HYPOTHERMIA A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2004 by ICON Group International, Inc. Copyright ©2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Hypothermia: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83986-7 1. Hypothermia-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.
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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 hypothermia. 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 HYPOTHERMIA ......................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Hypothermia ................................................................................. 5 E-Journals: PubMed Central ....................................................................................................... 67 The National Library of Medicine: PubMed ................................................................................ 68 CHAPTER 2. NUTRITION AND HYPOTHERMIA .............................................................................. 113 Overview.................................................................................................................................... 113 Finding Nutrition Studies on Hypothermia .............................................................................. 113 Federal Resources on Nutrition ................................................................................................. 117 Additional Web Resources ......................................................................................................... 118 CHAPTER 3. ALTERNATIVE MEDICINE AND HYPOTHERMIA ....................................................... 119 Overview.................................................................................................................................... 119 National Center for Complementary and Alternative Medicine................................................ 119 Additional Web Resources ......................................................................................................... 135 General References ..................................................................................................................... 136 CHAPTER 4. DISSERTATIONS ON HYPOTHERMIA ......................................................................... 137 Overview.................................................................................................................................... 137 Dissertations on Hypothermia ................................................................................................... 137 Keeping Current ........................................................................................................................ 138 CHAPTER 5. CLINICAL TRIALS AND HYPOTHERMIA .................................................................... 139 Overview.................................................................................................................................... 139 Recent Trials on Hypothermia ................................................................................................... 139 Keeping Current on Clinical Trials ........................................................................................... 139 CHAPTER 6. PATENTS ON HYPOTHERMIA .................................................................................... 141 Overview.................................................................................................................................... 141 Patents on Hypothermia ............................................................................................................ 141 Patent Applications on Hypothermia ........................................................................................ 159 Keeping Current ........................................................................................................................ 185 CHAPTER 7. BOOKS ON HYPOTHERMIA ........................................................................................ 187 Overview.................................................................................................................................... 187 Book Summaries: Online Booksellers......................................................................................... 187 The National Library of Medicine Book Index ........................................................................... 189 Chapters on Hypothermia .......................................................................................................... 190 CHAPTER 8. MULTIMEDIA ON HYPOTHERMIA ............................................................................. 195 Overview.................................................................................................................................... 195 Video Recordings ....................................................................................................................... 195 Bibliography: Multimedia on Hypothermia............................................................................... 196 CHAPTER 9. PERIODICALS AND NEWS ON HYPOTHERMIA .......................................................... 199 Overview.................................................................................................................................... 199 News Services and Press Releases.............................................................................................. 199 Newsletter Articles .................................................................................................................... 203 Academic Periodicals covering Hypothermia............................................................................. 204 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 205 Overview.................................................................................................................................... 205 U.S. Pharmacopeia..................................................................................................................... 205 Commercial Databases ............................................................................................................... 206 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 211 Overview.................................................................................................................................... 211 NIH Guidelines.......................................................................................................................... 211
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NIH Databases........................................................................................................................... 213 Other Commercial Databases..................................................................................................... 215 APPENDIX B. PATIENT RESOURCES ............................................................................................... 217 Overview.................................................................................................................................... 217 Patient Guideline Sources.......................................................................................................... 217 Finding Associations.................................................................................................................. 220 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 223 Overview.................................................................................................................................... 223 Preparation................................................................................................................................. 223 Finding a Local Medical Library................................................................................................ 223 Medical Libraries in the U.S. and Canada ................................................................................. 223 ONLINE GLOSSARIES................................................................................................................ 229 Online Dictionary Directories ................................................................................................... 232 HYPOTHERMIA DICTIONARY................................................................................................ 233 INDEX .............................................................................................................................................. 327
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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 hypothermia 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 hypothermia, 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 hypothermia, 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 hypothermia. 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 hypothermia, 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 hypothermia. 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 HYPOTHERMIA Overview In this chapter, we will show you how to locate peer-reviewed references and studies on hypothermia.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and hypothermia, 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 “hypothermia” (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: •
Mandible Fracture in a Child with Menkes' Kinky Hair Syndrome Source: Journal of Oral and Maxillofacial Surgery. 54(1): 105-107. January 1996. Summary: In this article, the authors present the case of a 26-month-old toddler with Menke's kinky hair syndrome who suffered mandibular fractures. Menke's kinky hair syndrome is a rare, X-linked recessive disorder that affects copper absorption and metabolism. The disorder is characterized by growth failure, psychomotor retardation, seizures, hypothermia, cerebrocellular atrophy, generalized osteoporosis, and kinky hair. The authors describe the preoperative assessment; surgical technique; and postoperative care of the child. They also provide a general discussion of Menke's syndrome and its treatment. They note that the combination of copper-histidine injections (provided to the child since diagnosis at 4 months of age) and longer fixation
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of the mandibular fracture seem to have allowed more complete healing of the fracture than was anticipated. 5 figures. 10 references. (AA-M). •
Getting up in the World Source: Diabetes Forecast. 48(5): 40-47. May 1995. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: The author of this article extols the virtues of hiking and mountain climbing. Presented as an ideal sport for people with diabetes, the different types of hiking are described. Topics covered include mountain hiking; risk factors and cautions; backpacking; peak bagging; judging the peak; the Sierra Club class and grade system; aid climbing; snow and ice climbing; rock climbing; top-rope climbing; levels of physical fitness; the mountain environment, including considerations of hypothermia, altitude, and dehydration; and diabetes essentials, including sunwear, footwear, food, insulin or medication, glucose, a companion, blood glucose monitoring, a log book, and emergency preparedness. The author includes lists of outdoor programs for people with diabetes, and hiking organizations. One sidebar provides definitions for mountain climbing terms, including belay, carabinner, frind, nut, and rappel.
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Cross-Country Skiing: A Wonderful Winter Workout Source: Diabetes Forecast. 45(1): 64-68. January 1992. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article encourages readers to consider cross-country skiing as a winter component of their regular exercise plan. The author describes the different types of skiing; how to get started; where to ski; equipment; appropriate clothing; the importance of skiing at a level appropriate to one's degree of fitness and conditioning; diabetes management before, during and after skiing; and the danger signs of hypothermia.
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Fever: Thermal Regulation and Alteration in End Stage Renal Disease Patients Source: American Nephrology Nurses Association Journal. 19(1): 13-18. February 1992. Summary: This article presents an overview of thermoregulatory mechanisms, the pathophysiology of fever, and alterations of the febrile response in end-stage renal disease (ESRD) patients. Topics include definitions of fever; mechanisms of thermal regulation, including hypothalamic control of temperature; the pathophysiology of fever; fever management; uremia and body temperature; the possible mechanisms of hypothermia; and infection in ESRD patients. The author stresses that many ESRD patients do not exhibit the expected rise in white blood cell count or body temperature during clinical and laboratory-confirmed infections. Therefore, leukocytosis and fever cannot be relied on for the diagnosis of bacterial infection in ESRD patients. 3 figures. 4 tables. 16 references. (AA-M).
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Is Presentation of Bacteremia in the Elderly the Same as in Younger Patients? Source: American Journal of Medicine. 100(1): 65-70. January 1996. Summary: This article reports on a study to compare the presentation of bacteremia in young and elderly patients. Seventy-one elderly (mean age 80.4 years) and 34 younger
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patients (mean age 45.7 years) with bacteremia were prospectively studied. These were compared with a control group of 187 geriatric patients (mean age 81.3 years) with clinical signs of bacteremia but in whom blood cultures were negative. Only 3 clinical findings of the 16 studied were found in at least 70 percent of the bacteremic elderly patients: fever, increased erythrocyte sedimentation rate, and a clinical indication of the source of infection. Seven other signs (hypothermia, chills, sweating, splenomegaly, recently altered mental state, leukopenia, and lymphopenia) had a specificity above 80 percent. Younger infected patients had more chills, sweating, altered general state, altered mental state, or lymphopenia than did the bacteremic elderly patients. The authors conclude that, in elderly patients with early stage bacteremia, most of the signs or symptoms that are considered typical in the literature appear irregularly. 1 figure. 5 tables. 26 references. (AA-M). •
Acute Liver Failure Source: Current Opinion in Gastroenterology. 15(3): 270-277. May 1999. Contact: Available from Lippincott Williams and Wilkins Publishers. 12107 Insurance Way, Hagerstown, MD 21740. (800) 637-3030. Fax (301) 824-7390. Summary: This article reviews the advances and research on acute liver failure (ALF) over the past year. Severe hepatitis A is an infrequent but well recognized cause of ALF that can now be effectively prevented with vaccination against hepatitis A virus. Bromfenac and troglitazone hepatotoxicity, as well as various herbal remedies, are some of the newly identified causes of ALF. The recently identified transfusion transmitted virus has been implicated in some case of idiopathic ALF but hepatitis G virus does not appear to be a causative agent. Recognizing, monitoring, and treating patients with life threatening cerebral edema remain critically important but difficult aspects of the clinical care of ALF. Hypothermia and N acetylcysteine are promising experimental approaches to cerebral edema, but emergency liver transplantation is the only proven means of improving patient survival. Although recent changes in organ allocation may reduce the waiting time for transplantation, more reliable and validated markers of liver regeneration and prognosis are needed to triage patients. The potential application and limitations of novel technologies, including bioartificial liver devices and auxiliary liver transplantation, continue to evolve from pioneering work in animal models and human subjects. 2 figures. 2 tables. 56 references (19 annotated).
Federally Funded Research on Hypothermia The U.S. Government supports a variety of research studies relating to hypothermia. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to hypothermia. 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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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 hypothermia. The following is typical of the type of information found when searching the CRISP database for hypothermia: •
Project Title: ACUTE/SUBACUTE METABOLIC & HEMODYNAMIC TRAUMATIC BRAIN INJURY DETERMINANTS Principal Investigator & Institution: Ginsberg, Myron D.; Professor; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2001 Summary: We propose to investigate in detail the interrelationships between local brain glucose metabolism (ICMRgl) and blood flow (ICBF) in the acute and subacute periods following cortical fluid-percussion injury (FPI) in the rat. Exciting pilot data obtained using novel 3D autoradiographic image- averaging strategies developed by us have disclosed marked metabolism > flow uncoupling in the acute period after FPI, which we believe imposes a severe metabolic stress upon the tissue. In contrast, hyperemia was observed at five days. Using matched animal groups and the disparity analysis algorithm, we shall comprehensively characterize ICBF, ICMRgl and the ICMRgl/ICBF ratio over the first five days following FPI. We hypothesize that uncoupling persists during the first few hours but remits after 1-2 days. Next, we shall ascertain how these perturbations are influenced by post-traumatic therapeutic hypothermia, administered either early (first 3 h). or initiated somewhat later (3-5 h) following trauma. We hypothesize that therapeutic hypothermia reverse uncoupling and thereby protects the tissue. We shall establish the role of the nitric oxide/nitric oxide synthase (NOS) system in post-traumatic ICBF changes, either via diminished vascular NO production acutely or by expression of iNOS at later time. This will be studied via in situ hybridization, immunohistochemistry, and enzymatic activity assays, coupled with assessment of cyclic GMP production in the traumatic brain. As endothelin and/or serotonin are potential modulators of ICBF following trauma, these will also be assessed via intracerebral microdialysis and the use of specific pharmacologic anatagonists. Finally, we intend to characterize more fully the relationship between the localized evidence of metabolic stress (metabolism > uncoupling) and the temporal and spatial features of gene expression: we shall concentrate on hsp7O, immediate early genes, glial fibrillary acidic protein, and the neurotrophin, brain- derived neurotrophic factor. Our pilot data, in each instance, have revealed trauma-related changes in gene expression. The relationship of these patterns of gene expression to apoptosis will be assessed. Finally, we shall investigate the effect of specific therapeutic interventions, including NMDA and non-NMDA antagonism, and the scavenging of oxygen radicals, on CMRgl/CBF interrelationships and gene expression. These studies will provide a comprehensive overview of hemodynamics and metabolism in the acute and subacute periods. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ADENYLYL CYCLASE TRANSGENIC MICE AND ALCOHOLISM Principal Investigator & Institution: Yoshimura, Masami; Pharmacology; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 01-APR-1997; Project End 31-MAR-2002 Summary: The cAMP signal transduction system may play an important role in the development of alcohol sm. The long-term goal of this research is twofold: 1) To elucidate the molecular and cellular mechanisms underlying ethanol's effects on the
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cAMP signaling pathway in the central nervous system, and 2) To determine the role that the cAMP signaling pathway plays in the physiological and behavioral responses to alcohol abuse. If a change in cAMP signaling is one of the determinants of an alcoholic phenotype, it is conceivable that alterations in the cAMP signaling system in an animal model may change the animal's response to ethanol. The hypothesis to be evaluated is that the response of animals to ethanol can be altered by the modification of adenylyl cyclase (AC) expression. To test this hypothesis, transgenic mice that overexpress type VII AC (AC7: the most ethanol sensitive isoform) and knockout mice that lack expression of AC7 will be generated. Once changes in the expression of AC7 are confirmed, the ethanol sensitivity of AC activity in the brain of the mutant mice will be examined. Ethanol's effect on the firing rate of the cerebellar Purkinje neurons of the mutant mice will be examined by electrophysiological recording. The sensitivity of the mutant mice to acute ethanol intoxication will be examined by measuring the duration of loss of righting reflex (sleep time) and the changes in body temperature (hypothermia). The development of tolerance in the mutant mice chronically treated with ethanol will be examined by measuring the decrease in the hypnotic and hypothermic effects of ethanol. The development of physical dependence in the mutant mice to ethanol will be examined by assessing the intensity of handling-induced convulsions after ethanol withdrawal. The proposed studies will generate valuable animal models for alcoholism research. These animals will also be useful for a widerange of physiological and behavioral research dealing with cAMP signal transduction. The proposed studies will also provide information critical to the determination of whether abnormal cAMP signaling is one of the determinants of an alcoholic phenotype. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ADOLESCENT ALCOHOL ADAPTATION: TOLERANCE & STRESS Principal Investigator & Institution: Spear, Linda P.; Distinguished Professor and Chair; Psychology; State University New York Binghamton Vestal Pky E Binghamton, Ny 13901 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Adolescents differ from adults in responsivity to a number of ethanol effects. Their insensitivity to the motor incapacitating and sedating effects of ethanol may increase consumption capacities and support higher levels of adolescent drinking, thereby contributing to the unique risks associated with alcohol drinking during adolescence. It has yet to be established whether this unique pattern of alcohol responsivity during adolescence is a function of age-related differences in initial neural sensitivity to alcohol or in the magnitude of tolerance developing within ethanol exposure periods (acute tolerance) or across exposures (rapid and chronic tolerance). There are, however, recent observations of notable ontogenetic alterations in the expression of these ethanol adaptations. Such ontogenetic differences in ethanol tolerance may be particularly pronounced under stressful circumstances, given evidence that vulnerability to stressors may be increased during adolescence and that development of ethanol tolerance is enhanced by stressors. Consequently, the work outlined in this proposal will explore the contribution of tolerance to the unique pattern of alcohol responsivity during adolescence, and the effects of stressors on these adaptational processes. Studies will compare the expression of acute, rapid and chronic tolerance to various characteristic effects of ethanol and the impact of stressors on these ethanol adaptations in male and female, adolescent and adult (as well as weanlings, where feasible) Sprague-Dawley rats. It is predicted that age-related attenuations in sensitivity to specific ethanol effects will be associated with greater acute tolerance but
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less rapid and chronic tolerance to those effects, with adolescents being particularly vulnerable to stress-induced facilitation of acute, rapid and chronic tolerance. Characterizing the ontogeny of ethanol tolerance and the effects of stressors on these adaptational processes is not only critical for assessing determinants of the unique pattern of alcohol responsivity seen during adolescence, but also may contribute to our understanding of the long-term consequences of adolescent alcohol exposure for later alcohol use and abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ADOLESCENT ETOH EXPOSURE: EFFECT ON ADULT ETOH RESPONSE Principal Investigator & Institution: Diaz-Granados, Jaime L.; Associate Professor; Psychology and Neuroscience; Baylor University Waco, Tx 76798 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: Alcohol use and abuse is prevalent among adolescents. Alcohol remains to be the primary drug of choice among this population. However, due to ethical considerations, it is impossible to investigate the effects of adolescent alcohol exposure in the human population. Therefore, animal models must be utilized to examine the effects of alcohol exposure during this developmental period. Recent preliminary data from our laboratory suggests that exposure to alcohol during adolescent development attenuates the adult's initial response to ethanol-induced ataxia. In addition, preliminary results from our laboratory suggest that adolescent alcohol exposure exacerbates the alcohol withdrawal response in adulthood. The overall objective of this proposal is to investigate more fully whether exposure to alcohol during the adolescent period will alter the pharmacological response to alcohol in adulthood. Specifically, the proposed work will examine the effect of adolescent alcohol exposure on (1) the adult's initial response to the intoxicating effects of alcohol, (2) the development of rapid tolerance to the intoxicating effects of alcohol, (3) the development of chronic tolerance to the ataxic and hypothermic effects of alcohol, and (4) the severity of the alcohol withdrawal reaction. Specific aim 1 will address the sensitivity of these responses to the level of intoxication achieved during adolescence. The second specific aim will examine whether exposure to alcohol during early, middle, and late periods of adolescent development will result in differential effects on the adult response to alcohol. Specific aim 3 will investigate whether the pattern of alcohol exposure (i.e., chronic versus intermittent) will differentially alter the adult response to alcohol. Findings from these studies will significantly characterize the effects of the dose, timing, and pattern of alcohol exposure during adolescence on later responsiveness to ethanol in adulthood. This requisite characterization of adolescent developmental alcohol effects, coupled with the known ontogeny of neural systems during the adolescent period, should lead to further investigation of possible alcohol-induced perturbations of the developing central nervous system which may underlie an altered adult response to alcohol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ADRENERGIC DEVELOPMENT
RECEPTORS
DURING
PERIADOLESCENT
Principal Investigator & Institution: Bylund, David B.; Professor and Chair; Pharmacology; University of Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2002; Project Start 20-SEP-2002; Project End 30-JUN-2006
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Summary: (provided by applicant): The up-regulation or down-regulation of neurotransmitter receptors has become one of the major, proposed mechanisms for a variety of therapeutic drugs. Drug-induced regulation of central catecholamine receptors has been extensively studied in adults, but little is known about their regulation in young animals. It is particularly important to understand the nature of drug-induced regulation of adrenergic receptors in young animals for two reasons. First, adrenergic agents are used clinically in children and adolescents. Our preliminary data show that the effects of adrenergic agents on the young adrenergic system are qualitatively different from their effects on the adult. Second, because the adrenergic system is late developing, and is still changing during periadolescent development, perturbations in this system are more likely to have greater, qualitatively different, and longer-lasting effects than on a mature system. The central hypothesis of the proposed studies is that CNS alpha-2 and beta adrenergic receptors are differentially regulated in periadolescent as compared to adult rats, as reflected by responses to two drugs that effect the noradrenergic and serotonin systems (the selective re-uptake inhibitors desipramine and fluvoxamine). The first specific hypothesis, that central adrenergic receptors will be up-regulated in periadolescent animals rather than down-regulated as observed in adult animals, will be tested using quantitative autoradiography to determine alpha-2 and beta adrenergic receptor density. The second hypothesis, that the functional coupling between the adrenergic receptors and their G proteins will be increased in the young animals as compared to adults, will be tested using cyclic AMP accumulation and GTPyS binding assays. The third hypothesis, that the functional responses to agonist stimulation will be increased in periadolescent animals as consequences of these alterations in regulation and coupling, will be studied using regulation of immediate early gene expression and agonist induced-hypothermia. These studies in rats will help provide the necessary foundation for understanding the regulation of the adrenergic receptor systems in young animals leading to an eventual understanding of the effects of chronic drug treatment in children. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AGE AND CONTROL OF HUMAN SKIN BLOOD-FLOW Principal Investigator & Institution: Kenney, W. L.; Professor of Physiology and Kinesiology; Noll Physiological Res Ctr; Pennsylvania State University-Univ Park 201 Old Main University Park, Pa 16802 Timing: Fiscal Year 2003; Project Start 30-SEP-1987; Project End 31-AUG-2008 Summary: (provided by applicant): This competitive renewal of R01 AG07004 continues our systematic investigations into mechanisms underlying altered thermoregulatory control of skin blood flow (SkappaBF) with primary human aging, and the consequences thereof. Both cutaneous vasodilation (VD) in response to hyperthermic stimuli and cutaneous vasoconstriction (VC) in response to hypothermic stimuliare significantlyattenuated in aged skin. The previous funding cycle involved a systematic investigation of the mechanisms related to altered cutaneous VD in older men and women (briefly summarized in Section C of this proposal). The next sequence of proposed studies is the logical extension of this line of investigation, i.e., examining the mechanisms and consequences of altered cutaneous VC in aged skin, since (1) primary aging is associated with both a larger decrease in core temperature with cold stress and an increased incidence of clinical hypothermia, (2) these untoward outcomes are primarily the result of a relative inability to vasoconstrict the skin vasculature leading to an increased core-to-skin heat transfer, (3) several plausible sites of age-related changes exist in the efferent VC control pathway which have not been tested in vivo.
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Furthermore, older men and women with a low body mass and lean muscle mass are at ever) greater risk of hypothermia because of the combined effects of reduced VC and decreased core-to-skin thermal resistance. Specific Aims 1-3 examine basic efferent mechanisms of attenuated reflex VC in aged skin at the sympathetic nerve transmission, neurotransmitter/receptor, and end-organ response levels, respectively. These studies make use of new and recently refined techniques that allow for the in vivo examination of age-related changes in human skin. Specific Aim 1 quantifies the skin sympathetic nerve activity (SSNA) during progressive skin cooling in older vs. young men and women and its relation to VC. Specific Aim 2 addresses the relative contributionsof noradrenergic and nonnoradrenergic mechanisms in reflexVC inyoung and older subjects. Follow-up experiments are described that will determine the potential role of neuropeptide Y in this age-specific VC response. Specific Aim 3 will examine the dose response characteristics of noradrenergicVC to assess the responsiveness of the aged cutaneous vasculature to norepinephrine. Finally, Specific Aim 4 involves a series of whole-body chamber experiments designed to determine and model the effects of altered VC on the resistance to core-to-skin heat transfer, i.e., tissue resistance (insulation) in the fully vasoconstricted state. Resistance to heat loss is a function of both physiological adjustments (VC) and characteristics of the passive system (e.g., muscle mass). Because a common sequelae of human aging is a progressive loss of muscle mass (sarcopenia), sarcopenic elderly men and women may be at even greater risk of hypothermia and hypothermia-related problems. Therefore, the proposed studies under Specific Aim 4 will include differences in muscle mass within age groups. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AGING AND GENDER EFFECTS ON RESPONSES TO COLD IN RATS Principal Investigator & Institution: Horwitz, Barbara A.; Vice Provost of Academic Personnel; Neurobiol/Physiol & Behavior; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2001; Project Start 01-APR-1988; Project End 31-JUL-2003 Summary: The unprecedented growth in number of persons over 65 yrs of age will place an increasing percentage of our population at risk for poor health. It has been suggested that this increased risk can be explained in part by the aging organisms' blunted ability to adapt to internal or external stress. That is, aging may be characterized by a general decline in the ability to maintain homeostasis. One such homeostatic response is the ability to maintain homeothermy which is compromised in older cold-exposed humans and rodents. Of special interest is the observation that this effect of age appears to be more pronounced in males than in females (in humans and in rats). Thus, the effect of aging on the ability to maintain homeothermy in particular and homeostasis in general may be gender dependent. Our study of thermoregulatory function in aging rats will provide a model by which we will gain a clearer understanding of these effects of aging and gender on homeostasis. A major objective of this project is to evaluate the physiological/biochemical basis for the attenuated effectiveness of thermoregulatory responses in older male/female rats. As a model system for studying the aging/gender effects on homeostatic alterations, we will use brown adipose tissue (BAT) for which we have demonstrated blunted thermogenic responses in older vs younger males and in older males vs their female counterparts. Since BAT function is regulated by the sympathetic nervous system and modulated by several hormones, our proposal examines the Interaction of gender and aging on BAT thermogenic capacity (uncoupling protein), adrenergic receptors, signal transduction, substrate availability and
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mobilization, availability of insulin and thyroid hormone, and sensitivity to Insulin. We will also examine possible alterations in skeletal muscle, whose thermogenesis may also be attenuated in aging animals. Procedures include membrane and cell isolations, Scatchard plot analysis, immunobinding, in vitro and in vivo uptake of 2-deoxyglucose, radioimmunoassays, euglycemic clamp, hindlimb perfusion, and variety of enzyme assays. These studies should provide considerable insight into gender/aging interactions relevant to neural and hormonal modulation of metabolic regulation, thermoregulation, and homeostatic maintenance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANNUAL RHYTHMS OF ENERGY BALANCE AND BEHAVIOR Principal Investigator & Institution: Dark, John G.; Psychology; University of California Berkeley Berkeley, Ca 94720 Timing: Fiscal Year 2001; Project Start 16-SEP-1996; Project End 31-MAR-2003 Summary: The overall goal of this proposal is to further characterize the neuroendocrine mechanisms that underlie the initiation and expression of daily torpor, an extreme form of temperature regulation that evolved to help animals contend with limited food availability. The relation of torpor to overall energy balance and body fat stores will be explored. Annual rhythms of daily torpor are well documented in the Siberian hamster (Phodopus sungorus), the model species in all experiments. Specific aims include: 1) clarifying the relation between decreases in body fat stores and its feedback mechanisms in the initiation of torpor; 2) characterizing the role of leptin as a metabolic signal inhibiting initiation of torpor; 3) exploring the role of NPY in torpor; 4) determining the role of diencephalic mechanisms in initiation of daily torpor There is much that we still do not understand about the physiological mechanisms underlying the control of energy balance and thermoregulation. Delineating the interaction between metabolic feedback signals and daily torpor in a model system like the Siberian hamster could provide important insights into the regulation of these processes for mammals in general and humans in particular. A better understanding of the mechanisms of reversible hypothermia is of medical import. The reduced metabolism, blood flow, etc. coincident with hypothermia may be very beneficial during many types of major surgery. At this time, we know little of the mechanism that allows Siberian hamsters and several other mammalian species to undergo hypothermia which is lethal to humans and most other mammals. The proposed research addresses fundamental questions in regulatory biology and, thereby, affords the opportunity of establishing general principles applicable to all mammals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: AXONAL RESPONSE TO TRAUMATIC BRAIN INJURY Principal Investigator & Institution: Povlishock, John T.; Professor and Chair; Anatomy and Neurobiology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2003; Project Start 01-DEC-1983; Project End 30-NOV-2006 Summary: (provided by applicant): This application seeks to continue 20 years of support focusing on the microvascular, neuronal somatic, axonal and deafferentationmediated responses to traumatic brain injury. In previous funding periods, we have shown that the injury does not tear axons. Rather, it triggers local axonal damage that leads to continued alteration and ultimate disconnection. It has been assumed by all that once disconnected the proximal axonal tip swells, due to the delivery of substances via anterograde transport, with the resulting axonal bulb formation becoming the
12
Hypothermia
universally recognized endpoint for all contemporary forensic, neuropathological and experimental studies. Recently, our laboratory has suggested that many injured axons may not progress to bulb formation, which suggests differing modes of pathogenesis and potential therapeutic modulation. In this application we focus on this issue using different animal models of TBI, employing lissencephalic and gyrencephalic species. The resulting TAI will be followed over time by double label immunocytochemical strategies targeting various cytoskeletal, axolemmal and axonal transport abnormalities. Quantitative, computer-assisted EM analysis will be used to better understand the precise subcellular changes associated with TIA as well as the mechanisms related thereto. Moving on the premise that we will observe different populations of injured axons, with differing forms of pathogenesis, we will also pursue descriptive and mechanistic studies related to their response to agents reported to attenuate TAI. Cyclosporin A and FK506 will be used in addition to hypothermia to assess their impact on these differing forms of TAI via the same strategies noted above. These studies will be interfaced with electrophysiological and neurochemical assessments to examine any therapeutic modulation of action potentials, calcineurin activity or mitochondrial function. The successful conduct of these studies should provide new insight into the complex pathobiology of TAI and its therapeutic modulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BRAIN AS TARGET FOR ANTISENSE PEPTIDE NUCLEIC ACID DRUGS Principal Investigator & Institution: Richelson, Elliott; Professor; Mayo Clinic Jacksonville 4500 San Pablo Rd Jacksonville, Fl 32224 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2002 Summary: (Applicant's Abstract) The goal of the proposed research is to characterize in rat the pharmacokinetics and pharmacodynamics of three antisense polyamide ("peptide") nucleic acids (PNAs) directed toward three different proteins in rat brain: the neurotensin receptor subtype 1 (NTR1), the morphine receptor subtype (MOR1), and the serotonin transporter (SERT). The long term goal of this research is to develop PNAs as antisense and antigene drugs to treat a variety of diseases, especially those affecting brain. In different experiments, different PNAs (either in unlabeled or in radioactivelylabeled or fluorescently-labeled forms) will be administereed to rats by intravenous, intraperitoneal, or oral routes. From measurement of concentrations of PNAs in blood over time, pharmacokinetic variables, including absolute bioavailability of PNAs by the oral route, will be determined. The kinetics of entry of these PNAs into brain (as well as other organs) and their distributions within the brain will also be determined by various techniques, including histological. The kinetics of entry into brain will be correlated with the time course for the onset of and the recovery from their functional effects from behavioral, physiological, biochemical, and molecular biological experiments. Behavioral studies will measure antinociception (NTR1 and MOR1); physiological studies, hypothermia (NTR1); biochemical studies, binding sites for NTR1, MOR1, and SERT, as well as brain levels of serotonin and its metabolite, and molecular biological studies, levels of mRNA for each targeted protein. This research represents the initial studies that might lead to viable antisense and antigene therapies for many types of diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BRAIN ADAPTATION
CANNABINOID
SIGNALING:
SELECTIVITY
13
AND
Principal Investigator & Institution: Sim-Selley, Laura J,.; Assistant Professor; Pharmacology and Toxicology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2007 Summary: (provided by applicant): Cannabinoid (CB1) receptors in brain mediate the effects of delta 9-tetrahydrocannabinol (THC) and endocannabinoids, primarily by activation of inhibitory G-proteins of the Gi/Go family. However, it is our premise that CB1 receptor- G-protein coupling is not uniform throughout the brain, and CB1 receptors may couple to multiple G-proteins to account for the multiplicity of cannabinoid effects. Indeed, our progress to date demonstrates regional differences in CB1 receptor-mediated G-protein activity in both normal brain and in adaptive responses to chronic THC administration. Moreover, the pattern of tolerance development is not identical for all THC effects, a finding we hypothesize is related to these regional differences in CB1 receptor-G-protein coupling. The proposed studies will investigate the relationship between cannabinoid tolerance and CB1 receptor desensitization and downregulation, and examine whether selective coupling of CB1 receptors to specific G-protein subtypes is correlated with regional differences in CB1 receptor adaptation. We propose examining in a systematic manner the role of CB1 receptor- G-protein coupling in neuroadaptation not only as a means of understanding cannabinoid tolerance but as a way of characterizing the endocannabinoid system. In order to address the role of receptor occupancy in adaptation, the magnitude of THC tolerance will be varied by administering different doses of THC. We will then assess 1) tolerance to cannabinoid-mediated hypoactivity, antinociception, hypothermia and memory impairment in behavioral assays and 2) CB1 receptor downregulation and desensitization using radiolabeled ligand and agonist- stimulated [35S]GTPgammaS autoradiography. We also hypothesize that differences in CB1 receptor-G-protein coupling throughout the brain account for differences in recovery of tolerance to separate THC-mediated behavioral effects. Therefore, the temporal relationship between recovery of tolerance and CB1 receptor function will be evaluated by treating mice with THC, then evaluating tolerance and downregulation/desensitization at different times after cessation of treatment. We will also conduct experiments to determine whether CB1 receptor coupling to different G-protein subtypes is responsible for variations in cannabinoid actions in different brain regions. We will examine co-localization of CB1 receptors and specific G-beta and G-gamma subtypes using immunocytochemistry to determine whether there is selective co-localization of CB1 receptors and specific subunits in different regions. We will then examine whether chronic THC administration selectively alters CB1 receptor coupling to specific G-alpha subtypes using agoniststimulated [35S]GTPgammaS binding with subsequent immunprecipitation of activated G-alpha subtypes. These studies will contribute to elucidation of the mechanisms of action of CB1 receptors in brain, as well as determine the effects of chronic cannabinoid administration on cellular function during tolerance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BRAIN COOLING AND REPERFUSION INJURY IN STROKE Principal Investigator & Institution: Nowak, Thaddeus S.; Professor; Neurology; University of Tennessee Health Sci Ctr Health Science Center Memphis, Tn 38163 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2005
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Summary: (Verbatim from the Applicant's Abstract) Early reperfusion is of proven benefit in stroke but intervention is only effective after brief ischemia, and it is critical that methods be found to extend its therapeutic window. Delayed, brief hypothermia can reduce infarct volume after focal ischemia in several rat models, provided cooling is initiated prior to or soon after the onset of recirculation. Preliminary results indicate significant strain differences in this effect, with a more prolonged window for intervention in Long-Evans rats, suggesting that cooling is particularly protective against "reperfusion injury" that is an established feature of this model. A novel approach is the selective cooling of blood reperfusing the previously ischemic territory, specifically targeting tissue at risk and reducing the potential for complications associated with deep systemic hypothermia. This robust model provides an opportunity to both define the practical limits of hypothermic protection and identify mechanisms by which hypothermia impacts postischemic injury cascades. Proposed studies will: 1) fully define the range of insult duration and temperature modulation over which protection can be achieved; 2) determine the impact of protective cooling on molecular markers of postischemic injury in neurons and other cell types; and 3) elucidate the impact of cooling on intravascular injury mechanisms that may contribute to infarct evolution. These results will establish the relative accessibility of intravascular vs. parenchymal injury cascades to hypothermic protection, and define critical targets for pharmacological intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CARDIAC ARREST AND RESUSCITATION--MECHANISMS OF BRAIN INJURY Principal Investigator & Institution: Traystman, Richard J.; Professor; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001 Summary: Severe hypoxia and complete asphyxia are the most common causes of cardiac arrest in newborn and infant children and can result in cerebral palsy, mental retardation and severe seizures. We have developed a model of asphyxic cardiac arrest in the immature pig that resembles the clinical course of birth asphyxia with selective injury to basal ganglia, cortex and thalamus and with emergence of clinical seizures one day after resuscitation. Our preliminary data indicate that injury to neurons and astrocytes, accompanied by loss of their respective glutamate transporter isoforms, is dense in putamen by 24 hours, whereas neurodegeneration is largely delayed until 48 hours in primary sensorimotor cortex and until 96 hours in thalamic sensory nuclei. Our goal is to understand the mechanism of injury at each step of recovery so that specific therapeutic modalities can be designed to prevent the maturation of injury at each location. We will determine if decreased capacity of the glutamate reuptake transporters occurs during the early hours of reoxygenation when bursts of electrical activity are seen. Mild hypothermia and the glutamate release inhibitor lamotrigine will be used to reduce the overflow of glutamate into the extracellular space as monitored by microdialysis during the first day of recovery. We will determine if suppressing glutamate overflow after resuscitation reduces early neuronal and astrocyte loss in putamen, delayed loss in cortex and thalamus, and neurobehavioral deficits. A component of the delayed neuronal loss in sensorimotor cortex and thalamus may be apoptotic in nature resulting from a) target deprivation secondary to loss of other neurons in the sensorimotor axis, and b) seizures. We will use various morphological and biochemical markers of apoptosis to determine when and where programmed cell death occurs. Phenobarbital loading, as used clinically to suppress birth asphyxia
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seizures in newborns, will be used to determine the role of seizure activity in the progression of the injury process. The integrative approach of systems neuropathology, immunocytochemical localization, microdialysis and EEG spectral analysis will generate unique mechanistic insights in a model of neonatal brain injury. In mature brain, transgenic mice have been useful for investigating focal ischemic injury, but this approach has not been applied to cardiac arrest. In a model of cardiac arrest and resuscitation in mice, we will test the hypothesis that the combination of neuronal nitric oxide (NO) synthase gene deletion with overexpression of Cu, Zn- superoxide dismutase provides better neuroprotection and improve memory and learning than either gene alteration alone. This study provides a novel approach for understanding the role of NO and oxygen radicals in delayed neuronal injury after cardiac arrest/CPR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CARDIAC SURGICAL ISCHEMIA: BIOPHYSICAL ASPECTS Principal Investigator & Institution: Krukenkamp, Irvin B.; Director, Heart Center; Surgery; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Most cardiac surgical procedures require induction and management of myocardial ischemia and reperfusion. Preconditioning by a brief period of unprotected ischemia and reperfusion confers myocardial protection subsequent to a more prolonged insult. The central hypothesis of this application is that understanding the changes in sarcolemmal membrane currents which underlie the ability of the myocyte to maintain excitability consequent to preconditioning may provide an avenue for new approaches to myocardial protection that would improve myocyte function as well as survival. Our novel models use guinea pig myocytes isolated preischemically, prior to metabolic inhibition by NaCN, and rabbit myocytes first exposed to global ischemia, and then isolated during reperfusion. Studies of intracellular calcium and pH, and sarcolemmal current-voltage relations demonstrate an increase in an outward potassium current that appears either during prolonged ischemia, or during reperfusion. This current is not blocked by glybenclamide, indicating an identity other than i(kATP) Ischemic preconditioning shortens the time to appearance of the current during ischemia, and prevents its expression during reperfusion. Using these biological markers, our specific aims are to study, 1.) whether preconditioning triggers intracellular calcium, pH, or potassium conductance changes evident during preischemia, 2.) whether depolarizing (K+ or K+/Mg ++) and/or hyperpolarizing (pinacidil or ACh) cardioplegic ischemia imparts protection by sarcolemmal conductance and intracellular ionic changes similar to preconditioning evident during reperfusion, and 3.) whether maintenance of a specific membrane potential during ischemia limits deleterious biophysical changes, and whether i(kl) or other inward rectifiers may act as mediators of the observed K+ current changes. This translational research effort supports our long-term aim to understand the biophysical mechanisms and triggers that will direct the development of specific methods to enhance the clinical conduct and outcome of cardiac ischemia for patients who must undergo surgical repair. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CELLULAR AND NEUROCHEMICAL MECHANISMS OF REM SLEEP Principal Investigator & Institution: Datta, Subimal; Professor; Psychiatry; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118
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Hypothermia
Timing: Fiscal Year 2003; Project Start 01-APR-1999; Project End 31-MAR-2008 Summary: (provided by applicant): The long-term objective of this application is to further our understanding of cellular and neurochemical mechanisms of REM sleep. More specifically, the goal is to identify Pedunculo Pontine Tegmentum (PPT) intracellular signal transduction pathways involved in the receptor activation-mediated regulation of REM sleep in the freely moving rat. Recent evidence indicates that novel compounds designed to modify intracellular transduction pathways have therapeutic potential for endogenous depression, cancer, hypothermia, and pathological aggregation of platelets, thus the identification of the intracellular molecules involved in normal regulation of REM sleep may lead to the design of the future generation of drugs to treat REM sleep disorders in humans (e.g. endogenous depression, schizophrenia, panic attacks, bipolar disorders, narcolepsy, excessive daytime sleepiness).The central hypothesis of this proposal is that the activity of REM sleep generating cells in the PPT cholinergic cell compartment is regulated by the activation of specific glutamate and GABA receptors. These particular receptors convey their message via cAMP-dependent protein kinase A (PKA) to regulate normal and glutamate-induced REM sleep. To test this hypothesis systematically, there are four specific aims: 1. Test the hypothesis that cAMP-PKA intracellular signaling molecules in the PPT cholinergic cell compartment are involved in natural and glutamate-microinjection-induced REM sleep. Microinjecting cAMP and PKA inhibitors directly into the PPT to block spontaneous and glutamate-induced REM sleep will achieve this goal. 2. Test the hypothesis that the activation of specific GABA-receptors in the PPT cholinergic cell compartment suppresses REM sleep. This goal will be achieved by microinjecting selective GABA receptor agonists into the PPT to block REM sleep. 3. Test the hypothesis that the induction of GABA-receptor-mediated suppression of REM sleep is due to the inhibition of the cAMP-PKA signal transduction pathway. Microinjecting selective cAMP-PKA activator into the PPT to block the REM sleep suppressing effect of GABA receptor agonist will achieve this goal. 4. Test the hypothesis that the activation of specific GABA receptors suppresses REM sleep by suppressing the activity of REM-on and Wake-REMon cells in the PPI. This aim will be achieved by applying the REM sleep suppressing GABA receptor agonist to identified REM-on and Wake-REM-on PPT cells while recording single cell activity in freely moving rats. These studies are relevant not only to questions about the basic neurobiology of sleep but also to questions of sleep disorders and mental illness. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CEREBRAL FUNCTION AFTER HYPOTHERMIC CIRCULATORY ARREST Principal Investigator & Institution: Griepp, Randall B.; Chief, Div of Cardiothoracic Surgery; Cardiothoracic Surgery; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2001; Project Start 01-SEP-1991; Project End 31-JUL-2004 Summary: This proposal is for ongoing study of ways to improve cerebral protection during operations on the heart and great vessels which require arrest of antegrade circulation. Clinical and experimental data suggest that subtle cerebral injury occurs if the duration of hypothermic circulatory arrest (HCA) is more than 30 minutes even under optimal circumstances, and some complex procedures cannot reliably be completed in so short a time. In our porcine experimental model, the effect of strategies such as retrograde cerebral perfusion (RCP) can be studied to see whether they can be used to extend the safe duration of HCA to 60 minutes. In this clinically relevant model,
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the effect of changes in the implementation of HCA and RCP on cerebral blood flow, cerebral metabolism, intracranial pressure, electrophysiological recovery, behavioral outcome (including preservation of ability to learn conditioned reflexes) and cerebral histopathology can be used to see whether new approaches, such as use of lower temperatures, postoperative ultrafiltration, cold reperfusion, and treatment with various pharmacological agents are likely to improve neurological outcome after operations requiring HCA. The hypothesis that some of the cerebral injury following HCA/RCP is occurring as a consequence of apoptosis, or programmed cell death, opens up the possibility of arresting this suicidal cascade using specific inhibitors of the proteases and endonucleases which participate in this process as well as inhibitors of protein synthesis, all of which have had dramatic success in reducing injury in rodent models of cerebral ischemia. The results of this study will make a significant contribution toward improving long-term outcome of complex surgery on the heart and great vessels in both infants and adults. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COGNITIVE FUNCTION AFTER INTRACRANIAL ANEURYSM SURGERY Principal Investigator & Institution: Samra, Satwant K.; Anesthesiology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 30-NOV-2005 Summary: (provided by applicant): This is an ancillary study to be conducted in conjunction with a multicenter trial of mild intraoperative hypothermia on neurological outcome (IHAST), already funded by NINDS (NS38554), which is currently in progress. This will be a multicenter, prospective, partially blinded clinical study of the rate of recovery of cognitive function in patients who have undergone craniotomy for clipping of intracranial aneurysms. Specific aim of this investigation is to study the effects of intraoperative hypothermia and anatomical location of aneurysm on the rate of recovery of neurocognitive function. Patients in IHAST are randomized to normothermic (36.5 degrees C) and hypothermic (33 degrees C) groups based on the core body temperature at the time of aneurysm clip application. Patients, neurosurgeons, neurological examiners and study coordinators are blinded to the group assignments. Long term outcome is assessed 3 months after surgery, which is the end point of current study. We propose to do two additional tests of neuropsychological function and prolong the period of follow up to 1 year in a subset of English speaking patients, enrolled in IHAST. Patients will be recruited for this study, at the time of last visit for IHAST, therefore this study can not possibly interfere with IHAST protocol. In consenting patients, an assessment of neuropsychological function will be done at 3, 6 and 12 months after surgery. Neuropsychologists, administering/scoring these tests will be blinded to the group assignment (hypothermia/normothermia) and location of the aneurysm. The effect of hypothermia and location of aneurysm (anterior communicating, anterior cerebral, middle cerebral, posterior communicating and basilar arteries) on performance and rate of recovery of neuropsychological function will be studied by appropriate statistical analyses. We hypothesize that intraoperative hypothermia will result in better preservation of neurocognitive function and aneurysm location will have significant effect on rate of recovery of cognitive function. Information gained from this investigation will be important in giving a prognosis for returning back to work as well as planning rehabilitation of patients suffering from aneurysmal SAH in future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: COMPUTATIONAL ASPECTS OF PRIMATE MEMORY Principal Investigator & Institution: Fuster, Joaquin M.; None; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 30-SEP-1994; Project End 30-APR-2005 Summary: Active short-term memory plays a critical role in the temporal organization of behavior, reasoning, and language. It is impaired in a variety of mental disorders, notably in the psychoses, major affective disorders and syndromes resulting from pathological aging of the brain. Recent experimental evidence indicates that active shortterm memory consists in the sustained activation of an extensive network of interconnected neuronal assemblies of the cerebral cortex. Memory networks are widely distributed, extending beyond the boundaries of anatomically defined cortical areas. The mechanisms of active memory are believed to include the sustained circulation of neuronal impulses within one such network. This research will attempt to substantiate the distributed nature of active short-term memory and the reentry of neural impulses presumed to be the basis of short-term memory retention. Experiments with that objective will be conducted in nonhuman primates trained to perform auditory, tactile, and cross-modal memory tasks. Fields potentials and cell discharge will be recorded from frontal and parietal regions of the cortex during performance-and also to some extent during learning-of those tasks. Frequency and pattern of cell discharge will be analyzed for evidence of neuronal interactions within and between those cortical regions during the short-term memorization of sensory information. Special computational methods of time-series analysis will be used to explore those interactions. Some of the interactions will be further explored by reversible functional depression (by local cooling) of frontal cortex and the study of its effects on parietal cell discharge and the animal's performance of haptic memory tasks. The results of these studies are expected to shed light on the functional architecture of cortical memory networks and on the mechanisms of encoding, retention, and retrieval of memory. A better understanding of the neural dynamics of memory may help us better understand the pathogenesis of memory disorders in the mentally ill and thus lead to better treatments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CORE--ANIMAL MODELING AND OUTCOMEN Principal Investigator & Institution: Kochanek, Patrick M.; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001 Summary: We propose to operate a core facility that performs the necessary procedures related to Animal Modeling and Outcome Assessment for the University of Pittsburgh Brain Trauma Research Center program project grant (PPG). The facilities in this core will be used by the following principal investigators (PIs) involved in the individual proposals in this PPG application: 1) Steven Graham, M.D., Ph.D., Project #1, "bcl-2 family genes in traumatic brain injury (TBI)", 2) Steven Dekosky., Project $2, "IL-1beta, APP metabolism and hypothermia in head injury", 3) Patrick Kochanek, M.D., Project #3, "iNOS and TBI", 4) Edward Dixon, Ph.D., Project #4 "Dopaminergic mechanisms of TBI," and 5) Robert Clark, M.D., Project #5 "PARS activation after TBI." The core facility will address the following Specific Aims 1) To provide a centralized facility for surgery and anesthesia for all of the proposed experimental manipulations of mice and rats within the PPG, 2) To provide uniform injury for all studies in mice and rats in the PPG (controlled cortical impact [CI] model, and CCI model with secondary insult) and ensure consistency by performing quality control analysis, 3) To provide a centralized
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facility for the standardized assessment of functional outcome parameters (motor and cognitive) within the PPG, 4) To provide a centralized facility for the standardized assessment of histological outcome parameters (contusion volume and hippocampal neuron counting) within the PPG, 5) To facilitate interaction between the PIs within the PPG, and facilitate interaction with collaborating investigators at the Pittsburgh NMR Center for Biomedical Research (Carnegie Mellon University), and 6) To provide a standardized hypothermia regimen for all studies using this therapy in rats in the PPG. The successful execution of these specific aims will provide for optimal resource utilization by the investigators include the use of 1) technician time, 2) laboratory space, 3) equipment, 4) supplies, 5) animals, and 6) Magnetic Resonance Imaging time. At the same time, quality control will be ensured for all of the studies in mice and rats, and a structured environment for interaction between the PIs within the PPG will be provided. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DELAYED PRECONDITIONING
TOLERANCE
AFTER
HYPOTHERMIC
Principal Investigator & Institution: Lee, Kevin S.; Professor and Chair; Neurosurgery; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 30-APR-2004 Summary: (Adapted from applicant's abstract): Ischemic injury is a common complication in a wide range of surgical procedures. Hypothermia administered during and/or after an ischemic event has proven to be clinically beneficial, and its effects rival or exceed those of other therapeutic strategies. This application describes a novel therapeutic strategy in which brief hypothermic preconditioning is used to induce a delayed form of ischemic tolerance that persists for a few days. Evidence is presented demonstrating that hypothermic preconditioning substantially reduces cerebral infarction elicited by transient focal ischemia, that this tolerance phenomenon is protein synthesis dependent and that it occurs in cells located in the brain parenchyma. The proposed work will characterize therapeutic, cellular and molecular features of hypothermia-induced tolerance by addressing the following specific issues: 1) What are the optimal hypothermic conditions for inducing tolerance? 2) Can hypothermiainduced tolerance complement the protective effects of intraischemic hypothermia? 3) Which cell types contribute to hypothermia-induced tolerance? 4) a. What are the candidate genes for mediating tolerance? b. What cell types express the candidate genes? c. What role do these genes play in ischemic neuroprotection? The ultimate goal of this project is to develop a new therapeutic strategy wherein a simple preconditioning treatment, administered well before surgery, can be used to limit subsequent ischemic injury. A parallel goal is to identify cellular sites and molecular mechanisms responsible for tissue tolerance. In as much as hypothermia is already used safely during human surgery, it is plausible that this new strategy could be implemented rapidly in the clinical setting. Hypothermic preconditioning could provide a low risk approach for improving surgical outcome after virtually any form of invasive surgery, including high-risk neurological and cardiovascular procedures. Moreover, because of the relatively benign nature of hypothermic preconditioning, it will also be possible to refine the search for salient cellular and molecular events responsible for neural tolerance. This approach will ultimately facilitate the development of novel gene-based therapies for limiting ischemic injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DETERMINANTS HYPOTHERMIA
OF
TOLERANCE
TO
NITROUS
OXIDE
Principal Investigator & Institution: Kaiyala, Karl J.; Doctor; Dental Public Health Sciences; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2002; Project Start 15-MAR-2002; Project End 31-JAN-2005 Summary: (provided by applicant): This is an R21 proposal to investigate the physiological mechanisms of tolerance development to nitrous oxide (N2O)-induced hypothermia. Influential theories of drug tolerance contend that CNS-mediated drugopposing responses underlie the etiology of drug tolerance and dependence. Evidence for such responses is primarily based on the observation of withdrawal effects when the drug is discontinued (or antagonized) as well as on the elicitation of the responses by conditioned stimuli. This proposal uses a novel approach for measuring these responses directly, while the drug is present, during both an initial drug administration as well as over repeated administrations. This research will also determine bow individual differences in the identity, latency and/or intensity of these responses are related to individual differences in initial sensitivity and acute tolerance to N2O hypothermia. Using a rat model that combines direct and indirect calorimetry with implanted temperature sensors, synchronous measures of core temperature and the dynamic processes of metabolic heat production and heat loss will be made during a steady-state administration of 60 percent N20. In an initial experiment, experimental (N2O) and control (placebo gas) rats will receive a 5-hour gas exposure during which core temperature and the components of heat balance are measured. The same rats will be retested 2 weeks later to determine the reliability of the mechanisms that determine core temperature. In a second experiment, individual rats given an initial N2O exposure will be classed as: a) insensitive to N2O-induced hypothermia, b) sensitive to N2O-induced hypothermia and develop acute tolerance, or c) sensitive to N2O-induced hypothermia with little or no acute tolerance. Rats in each group will be randomly assigned to receive either N2O or placebo during three additional five-hour gas exposures at one-week intervals to determine how the physiological responses controlling heat balance change as chronic tolerance develops. These studies have theoretical importance for understanding the mechanisms of drug tolerance and will begin to suggest the physiological basis of individual differences in vulnerability to addiction and drug abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EARLY EXPERIENCE AND ADOLESCENTS' RESPONSES TO ETHANOL Principal Investigator & Institution: Spear, Norman E.; Distinguished Professor of Psychology; Psychology; State University New York Binghamton Vestal Pky E Binghamton, Ny 13901 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2004 Summary: In both humans and animals prenatal exposure to ethanol increases susceptibility to subsequent ethanol abuse and alters related aspects of responsiveness to ethanol. Postnatal exposure to ethanol also has been found to increase later ethanol intake and related aspects of responsiveness to ethanol in animals. Early onset of ethanol use in adolescence or even pre-adolescence has been shown to be associated with a greater probability of ethanol abuse in adulthood, although causality in these studies with humans has yet to be demonstrated. One determinant of ingestion and related responsiveness to ethanol during early adolescence may be still earlier exposure to
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ethanol, a possibility to be explored in the present experiments. Toward improvement over previous experimental procedures in which early ethanol exposure occurs in relatively stressful circumstances, we propose to provide early exposure to ethanol in relatively nonstressful, ecologically representative circumstances and assess the consequences for responsiveness to ethanol in adolescence. Our preliminary results indicate that as adolescents, the offspring of dams living with their litter in large enclosures and free to consume ethanol ad libitum chose to drink relatively large amounts of ethanol. The present proposal is to determine the ontogenetic locus of this effect -- whether exposure during gestation, lactation or weaning is differentially effective -- and to determine controlling parameters of this effect. The second proposed step is to assess the breadth of consequences from these forms of early exposure for several key indices of responsiveness to ethanol during adolescence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ENHANCED PRESERVATION
GLYCOLYSIS
FOR
HYPOTHERMIC
HEART
Principal Investigator & Institution: Chien, Sufan; Associate Professor; Surgery; University of Louisville University of Louisville Louisville, Ky 40292 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-JUL-2004 Summary: The ultimate goal of this project is to develop a safe and effective technique for long-term organ preservation. The specific aim of this study is to enhance glycolytic energy production during hypothermic heart storage. Despite more than three decades of extensive research, safe preservation times for the heart remain very short. This is the result of two major deficiencies: 1) the critical energy requirement for the heart during ischemia has been mostly ignored, and 2) little attention has been paid to the fact that there are many rate-limiting factors in glycolysis, and, therefore, the use of a single chemical may not be effective. The investigators propose a new approach for improving heart protection. Their general hypothesis is that hypothermic heart preservation times can be extended by enhancing glycolytic energy production. This goal is achieved by using a glycolytic intermediate, fructose-1,6-diphosphate (FDP), to bypass two ATPconsuming steps, by adding AMP precursors to facilitate ATP re-synthesis, and by using insulin to reduce lactate production. They have evidence that adding FDP to EuroCollins or St. Thomas solution can substantially enhance hypothermic heart preservation in rats and rabbits, and that FDP can cross the cell membrane in a dosedependent fashion. Although FDP has been used in tissue ischemia with impressive results, it has not been used in heart preservation, and studies on its mechanism of action are surprisingly superficial and scarce. The hypothesis will be evaluated using three different approaches: 1) in cardiomyocytes in normoxia and hypoxia at normal temperature and during hypothermia, 2) in hypothermic rabbit heart preservation, and 3) in rabbit and dog heart transplantation. Cardiomyocyte function, FDP uptake and metabolism, pyruvate dehydrogenase (PDH) activity, pyruvate and lactate production, and membrane and mitochondrial integrity will be examined in cardiomyocyte culture. Mechanical performance, tissue biochemical integrity, enzyme release, adenine nucleotide production and consumption, pyruvate and lactate production, and histological changes will be quantified in heart preservation. This project will greatly enhance our understanding of ischemia and tissue protection, and provide a mechanism that could significantly increase heart preservation times for transplantation. These glycolytic modulators might produce a synergistic effect and serve potentially as effective tissue-protective agents during ischemia, not only in heart preservation and
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Hypothermia
cardioplegia, but also in other ischemic conditions, such as shock, stroke, coronary heart disease, and cardiopulmonary bypass. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ETHANOL SENSITIVITY IN BETA ENDORPHIN DEFICIENT MICE Principal Investigator & Institution: Grisel, Judith E.; Psychology; Furman University Poinsett Hwy Greenville, Sc 29613 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2004 Summary: (provided by applicant): The influence of opioid peptides on alcohol sensitivity has been studied for a number of years, and the endogenous opioid system is hypothesized to be an important substrate for alcohol actions. The experiments proposed in this application will utilize transgenic mice that differ in their ability to synthesize B-endorphin in order to study the way that B-endorphin affects the response to alcohol. We have shown that these mice differ with respect to self-administration of alcohol. Other preliminary data indicate that mice lacking B-endorphin have an enhanced alcohol-mediated reduction in anxiety - in spite of the fact that under basal conditions anxiety increases as B-endorphin levels decrease. In addition, B-endorphin deficient mice show increased sensitivity to EtOH-induced ataxia and analgesia. These data support the hypothesis, deriving from both clinical and basic research, that Bendorphin affects sensitivity to alcohol. The overarching aim of these studies is to more fully characterize alcohol's differential effect on behavior in mice possessing varying amounts of B-endorphin. Moreover, we are hopeful that a better understanding of the relationship between alcohol and B-endorphin levels will lead to studies in which the mechanism of interaction can be elucidated. Because this peptide appears to differ between humans with varying genetic risk for alcoholism, a greater understanding of its relationship to alcohol sensitivity will contribute to our knowledge of the mechanisms underlying excessive alcohol use. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ETHANOLS ACTIONS IN GAMMA PKC NULL MUTANTS Principal Investigator & Institution: Wehner, Jeanne M.; Professor; Inst of Behavioral Genetics; University of Colorado at Boulder Boulder, Co 80309 Timing: Fiscal Year 2001; Project Start 01-MAR-1999; Project End 28-FEB-2003 Summary: Protein phosphorylation is a basic regulator of cellular processes. One gene family, the calcium/lipid activated protein kinase C (PKC) encodes at least 11 isotypes. Among these isotypes the y-PKC isotype is the only PKC solely expressed in neurons of the brain and spinal cord. Until the creation of null mutant mice ("knock-outs") that carry a disrupted y-PKC gene, it has been difficult to analyze the role of specific isotypes in behavioral, biochemical, and physiological processes. We have previously demonstrated that y-PKC null mutants are less sensitive to the hypothermia-inducing and sedative-hypnotic effects of alcohol compared to their wild-type littermates. We provide data here showing that y-PKC mutants do not develop tolerance to some of alcohol's effects. Therefore, it appears that the y-isotype of PKC may play a role in the mediation of ethanol's action. The goal of this proposal is to investigate the role of yPKC in determining behavioral responses to acute and chronic ethanol treatment. In specific aim #1, the y-PKC null mutants will be compared to mice that are either wildtype or heterozygous for the mutations using several measures of initial sensitivity and tolerance. In specific aim #2, transgenic mouse lines over-expressing y-PKC will be created and characterized for initial sensitivity and tolerance to ethanol. A genetic rescue
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of the y-PKC null mutants will also be performed by a genetic cross between transgenics and null mutants. The results of these studies will establish whether y-PKC plays a role in the pharmacological actions of ethanol that underlie the determination of ethanol sensitivity and tolerance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EVALUATION OF COOLING THERAPY FOR MULTIPLE SCLEROSIS Principal Investigator & Institution: Schwid, Steven R.; Assistant Professor of Neurology; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EXCITOTOXICITY IN CIRCULATORY ARREST--BRAIN INJURY Principal Investigator & Institution: Baumgartner, William A.; Professor; Surgery; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 01-DEC-1992; Project End 30-NOV-2004 Summary: (Verbatim from Applicant's Abstract): The goal of the project is to define the mechanisms of excitotoxic neuronal injury caused by hypothermic circulatory arrest (HCA) and to develop the means to prevent it. In our canine survival model of HCA, replicating clinical experience during cardiac operations, dogs subjected to 2 hours of circulatory arrest at 18degreesC sustain a consistent neurologic deficit and histologic pattern of selective neuronal death. We originally showed that administration of selective glutamate receptor antagonists before and after HCA-induced injury reduced the neuronal necrosis. We have now shown that neuronal death can occur by apoptotic or necrotic mechanisms. We showed that glutamate release after HCA results in accumulation of nitric oxide (NO), which mediates neuronal death and that inhibition of neuronal nitric oxide synthase (NOS) reduces production of NO in the brain and prevents apoptosis. We hypothesize that mitochondrial dysfunction determines the mechanism of delayed excitotoxic neuronal injury after HCA by apoptosis or necrosis and that neuronal apoptosis can be prevented by ischemic preconditioning (IPC), achieved pharmacologically by opening ATP-dependent potassium channels on the inner mitochondrial membrane. We further hypothesize that NO may act as a mediator both of neuronal injury and neuronal protection by IPC. In preliminary experiments we have shown that diazoxide, an ATP-dependent potassium channel opener can produce pharmacologic IPC and that that this agent can prevent apoptosis in cardiomyocytes acting on the inner mitochondrial membrane. In our canine model, diazoxide has shown near total elimination of neurologic deficit following HCA, with reduction in apoptosis in select neuronal populations. We also showed that hypoxia can activate HIF-1 with induction of iNOS and production of NO, a putative molecular pathway of the late form of IPC. We propose to: (1) measure metabolic indicators of mitchondrial dysfunction in specific brain regions using 'H and 'P MRSI following HCA in our canine model and (2) correlate these with neuronal survival, apoptosis and necrosis; (3) to examine pharmacologic IPC with diazoxide as means of neuroprotection and (4) determine how opening the potassium channels in the mitochondrion alters its function to effect IPC; (5) to establish how NO can act as mediator of both injury and protection in the brain. This research will expedite the clinical use of inhibitors in the excitotoxic cascade and facilitate exploitation of IPC by pharmacologic means to provide cerebral protection resulting in better patient outcomes after HCA in cardiovascular operations.
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Hypothermia
Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FEVER RESPONSES AND THEIR REGULATION IN AGED RATS Principal Investigator & Institution: Satinoff, Evelyn; Professor; Psychology; University of Delaware Newark, De 19716 Timing: Fiscal Year 2001; Project Start 01-MAR-1986; Project End 31-DEC-2003 Summary: Old female and male rats are heterogeneous in their fever responses to lipopolysaccharide (LPS); some get moderately good fevers, some no fevers, and some become hypothermic. LPS stimulates the immune system to produce proinflammatory cytokines, such as interleukin-1beta (IL-1beta), which induce fever by causing synthesis and release of prostaglandin E2(PGE2). Old rats have very high levels of these cytokines. yet do not get good fevers. We have evidence that if IL-1 beta or PGE2 is infused into the brains of old rats, they show very good fever responses. Therefore, the problem must be in the periphery, but it cannot be in the lack of production of proinflammatory cytokines. We will measure the PGE2 released in the hypothalamus after LPS, which we predict will be lower than that induced in young rats after the same procedure. Old rats also have very high plasma levels of corticosterone (CORT), and CORT inhibits cytokine action and fever. Possibly the overproduction of cytokines in old animals is an attempt by the CNS to overcome the inhibiting effects of excess CORT. If so, then old rats injected with a CORT receptor antagonist should get higher fevers than controls will, and may need to generate lower levels of proinflammatory cytokines. It may also be that old rats do not get as high a fever as do young rats because they are generating higher levels of anti-inflammatory cytokines. One goal of this proposal is to measure brain, tissue, and plasma pro- and anti-inflammatory cytokine and hypothalamic-pituitaryadrenal (HPA) axis product levels in old rats to determine differences in the profiles that might explain differences in responses to LPS. We have recently found that when young rats were injected with LPS and left at an ambient temperature (Ta) of 23 C for three hr, they all developed fevers, as expected. Similarly treated old rats either had blunted fevers, no fever, or became hypothermic, also as anticipated. Unexpectedly, three hr post-injection. when the old rats were placed in a thermal gradient, they chose warm positions and became febrile. Thus, the drive towards fever was present in the old rats but could not be expressed without behavioral choice. We want to understand the basis of this surprising result. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FIELD COOLING SYSTEM FOR THERPEUTIC HYPOTHERMIA Principal Investigator & Institution: Izenson, Michael G.; Creare, Inc. Box 71, Etna Rd Hanover, Nh 03755 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-MAR-2004 Summary: (provided by applicant): Recent clinical research indicates a significant benefit to neurological outcomes associated with mild therapeutic hypothermia after cardiac arrest. Presumably, the sooner such treatment can begin, the greater the potential benefit and the greater the number of patients who might benefit. However, there is presently no practical way for paramedics or first responders to provide cooling for hypothermia in the field. Mechanical cooling systems are power hungry, heavy, and expensive. Ice and chemical ice packs have many obvious practical problems with field storage, transport, patient treatment when wet, and lack of temperature control. In the proposed effort, a novel spacesuit cooling technology will be adapted to provide a reliable, lightweight, inexpensive, very low power, easily controlled cooling source that
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will enable mild therapeutic hypothermia treatment to begin early in the field immediately after cardiac resuscitation. The proposed cooling system is based on regenerable heat absorption. During Phase I, a proof-of-concept cooler with a capacity of approximately 200 W-hr of refrigeration and a cooling pad will be fabricated and demonstrated in bench top and animal experiments. During Phase I, a complete prototype will be developed and demonstrated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FORMATION, INTERACTION & FUNCTION OF SPINDLE COMPONENTS Principal Investigator & Institution: Rieder, Conly L.; Professor; Wadsworth Center Empire State Plaza Albany, Ny 12237 Timing: Fiscal Year 2001; Project Start 20-JAN-1988; Project End 31-DEC-2005 Summary: (applicant's description): The broad objectives of this proposal are to determine how entry and exit from mitosis is controlled, how centrosomes and kinetochores function and interact to form the spindle, and how the forces for chromosome motion and positioning are generated and regulated. In Aim #1 time-lapse video light microscopy (VLM), GFP-imaging and 3-D electron microscopy (3D-EM) will be used to: a) test the hypothesis that microtubules are involved in the checkpoint regulating progression through prophase in vertebrates; and to determine b) if prophase cells, induced by hypothermia to revert to G2, fail to re-enter mitosis after 24 hrs because they lack cyclin A or Cdc25; and c) the etiology of chromosome segregation abnormalities in such revertants when induced to re-enter mitosis after 16 hrs in G2. In Aim #2 we will use cell fusion, GFP-imaging, 3D EM and antibody injection to evaluate the hypotheses that in vertebrate cells: a) the numbers and length of astral microtubules, formed by centrosomes not associated with chromosomes, changes during prometaphase; b) that separating asters interact during prometaphase in the absence of associated chromosomes; c) that the acentrosomal pathway for spindle assembly is a constitutive component of mitosis; and d) that centrosomes and/or centrioles are required for the completion of cytokinesis. In Aim #3 we will use antibody injection, VLM and 3D-EM to test the hypotheses that: a) the kinetochore associated motor responsible for fast poleward motion during kinetochore attachment is no longer functional during anaphase, and b) that ZW- 10 is involved in kinetochore re-orientation during mitosis and meiosis in Drosophila. In Aim #4 we will use laser microsurgery to determine: a) if "polar winds" are present during meiosis and mitosis in Drosophila spermatocytes and neuroblasts and if so whether they are present in neuroblasts lacking functional Klp3 Sb and/or Nod proteins. We will also test the hypotheses that: b) destroying part of one kinetochore does not inhibit chromosome congression in vertebrates, and c) that a chromosome, bioriented on a spindle formed from two poles that nucleate vastly different numbers of microtubules, congresses closer to the weak spindle pole. Finally, in Aim #5 we will use laser microsurgery and GFP-imaging to test the hypotheses: a) that the mitotic arrest induced in vertebrate cells by nocodazole or Taxol is due to kinetochores; b) that C-anaphase in these cells requires a functional centrosome; c) that C-anaphase is correlated temporally with the destruction of cyclin B; and d) that Drosophila spermatocytes lack a spindle assembly checkpoint. The knowledge obtained from these studies is required to better understand the etiology of various birth defect syndromes and cancers, to design new therapeutic strategies for the control of cell proliferation, and for the treatment of other disease states involving microtubules including arthritis, metastasis and Alzheimer' s. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Hypothermia
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Project Title: GENETICS OF ACUTE TOLERANCE Principal Investigator & Institution: Deitrich, Erwin; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001 Summary: The focus of this component of the Alcohol Research Center is on acute functional tolerance. We now have lines of mice selectively bred for High Acute Functional Tolerance (LAFT1 and 2). These mice will be used to study the mechanisms of this acute tolerance and to define its relationship to other forms that are being studied in this component, ie, Very Rapid Acute Functional Tolerance (VRAFT) and Rapid Tolerance. Over components are investigating the mechanisms of chronic tolerance. By processes well established in this center we will correlate the various forms of tolerance with other behavioral aspects of ethanol's action such as sleep time, hypothermia, ethanol consumption, and locomotor activity. By utilizing the LS X SS recombinant inbred strains of mice, we have identified potential QTLs for AFT and will do the same for VRAFT. By selectively breeding for AFT we have generated lines of animals (HAFT and LAFT) from which QTLs can be determined for AFT as well as for VRAFT in F2 crosses of these lines. Other studies will investigate the neurochemical mechanisms responsible for these forms of tolerance. This will be accomplished by determining the specificity of AFT and VRAFT for ethanol by use of other CNS active drugs , specific for various receptor systems, and also investigate the ability of agonists and antagonists to influence development of AFT and VRAFT. Recent studies point to initial sensitivity and tolerance as important determinants of the risk of alcoholism in humans. These studies should provide a road map to studies in humans in these areas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HEPATOCYTE GENE EXPRESSION UNDER HYPOTHERMIC STORAGE Principal Investigator & Institution: Kosari, Kambiz; Surgery; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 11-FEB-2002 Summary: (provided by applicant):L Recent advances in tissue engineering have made possible the creation of a xenogeneic bioartificial liver (BAL) as part of an effort to improve the survival of patients with acute liver failure (ALF). A major obstacle that faces this and most other tissue-engineered cell based products is the problem of storage. Potentially, hypothermic conditions may be utilized to allow the viable storage of the BAL from point of production to delivery. Indeed previous experiments using the BAL have shown that up to a 24-hour period of cold storage is feasible. However, longer storage time as well as improved viability and function is vital for its successful widespread application. Examination of the cellular mechanisms, specifically the gene expression patterns associated with the early phases of hypothermic damage, need to be examined in order to discover and subsequently test "protective" factors. New techniques in tissue culture and molecular/cellular biology make this goal attainable. We propose that exposure to hypothermia will cause an up-regulation in the expression of common motifs present in the cluster of co-regulated genes dealing with apoptosis and stress; furthermore, that these expression patterns are modified in the presence of "protective" factors. Our specific aims include establishment of gene expression patterns in cold-exposed mouse hepatocytes using microarray technology as well as suppression subtractive hybridization, studying modification of such patterns in the presence of a protective factor (sublethal pre-stress heat exposure), and finally, determination of the
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ideal cold-storage conditions in an "optimized" micro-BAL. We hope that our findings will facilitate prolongation of the cold storage period and improve the viability and function of the BAL. Even though the immediate benefit of this proposal will be for the BAL, we strongly believe that it will have significant implications for most xenogeneicbased, tissue-engineered artificial organs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HIGH EFFICIENCY HYPO/HYPERTHERMIA SYSTEM Principal Investigator & Institution: Ohley, William J.; Professor; Life Recovery Systems, Inc. 34 Hidden Glen Dr Sparta, Nj 07004 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JUL-2003 Summary: (provided by applicant): Sudden cardiac arrest remains a serious public health issue. Approximately 350,000 individuals are stricken in the U.S. annually, with overall survival rates on the order of only 5%. Even with the immediate availability of the most advanced care currently available, a survival rate of 25% appears to be the bestcase scenario. Improved therapies to deal with this situation are clearly needed. Prior studies have shown that moderate hypothermia (approximately 3-5 C degrees) provided during and after cardiac arrest can reduce the level of damage to vital organs, including the brain. However, conventional noninvasive means that are available for cooling (such as water-filled cooling blankets and cool air-emitting coverings) are too slow for optimal treatment. Furthermore, they are not well suited to being used during administration of cardiopulmonary resuscitation (CPR). Life Recovery Systems (LRS) intends to develop an advanced, noninvasive Therapeutic Hypothermia Device (THD) for rapid and controlled reduction of core body temperature. To achieve this goal, this system will combine the use of components, which will provide highly efficient and regulated cooling of the skin. The THD will be designed in such a manner that it can be used in combination with advanced forms of CPR, so that cooling can be efficiently delivered even while the subject is in a state of cardiac arrest. Initial swine tests of a THD prototype have shown that it is capable of reducing body core temperature approximately twice as quickly as can be done by covering the animal with packed ice. The THD cooling rate was approximately fifty times greater than that reported in recent clinical testing in which a cooled air system was applied to patients. LRS plans to initially conduct tests using a physical model of the body to optimize the design of the THD. It will then conduct animal studies (50 Kg swine) to further optimize the system, to evaluate the repeatability of the cooling which can be delivered, to compare the performance of the device to other cooling methods (such as standard cooling blankets), and to evaluate the ability of the THD to operate simultaneously with the delivery of CPR. During cooling experiments, temperatures will be monitored in the animal's pulmonary artery, auditory canal, and skin. In addition, EKG, blood pressures, and other key physiologic parameters will be monitored. The tests described in this proposal will be followed in the future by other tests (in both animals and humans) investigating the ability of the THD, in combination with other measures such as CPR, to improve neurologically intact survival following cardiac arrest. Long term, LRS believes that the THD has the potential to significantly increase the chances of neurologically intact survival following cardiac arrest. It also plans to evaluate the effectiveness of the THD in the treatment of other conditions, such as stroke. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HIGH EFFICIENCY MAPPING OF ALCOHOL SENSITIVITY GENES Principal Investigator & Institution: Johnson, Thomas E.; Professor; Inst of Behavioral Genetics; University of Colorado at Boulder Boulder, Co 80309 Timing: Fiscal Year 2001; Project Start 01-MAR-2000; Project End 29-FEB-2004 Summary: We propose to complete the construction of a large number of recombinant inbred strains (RIs) from the inbred Long Sleep (ILS) and the inbred Short Sleep (ISS) strains and to map genetically eight traits involved in alcohol action. This newly generate RI series will be useful in dozens of different behavioral analyses, while only one set of genotypic assessment swill need to be performed. From the single assessment of genotype will flow mapping results applicable to a myriad of various phenotypes that have been assessed in the parental strains (ILS and ISS) or in the LS and SS selected lines. The major disadvantages. associated with RI strains (lack of power in QTL identification and lack of resolution in mapping) are overcome through the use of such a large set of strains. The RI construction has already begun, funded by internal resources of the University of Colorado and the Institute for Behavioral Genetics and we propose to carry these RIs to the F22, which will allow greater than 98% fixation. At the completion of this project we will create an electronic data base allowing all alcohol researchers easy access to all of our results. We will also begin making arrangements to distribute these mice to searchers who wish to use them. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HSPS, CYTOSKELETAL AND SURVIVAL RESISTANCE TO HEAT TO LOW PH ADAPTED CELLS Principal Investigator & Institution: Coss, Ronald A.; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2001 Summary: This project is designed to test if a causal relationship exists between upregulation of Heat Shock Proteins (HSPs) and heat resistance in cells grown in an acid environment. The long term objective is to develop approaches for the identification and the selective killing of tumor cells adapted to growth in low pH environments. The two hypotheses are: 1) Growth of human melanoma cells in an acidic environment induces elevated levels of HSPs, including HSP27 and HSP72, which, in turn, contribute to protection of the cytoplasm and nucleus from heat-induce protein aggregation and disruption, allowing for enhanced synthesis of HSPs and enhanced thermotolerance (TT). Cytoplasmic protection includes protection of the cytoskeleton (CSK) and proton pumps responsible for maintenance of intracellular pH (pHi). 2) The protection of the CSK, pHi homeostasis machinery and the nucleus by HSPs can be overcome by an acute reduction of pHi prior to an during hyperthermia. Specific Aims designed to test the model will examine: i) the interrelationships between levels of HSPs, the phosphorylation of HSP27, the resistance of the CSK to heat-induced collapse & the accumulation of heat-induced nuclear-associated proteins (NAPs), heat-induced synthesis of HSPs and survival in adapted cells; ii) the importance of an intact CSK for realkalinization during hyperthermia following an acid load; and iii) the sensitization of adapted cells by an acute extracellular acidification alone, and by an acute acidification of 0.3 pHe unit combined with inhibitors (DIDS, CNCn, HOE642 and mIBG) that further reduce pHi. HSP levels and phosphorylation of HSP27 will be monitored by Western blot analysis, CSK organization by morphometric and biochemical analyses, NAPs by FCM, and survival by colony formation. Project 2 will be perform all pHi measurements. A translational objective will determine if some of the endpoints will be useful as
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indicators of the presence of adapted cells in fresh xenograft explants and sections of the xenografts provided by Project 4. This study will contribute to our understanding of the importance of HSP27 and HSP72 for resistance of the CSK and nucleus in adapted cells during hypothermia, and the importance of an intact CSK for efficient function of proton pumps during hyperthermia. Successful accomplishment of the goals may lead to new approaches for identifying and sensitizing acidotic regions of solid tumors to thermoradiotherapy using inhibitors that reduce pHi and/or destabilize the CSK. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HYPERTHERMIC RESPONSE OF THE RESPIRATORY NEURAL NETWORK Principal Investigator & Institution: Tryba, Andrew K.; Organismal Biology and Anatomy; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2001; Project Start 01-JUN-2001 Summary: (Applicant's abstract): Breathing is modulated as the result of changes in the internal and external environment (e.g. ionic concentration, pH, pCO2 and temperature) and the behavioral state of the animal. In response to these challenges, respiratory neural network activity is modified to affect the timing and intensity of respiratory events. While these changes are specific to respiration, the issue of how neural networks adapt a behavior during environmental changes is of interest to those studying many motor systems. In mammals, hyperthermia causes an initial increase in respiration frequency (RF) that serves to enhance heat loss through evaporative cooling, but heat loss mechanisms are not always effective. For example, hyperthermia associated with conditions such as fever and heat-stroke may lead to cardiac arrest, cessation of breathing (apnea) and death. In fact, hyperthermia is a major risk factor for sudden infant death syndrome. Despite these implications, little is known about the neural mechanisms underlying the temperature-induced changes in respiratory activity. In this proposal: 1) I will determine the effects of hyperthermia on respiratory activity generated in the isolated brain-stem respiratory neural network. The response of the pre- Botzinger Complex (pBC) respiratory network to hyperthermia will be characterized by integrating population pBC neural activity and quantifying changes in RF. 2) I will use patch-clamp recordings from pBC neurons to test whether changes in RF during hypothermia result from modulation of pacemaker neurons or the emergent properties of the respiratory neural network. 3) I will also use patch-clamp recordings from pBC neurons to examine if membrane properties and/or synaptic inputs in respiratory pacemaker neurons are modulated during hypothermia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HYPOTHERMIA Principal Investigator & Institution: Lyden, Patrick D.; Professor; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2003; Project Start 19-MAY-2003; Project End 30-APR-2008 Summary: Among putative neuroprotection strategies, hypothermia has long been recognized as the most potent. Recent insights in understanding ischemia and reperfusion suggest that hypothermia may be an ideal modality for extending the stroke therapy time window. Although difficulties cooling patients limited testing of this potentially effective therapy, recent developments in technology allow us to mount a Phase 1 clinical trial of intravascular cooling for patients presenting beyond 3 hours. The purpose of this study is to confirm the performance of an endovascular cooling device
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and to establish the parameters for a larger clinical study, such as sample size and indices of measurement. Preliminary effectiveness of hypothermia treatment in combination with thrombolysis for stroke will also be evaluated in this limited patient population. To do this, we will address 2 specific aims: 1) Characterize the safety profile of hypothermia in stroke patients who initiate cooling between 3 and 6 hours after stroke. Substantial pre-clinical data supports the hypothesis that the window for effective hypothermia may be longer that 3 hours. We will establish safety of the cooling device, and collect outcome data to be used for estimating sample size in larger, Phase 2 trials. 2) Establish the safety of thrombolysis and hypothermia used together between 3 to 6 hours after stroke onset. Thrombolysis trials failed to demonstrate benefit to patients treated later that 3 hours following stroke onset. In each trial, however, there was a trend toward benefit, and meta-analyses suggest that there is a positive, but small effect in later treated patients. We hypothesize that hypothermia, combined with thrombolysis, may prove effective in such patients. We will establish the safety of invasive, endovascular-cooling catheter in combination with thrombolysis. We will collect safety and outcomes data to aid in the design of larger, controlled Phase 2 trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HYPOTHERMIA AND GENE EXPRESSION AFTER CARDIAC ARREST Principal Investigator & Institution: Callaway, Clifton W.; Associate Director; Emergency Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 30-JUN-2006 Summary: (provided by applicant): Neurological injury after resuscitation from cardiac arrest is a major impediment to improving survival for victims who experience sudden cardiopulmonary collapse. Induction of hypothermia after restoration of circulation improves neurological recovery and is being advanced clinically. However, mild hypothermia does not completely reverse brain injury and a rational approach to improve this intervention is required. This project will employ a rat model of cardiac arrest that mimics the whole-brain injury, and that replicates the beneficial effects of post-resuscitation hypothermia. Preliminary studies indicate that hypothermia increases intracellular signaling in the brain via the extracellular signal regulated kinase, ERK (a mitogen activated protein kinase), and also increases brain tissue levels of brainderived neurotrophic factor (BDNF). The time course of ERK and BDNF activation as well as the time window during which induction of hypothermia is beneficial suggest that induced hypothermia may affect new gene expression via these signaling systems. This proposal will expand our understanding of the beneficial effects of induced hypothermia and the by examining the relationship between BDNF, ERK and new gene expression in brain after cardiac arrest and resuscitation. This project will be divided into three specific aims: (1) The first aim will determine the role of neurotrophic factors in the control of ERK signaling after resuscitation and hypothermia. To accomplish this aim, we will employ neutralizing antibodies or antisense oligonucleotides or administration of exogenous neurotrophic factors after ischemia and hypothermic reperfusion. We will determine the localization and time-course of increased levels of particular neurotrophic factors in brain during hypothermic reperfusion. (2) The second aim will be to determine the participation of the downstream effectors of the ERK signaling pathway after resuscitation and hypothermia. We hypothesize that hypothermic reperfusion will increase activation of ERK-regulated transcription factors and expression of particular ERK-regulated gene products. Conversely, blockade of ERK
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activation is hypothesized to decrease expression of these same genes. (3) The final aim of the project will determine the participation of ERK and BDNF signaling in the hypothermia-induced improvement of neuronal survival and behavioral recovery after resuscitation. These pathways will be blocked and stimulated during hypothermic reperfusion, and behavioral and histological outcome for cardiac arrest will be measured. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HYPOTHERMIA DURING INTRACRANIAL ANEURYSM SURGERY Principal Investigator & Institution: Todd, Michael M.; Anesthesia; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2001; Project Start 05-SEP-1999; Project End 31-MAY-2004 Summary: Aneurysmal subarachnoid hemorrhage (SAH) remains a major cause of morbidity and mortality. Since the incidence peaks in mid-life, and since many survivors are permanently damaged, the human and economic costs are immense. Much of the death and disability is the acute and delayed result of blood in the subarachnoid space (e.g. vasospasm). However, an unknown - but we believe substantial - fraction of the adverse outcomes are a complication of surgery performed to obliterate the source of bleeding; as many as 25 percent of patients who undergo craniotomy for aneurysm clipping will have a new neurologic deficit when examined 12-24hrs postoperatively. This danger is well known, and almost all surgical teams utilize some method to protect patients during surgery, including barbiturates, etomidate, steroids, mannitol or varying degrees of hypothermia. Unfortunately, in spite of the popularity of such interventions, none has ever been systematically tested in humans (other than deep hypothermia and circulatory arrest), and none are known to provide any benefit at all. Of the aforementioned therapies, we believe the best laboratory evidence supports the use of hypothermia. Our goal, therefore, is to perform a prospective, randomized clinical trial to evaluate the safety and efficacy of intraoperative hypothermia (t=33 degrees C) as a means of reducing early and longterm postoperative neurologic morbidity following surgery for clipping of intracranial aneurysm. Control patients will remain normothermic during and after surgery; in hypothermic patients, body temperature will be normalized as quickly as possible after the aneurysm clip is in place. All other aspects of pre- and postoperative care will be managed routinely. We hypothesize that hypothermia, even when limited to the intraoperative period, will result in an improvement in neurologic outcome as measured by Glasgow Outcome Scale at 3months following surgery, and will also result in more rapid improvement during the first postoperative week. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HYPOTHERMIA FOR ACUTE BRAIN INJURY IN CHILDREN Principal Investigator & Institution: Cox, Charles S.; Surgery; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2003; Project Start 08-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): The Traumatic Brain Injury (TBI) Consortium at the University of Texas-Houston Medical School has a major commitment to multicenter clinical investigation. The PI, Charles Cox, M.D., is the Children's Fund for Pediatric Trauma Associate Professor of Surgery and Pediatrics and the Co-PI, Kevin Lally, M.D., the A.G. McNeese Professor and Chief of Pediatric Surgery. The TBI consortium has a track record for identifying and recruiting TBI patients for clinical studies across
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multiple points of care. The PI and Co-PI are board certified in both pediatric surgery and surgical critical care, which allows control of the acute care management of TBI patients. The group also includes a nationally recognized inpatient and outpatient rehabilitation center (The Institute for Rehabilitation and Research, TIRR). TIRR admits approximately 750 patients per year and has a 36-bed inpatient brain injury unit. TIRR also has a track record of NIH/NIDRR funded clinical research involving TBI patients. Post-rehabilitation outcomes follow-up is an established and mature component of the TBI component with outcome studies since 1982. Longitudinal studies of children with TBI are now in their 5th-9th year. UT-Houston provides: (A) A large patient population Approximately 4,500 patients are admitted to the UT-Houston/Memorial Hermann Trauma Service per year (958 with a GCS of < 12), of which 1,400 are pediatric patients (167 with a GCS 1 degree C every 2 minutes) during cardiac arrest with only chest compression to produce circulation, far superior to any external cooling techniques. Moreover, adverse effects of 30 minutes exposure to perfluorocarbon slurry instilled into the lungs of normal animals (not in cardiac arrest) were mild and improved with time. Animals survived unassisted for 48 hours with A-a gradients not significantly different from controls. Thus, creating an optimal cooling method with minimal adverse effects appears a realistic goal. Specific aims and milestones include: (i) bioengineering and developing two microparticulate slurries for pulmonary and intravenous use, (ii) using these slurries to optimize "intraarrest" cooling rates of the heart and brain of animals during cardiac arrest, (iii) describing and minimizing adverse effects of slurries, and finally (iv) testing whether slurry cooling to 2 different levels of intra-arrest low-flow cooling will improve survival in a swine model of cardiac arrest. Unlike any existing method, paramedics could use this cooling method after failed defibrillation in efforts to delay additional heart and brain damage until full reperfusion can occur. An international advisory committee of noted resuscitation experts will advise the project and many wish to test the slurries in
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their home laboratories after completion of these aims, increasing the potential impact of this work. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OUTCOME OF THERAPEUTIC HYPOTHERMIA IN PEDIATRIC ARREST Principal Investigator & Institution: Zaritsky, Arno L.; Health Services Administration; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005 Summary: (provided by the applicant): There are many important unanswered questions regarding the best methods to improve outcome in infants and children following cardiopulmonary arrest (CPA). There is also a need to identify reliable indicators of poor outcome/vegetative state in CPA survivors to help families make informed decisions and reduce potential life-long burdens on the family and healthcare system. The primary aim of this clinical trial planning grant is to organize an effective research team and develop the elements essential for conducting successful clinical trials of pediatric CPA. This planning grant will develop a clinical trial to assess (1) the effect of early mild therapeutic hypothermia on survival and functional outcome following pediatric CPA; (2) identify early clinical signs and biomarkers associated with survival and various degrees of functional outcome following CPA; and (3) establish the changes in functional outcome over time in children following CPA using more precise outcome measurement tools than previously employed. The latter goal will establish the basis for subsequent trials evaluating the effectiveness of different rehabilitative interventions on ultimate outcome. This planning grant will (1) identify additional collaborators, (2a) develop the experimental design and (2b) intervention protocols including treatment protocols for managing the patient following CPA, (3) select and establish neurological, biomarker, comorbid and functional outcome measurement data elements and tools, (4a) determine the effect size and power needed for clinically meaningful results and (4b) establish an analysis plan including a safety monitoring board, (5) develop a data coordination/management team, (6) assess the feasibility of subject recruitment strategies, (7a) identify the obstacles to conducting a randomized intervention trial waiving informed consent and (7b) determine the requirements that sites need to meet, (8) select study exclusion and inclusion criteria, (9) develop a training program to assure that the treatment intervention and overall patient care is replicated across sites, (10) select sites for the hypothermia randomized controlled trial (RCT) and obtain Institutional Review Board approval, and (11) develop administrative operations to manage the RCT. The long-term objective is to utilize the clinical trial network to conduct additional trials so as to advance the science of pediatric resuscitation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: OXIDATION CHEMISTRY OF INDOLES Principal Investigator & Institution: Dryhurst, Glenn; Professor and Chairman; Chemistry and Biochemistry; University of Oklahoma Norman Office of Research Services Norman, Ok 73019 Timing: Fiscal Year 2001; Project Start 15-SEP-1983; Project End 31-AUG-2003 Summary: (Adapted From The Applicant's Abstract): The goal of this project is to contribute to an understanding of the chemical and biochemical mechanisms that underlie the dopaminergic and/or serotonergic neurotoxicity of methamphetamine (MA) and 3,4-methylenedioxymethampetamine (MDMA). The project is based on the
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hypothesis that glutathione (GSH), released from both neurons and glia, and extracellular conditions that influence the activity of gamma-glutamyl transpeptidase (g-GT), are key factors in MA- and MDMA-induced neurotoxicity. It is proposed that extracellular conditions evoked by a MA-induced neuronal energy impairment, notably excessive HO* generation, cause upregulation of g-GT and hydrolysis of GSH to glutamate (Glu), glycine (Gly) and cysteine (CySH). Dopaminergic neuronal damage evoked by MA in the rat is proposed to be dependent on the intraneuronal oxidation of DA by O2-*, generated by NMDA receptor activation by elevated extracellular Glu, in the presence of translocated CySH forming dihydrobenzothiazine (DHBT) and benzothiazine (BT) mitochondrial (mt) toxicants. Similarly, serotonergic neuronal damage may be caused by intraneuronal oxidation of 5-HT by O-2-* in the presence of translocated CySH to give endotoxic metabolites. Mechanisms are proposed by which MDMA, because of its HO* scavenging properties, inhibits g-GT and hence hydrolysis of released GSH. Thus, not only is Glu-mediated NMDA receptor activation and intraneuronal O-2-* generation attenuated, CySH, essential for DHBT/BT formation, is not available and DA neurons are spared. In contrast, the O-2-* mediated oxidation of 5HT generates tryptamine-4,5-dione that in the absence of CySH inhibits mt enzymes and, hence, MDMA evokes selective serotonergic neurotoxicity. Specific aims are to: (1) monitor extracellular changes of DA, 5-HT and their metabolites, thiols/disulfides, and Glu, Asp and Gly in rat brain in response to MA and MDMA using microdialysis; (2) search for unusual products of oxidation of extracellular DA/5-HT/metabolites by HO* that might contribute to MA/MDMA toxicity, also using microdialysis; (3) study the influence of hypothermia, astroglial ablation, and the glucose metabolism inhibitor 2deoxy-D-glucose, on MA/MDMA-induced extracellular neurochemical changes; (4) investigate the effects of MA/MDMA on brain thiol/disulfide concentrations and g-GT activity; (5) study the effects of g-GT inhibition, manipulations of brain GSH, 5-Scysteinyldopamine (DHBT/BT precursor), and glial ablation on MA/MDMA-induced neurotoxicity; (6) analyze brain tissue for evidence of putative endotoxic metabolites and covalently modified proteins; (7) study interactions of putative endotoxins with mt and other enzymes; (8) assay rat brain for activities of mt and other enzymes, following MA/MDMA administration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHASE II TRIAL OF HYPOTHERMIA FLUOROURACIL/DOXORUBICIN IN MALIGNANCY
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Principal Investigator & Institution: Bull, Joan M.; Director of the Division of Oncology; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROTON MAGNETIC RESONANCE SPECTROSCOPY OF ACUTE TBI Principal Investigator & Institution: Hillary, Frank G.; Kessler Medical Rehab Res & Educ Corp Research & Education Corp. West Orange, Nj 07052 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2004 Summary: (provided by applicant): Each year 230,000 people are hospitalized and survive moderate and severe traumatic brain injury (TBI). As a result, a large number of individuals with TBI endure life-long impairment and disability. Acute rating scales
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such as the Glasgow Coma Scale (GCS) have shown limited predictive validity regarding patient outcome and traditional neuroimaging techniques such as CT and MRI maintain limited correlations with brain injury severity and cognitive functioning. Continued advances in neuroimaging, however, have provided researchers with an important opportunity to study the pathophysiology of brain dysfunction following TBI. According to the NCMRR, "the neurobiology of TBI in humans should be studied with modern imaging techniques". The purpose of this study is to correlate proton magnetic resonance spectroscopy (MRS), an advanced neuroimaging technique, with behavioral measures of TBI severity and cognitive outcome. MRS measures the concentration of cerebral metabolites such as N-acetylaspartate (NAA), choline (Cho), and glutamate (Glu). While MRS has shown promise in predicting brain injury severity and patient outcome, the exact protocols for using MRS with TBI remain undetermined and the purpose of the proposed study is to examine three critical areas: (1) the post-injury time period when the MRS data should be acquired (e.g., within one week or within one month of injury); (2) how metabolites should be measured (i.e., absolute concentrations or changes in concentration over time); and (3) the brain locations best suited for MRS data acquisition (i.e., acquisition near lesion sites or acquisition at sites remote from probable brain lesion). The proposed study will make determinations in these three areas through the use of two acute MRS scans following TBI to measure concentrations of NAA, Cho and Glu and their correlation with injury severity and cognitive variables. In addition, correlation of acute MRS data with behavioral data (e.g., duration of loss of consciousness, duration of post-traumatic amnesia) will elucidate the relationship between changes in brain metabolism and changes in patient behavior during acute recovery from TBI. The present proposal will employ a promising, noninvasive neuroimaging technique, MRS, to determine the most appropriate protocols (i.e., timing, metabolic measurement, brain location for data acquisition) for application of MRS to acute TBI. With an established protocol for using MRS, this instrument should prove useful for determining the effectiveness of acute interventions (e.g. hypothermia, pharmacologic intervention) and for predicting the acute course of patient recovery. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: QTL MAPPING FOR ETOH HYPOTHERMIA AND LOCOMOTER ACTIVITY Principal Investigator & Institution: Belknap, John K.; Professor; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2001; Project Start 20-DEC-1995; Project End 31-DEC-2005 Summary: This Component 4 presents the continuation of the QTL mapping efforts of the QTL mapping efforts of Component 7 of our present Center grant. In the renewal, we propose to use populations derived from two presently existing long-term selectively-bred-lines the FAST and SLOW lines bred for increased and reduced sensitivity to ethanol-induced locomotor activation, respectively, and the HOT and COLD lines bred for minimal or severe ethanol-induced hypothermia (body temperature loss). Both projects were developed beginning with an HS foundation population, which in turn was derived from an eight-way cross of inbred strains. [Continued studies of the third long-term selection project, WSP/WSR, are now part of an RO1 application in preparation (PI: K.Buck)]. Because of the markedly different gene pools in our HS-compared to our B6-, D2- derived populations, we expect most unique QTLs to emerged in this Component for these traits. In the first four years of Center support, a full genome scan was carried out as part of present Component 7 in the search for QTLs influencing both acute ethanol-induced hypothermia (HOTxCOLD F2)
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and chronic ethanol withdrawal severity (WSPxWSR F2). The third mapping project involving locomotor activation (FASTxSLOW F2) will be finished in the final year of our present support. Thus far, 8 suggestive (P
