Villous, 241, 297 Vinblastine, 295, 297 Vincristine, 295, 297 Viral, 18, 19, 294, 297 Virulence, 294, 297 Virus, 6, 255, 277, 295, 297, 298 Viscera, 266, 289, 298 Visceral, 21, 235, 296, 298 Visceral Afferents, 235, 296, 298 Vitro, 42, 298 Vivo, 51, 59, 298 Voltage-gated, 30, 55, 62, 68, 98, 171, 179, 227, 262, 298 W Warfarin, 69, 136, 298 White blood cell, 185, 232, 261, 265, 277, 298 Windpipe, 275, 294, 298 Withdrawal, 12, 75, 246, 298 X Xenograft, 231, 298 Xerostomia, 6, 298 X-ray, 53, 243, 244, 272, 298 Y Yeasts, 276, 298 Z Zymogen, 280, 298

314

Arrhythmias

Index 315

316

Arrhythmias