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

TRIGLYCERIDES A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES J AMES...

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

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

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

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Triglycerides: 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: 0-597-84104-7 1. Triglycerides-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on triglycerides. 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 TRIGLYCERIDES ......................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Triglycerides ................................................................................. 4 E-Journals: PubMed Central ....................................................................................................... 62 The National Library of Medicine: PubMed ................................................................................ 64 CHAPTER 2. NUTRITION AND TRIGLYCERIDES ............................................................................... 81 Overview...................................................................................................................................... 81 Finding Nutrition Studies on Triglycerides ................................................................................ 81 Federal Resources on Nutrition ................................................................................................... 85 Additional Web Resources ........................................................................................................... 85 CHAPTER 3. ALTERNATIVE MEDICINE AND TRIGLYCERIDES ......................................................... 91 Overview...................................................................................................................................... 91 National Center for Complementary and Alternative Medicine.................................................. 91 Additional Web Resources ........................................................................................................... 96 General References ..................................................................................................................... 103 CHAPTER 4. DISSERTATIONS ON TRIGLYCERIDES ......................................................................... 105 Overview.................................................................................................................................... 105 Dissertations on Triglycerides ................................................................................................... 105 Keeping Current ........................................................................................................................ 106 CHAPTER 5. CLINICAL TRIALS AND TRIGLYCERIDES ................................................................... 107 Overview.................................................................................................................................... 107 Recent Trials on Triglycerides ................................................................................................... 107 Keeping Current on Clinical Trials ........................................................................................... 109 CHAPTER 6. PATENTS ON TRIGLYCERIDES.................................................................................... 111 Overview.................................................................................................................................... 111 Patents on Triglycerides ............................................................................................................ 111 Patent Applications on Triglycerides......................................................................................... 139 Keeping Current ........................................................................................................................ 175 CHAPTER 7. BOOKS ON TRIGLYCERIDES ....................................................................................... 177 Overview.................................................................................................................................... 177 Book Summaries: Federal Agencies............................................................................................ 177 Book Summaries: Online Booksellers......................................................................................... 178 The National Library of Medicine Book Index ........................................................................... 179 Chapters on Triglycerides .......................................................................................................... 180 CHAPTER 8. MULTIMEDIA ON TRIGLYCERIDES ............................................................................ 187 Overview.................................................................................................................................... 187 Bibliography: Multimedia on Triglycerides ............................................................................... 187 CHAPTER 9. PERIODICALS AND NEWS ON TRIGLYCERIDES ......................................................... 189 Overview.................................................................................................................................... 189 News Services and Press Releases.............................................................................................. 189 Newsletter Articles .................................................................................................................... 191 Academic Periodicals covering Triglycerides............................................................................. 191 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 193 Overview.................................................................................................................................... 193 U.S. Pharmacopeia..................................................................................................................... 193 Commercial Databases ............................................................................................................... 194 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 199 Overview.................................................................................................................................... 199 NIH Guidelines.......................................................................................................................... 199

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NIH Databases........................................................................................................................... 201 Other Commercial Databases..................................................................................................... 203 The Genome Project and Triglycerides ...................................................................................... 203 APPENDIX B. PATIENT RESOURCES ............................................................................................... 207 Overview.................................................................................................................................... 207 Patient Guideline Sources.......................................................................................................... 207 Finding Associations.................................................................................................................. 209 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 211 Overview.................................................................................................................................... 211 Preparation................................................................................................................................. 211 Finding a Local Medical Library................................................................................................ 211 Medical Libraries in the U.S. and Canada ................................................................................. 211 ONLINE GLOSSARIES................................................................................................................ 217 Online Dictionary Directories ................................................................................................... 218 TRIGLYCERIDES DICTIONARY .............................................................................................. 221 INDEX .............................................................................................................................................. 307

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

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

Why Are Triglycerides So Important? Source: Diabetes Self-Management. 12(6): 31-32, 34. November-December 1995. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (800) 234-0923. Summary: The author covers triglycerides and stresses their importance in determining risk of heart disease. Topics include noninsulin-dependent diabetes mellitus (NIDDM) and heart disease; how heart disease develops; why triglycerides are so important; treating lipid abnormalities; lipid-lowering medications, including bile-acid sequestrants, nicotinic acid, fibrates, and HMG CoA reductase inhibitors; and reducing the risk of heart attacks. The author stresses that knowing one's total cholesterol level is

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not enough; learning one's triglyceride level and correcting it if it is high can lessen one's risk of heart disease.

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

Project Title: ALTERNATIVE THERAPIES FOR MENOPAUSE: A RANDOMIZED TRIAL Principal Investigator & Institution: Newton, Katherine M.; Associate Investigator; Center for Health Studies Seattle, Wa 98101 Timing: Fiscal Year 2002; Project Start 01-JUL-2000; Project End 30-NOV-2004 Summary: (Adapted from Investigator's Abstract) Hormone replacement therapy (HRT: estrogen and progestin) remains the treatment of choice for women with vasomotor symptoms, and long-term HRT has been recommended for prevention purposes. The demand for alternatives to HRT, and the availability and use of over-the-counter products including dietary phytoestrogen supplements and naturopathic medicines, has grown dramatically. Few of these products have faced the rigors of randomized trials and none have been tested to evaluate their effects on long-term outcomes. The purpose of this four-year randomized controlled trial is to evaluate the efficacy and safety of three alternative approaches utilizing phytoestrogens to treat vasomotor symptoms in peri- and postmenopausal women. The treatments were chosen because of the scientific evidence supporting a possible benefit, the availability of products with adequate quality control their frequency of use in naturopathic medicine, and our ability to blind participants to the intervention. The five proposed treatment arms are as follow: 1) esterified estrogen and micronized progesterone: 9) a single herbal product, black cohosh; 3) a multibotanical preparation; 4) a combination regimen that includes the same multibotanical preparation plus soy diet counseling; and 5) placebo. The primary aim is to compare the effects of three alternative treatments, HRT, and placebo on the frequency and intensity of vasomotor symptoms measured by The Wiklund Menopause Symptom Checklist and a daily Vasomotor Symptom Diary. The secondary aims are to compare the effects of three alternative treatments, HRT, and placebo on the following:

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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1) vaginal cytology (vaginal maturation index); 2) serum lipids (total cholesterol, HDL and LDL cholesterol, triglycerides); 3) bone mineral density (hip and spine dual energy x-ray absorptiometry scan); 4) glucose metabolism (insulin, fasting blood glucose); and 5) coagulation factors (fibrinogen, PAI-1). The hypotheses are that compared to placebo the three alternative treatments tested in this study will have the following effects: reduce frequency of hot flashes and night sweats, improve vaginal maturation and decrease vagina atrophy as measured by maturation index, lower total cholesterol and LDL with no effect on HDL, reduce the rate of decline in bone mineral density (BMD), and have no effect on glucose metabolism or clotting factors. To accomplish the specific aims the investigators propose to do the following: 1) recruit and randomize 400 periand post-menopausal women to one of five treatment arms for one year; 2) collect measurements of primary and secondary outcomes at baseline, three, six, and 12 months; and 3) compare changes in outcomes in the groups taking alternative treatments to those in the HRT and placebo groups. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANALYSIS OF SEX HORMONES AND LIPOPROTEINS IN YOUNG MALES Principal Investigator & Institution: Barton, Bruce A.; Senior Statistician and Vice President; Maryland Medical Research Institute, Inc 600 Wyndhurst Ave Baltimore, Md 21210 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: (Provided by Applicant) This application requests support for secondary analysis of the Sex Hormones and Lipoproteins in Adolescent Males Study (HD/HL18281), a 3-year (1984-1987) study of lipids, blood pressure, weight, fat patterning, and sex steroid hormones (SSH) in adolescent males. A total of 664 black and white males, ages 10-15, were enrolled into a study designed as a series of repeated data collections over 2 years within age cohorts. Cross-sectional analyses have been used to explain differences during adolescence in SSH and SSH-lipid relationships between black and white boys and between boys with and without a family history of CHD. When the data were originally collected for this study, theoretical models of flexible longitudinal analytic techniques had been developed, but were not available for computer use. These techniques, now supported by software, allow a more powerful and complete analysis of these data. The primary aim of these analyses is to explicate the contribution of changes in SSH and fat patterning to changes in plasma concentrations of high (HDL-C) and low (LDL-C) density lipoprotein cholesterol, triglycerides (TG), and apolipoproteins (apo) Al, All, and B occurring during puberty in males. SSH assayed included estradiol (E2) and free testosterone (T). We will test the following hypotheses: (1) increasing free T predicts/leads to decreases in HDL-C and increases in LDL-C, apo B, and the LDL-C/HDL-C ratio in adolescent males; (2) increasing E2 predicts decreases in apo B, LDL-C and the LDL-C/HDL- C ratio, but the resultant effects will vary with adiposity and fat patterning; (3) rapid weight gain predicts increased central adiposity, defined as the ratio of truncal skinfolds to total skinfolds, and with greater decreases in HDL-C and increases in triglycerides, apo B, LDL-C and the LDL- C/HDL-C ratio. Rapid weight gain predicts increased E2, but the atherogenic effects of increased central adiposity on lipids are greater than the antiatherogenic effects of E2. These analyses will provide a better understanding of metabolic factors underlying obesity-hormone-lipoprotein relationships. Given the welldocumented increase in obesity in American youth, these analyses are especially pertinent and address important public health issues.

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

Project Title: ANCILLARY STUDY DATA ANALYSIS IN VA-HIT Principal Investigator & Institution: Rubins, Hanna; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2003 Summary: The VA HDL Intervention trial (VA-HIT) was a multicenter, placebo controlled, randomized trial that showed that gemfibrozil significantly reduced major cardiovascular events in 2531 men with coronary heart disease, low levels of low density lipoprotein (LDL) cholesterol and low levels of high density lipoprotein (HDL) cholesterol. In addition to its unique lipid profile, the VA-HIT population also had a high prevalence of diabetes, impaired fasting glucose, or high fasting plasma insulin; central obesity; and hypertension, which are all components (together with high triglycerides and low ILL-cholesterol) of a constellation of risk factors known as the metabolic syndrome. Since prior clinical trials have not enrolled this type of population, the VA- HIT database is a unique resource. The purpose of the present proposal is to use this database to study additional risk markers that were measured in the study population. Specific proposed analyses are: 1. An analysis of the association between levels of glucose tolerance, insulin resistance and other features of the metabolic syndrome, occurrence of major cardiovascular outcomes, and gemfibrozil efficacy. 2. An analysis of the effect of gemfibrozil on progression of carotid atherosclerosis, as measured by B-mode ultrasound. 3. An analysis of the association between LDL particle size distribution and lipoprotein subclass distribution; homocysteine; lipoprotein(a); Creactive protein, tissue plasminogen activator; fibrinogen; and factor VII; major cardiovascular outcomes, and gemfibrozil efficacy. Written documentation that the data will be available to us is included in the letter from Dr. Peter Peduzzi of the VA Cooperative Studies Program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANIMAL MODELS OF DIABETIC VASCULAR DISEASE Principal Investigator & Institution: Breslow, Jan L.; Professor; Lab/Biomed Genetic/Metabolism; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: Since the mayor cause of morbidity and mortality in diabetics is macrovascular disease, we propose creating mouse models in which diabetes worsens macrovascular disease. These models will be of great use for studies of pathophysiology and to design new therapies. To produce such models, we have assembled a multidisciplinary team with expertise in mouse models of diabetes and dyslipidemia and in the evaluation of atherosclerosis progression, atherosclerosis regression/remodeling and injury/restenosis. We propose modern genetic approaches to generate diabetic mouse models in which hyperglycemia can be induced by compromising pancreatic (beta-cell function. This will be accomplished through the conditional expression of dominant-negative mutant forms of HNF-1 alpha or HNF-4 alpha or through the inactivation of HNF-1 beta using beta-cell specific promoters and inducible recombinases in transgenic mice. Mice in which hyperglycemia can be induced will be crossed with genetically manipulated mice that have defects of insulin resistance and /or obesity. This aim, in a novel way, will establish diabetic animal models that recapitulate the clinical history of the most common form of diabetes, type II, which is characterized by a variable period of insulin resistance/obesity (pre-diabetic

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state) followed by P-cell decompensation and the development of overt diabetes. A second challenge will be to mimic in the mouse the diabetic dyslipidemia phenotype, which is characterized by increased triglycerides, small dense LDL and decreased HDL cholesterol. Since we have already shown that this is insufficient to cause atherosclerosis in the mouse, we will also breed in traits to raise the levels of LDL cholesterol. To accomplish this we will use human apo CIII and cholesterol ester transfer, protein transgenes and either the human apo B transgene or the LDL receptor knockout trait. Our strategy will be to cross diabetic models with the diabetic dyslipidemia models to establish new models in which diabetes worsens macrovascular disease, as measured by atherosclerosis progression, regression/remodeling, and/or injury/restenosis. We will then use new genetic technology to combine the various required alleles to make a diabetogenic- macrovascular disease model that is easy to breed and transfer to other investigators. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIBODIES TO LIPOPROTEIN LIPASE AND ATHEROSCLEROSIS Principal Investigator & Institution: Reichlin, Morris; Vice President of Research; Oklahoma Medical Research Foundation Oklahoma City, Ok 73104 Timing: Fiscal Year 2002; Project Start 05-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Premature atherosclerosis in patients with Systemic Lupus Erythematosus (SLE) has been recognized for the past 25 years. As much as a 50fold increase in risk for coronary artery disease has been found in SLE patients compared to controls and an increased risk for thrombotic cerebrovascular disease has also been recognized. In the past decade lipid abnormalities have been recognized in SLE patients that are "proatherogenic". These include elevated LDL cholesterol, low HDL cholesterol and elevated triglyceride levels that are not due to nephrotic syndrome. Careful clinical studies suggest that conventional risk factors such as age, sex, smoking, hypertension, etc., do not completely account for the prevalence of premature atherosclerosis. Indeed, there appears to be an element of risk conferred by the lupus process itself We postulate that this mechanism of the SLE associated risk lies in autoimmune events that perturb lipid homeostasis in the direction of elevated triglycerides and cholesterol. We further suggest that part of this effect is due to an immune response to lipoprotein lipase which occurs in 50% of SLE patients and promotes hypertriglyceridemia. In addition, autoantibodies to apolipoprotein A-1, Apo B and Apo E may perturb lipid transport and promote decreased HDL cholesterol and increased LDL cholesterol. Our plan is to combine our expertise in autoantibody research with epidemiologic methods. We will conduct a prospective study of SLE patients and their matched controls to evaluate these immune responses on lipid levels, in the presence of conventional risk factors and confounders, and their association with premature atherosclerosis. Recognition of autoimmune mechanisms that promote elevated triglycerides could lead to specific interventions as therapy or even possibly prevention of premature atherosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: APOE IN CHOLESTEROL AND TRIGLYCERIDE HOMEOSTASIS Principal Investigator & Institution: Zannis, Vassilis I.; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2005

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Summary: (provided by applicant): Apolipoprotein E (apoE) is an important protein of the cholesterol transport system. ApoE is responsible for the clearance of lipoprotein remnants from the circulation via lipoprotein receptors, contributes to cholesterol homeostasis, and protects from atherosclerosis. ApoE has also been shown to have other functions which contribute to cholesterol and triglyceride homeostasis, including VLDL triglyceride secretion and VLDL lipolysis, two processes which may affect plasma triglyceride levels. It is our hypothesis, which is supported by preliminary data, that the carboxy terminal domain of apoE is responsible for the hypertriglyceridemia which is induced by overexpression of apoE. We also hypothesize that overexpression of carboxy terminal apoE variants may protect from atherosclerosis. Our specific aims are: 1) To use adenovirus-mediated gene transfer as well as transgenic mice to elucidate the role of apoE in triglyceride homeostasis and establish the mechanism of apoE-induced hypertriglyceridemia in vivo. 2) To use adenovirus-mediated gene transfer of different apoE forms (in appropriate receptor-deficient mouse models) to elucidate the role of apoE receptors in cholesterol clearance in vivo and in vitro. The mouse models that will be utilized for gene transfer are apoE-/-, LDLR-/-, liver-specific LRP-/- mice as well as crosses among these The gene transfer and receptor binding studies will define the ligand speciflcities for different receptors. 3) To express long-term apoE forms that do not induce hypertriglyceridemia using adenoassociated viral vectors (AAV-apoE) and transgenic mice in order to correct the hypercholesterolemic and atherogenic profile of apoE-deficient mice. This specific aim will explore the ability of selected truncated and mutant forms of apoE that do not induce hypertriglyceridemia to protect from atherosclerosis. We expect that apoE forms that can clear cholesterol and triglycerides and protect from atherosclerosis may provide new therapeutic tools in the near future for the correction of remnant removal disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ARCH PLAQUES AND STROKE IN AN ETHNICALLY MIXED COMMUNITY Principal Investigator & Institution: Di Tullio, Marco R.; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 01-JUN-1997; Project End 31-MAY-2003 Summary: (Adapted from Applicant's Abstract). Atherosclerotic plaques (atheromas) in the aortic arch are considered a potential cause for ischemic stroke in the elderly. The impact of arch atheromas in different racial-ethnic groups is unknown. Moreover, the association of arch atheromas with lipid disorders or hypercoagulability, that may enhance their embolic potential, has not been investigated. A population-based, casecontrol study is proposed to address the following Specific Aims: 1) to determine if aortic arch atheromas are a risk factor for ischemic stroke in the elderly, and their importance in different racial-ethnic subgroups; and 2) to determine if aortic arch atheromas are associated with lipid abnormalities or hypercoagulable states in elderly stroke patients. Secondary Aims will be to evaluate the 4-year stroke recurrence risk in patients with and without atheromas in the overall group and by racial-ethnic subgroups, and the additional risk associated with morphological characteristics of the atheroma (presence of ulcerations or mobile components). A total of 300 cases of ischemic stroke and 300 stroke-free controls, matched by age, gender and race will be enrolled in this 5-year population-based case-control study. Study subjects will be drawn from the ongoing Northern Manhattan Stroke Study (NoMaSS), which will assure recruitment and provide other data collection. The presence of arch atheromas will be ascertained by transesophageal echocardiography. Lipid tests will include total

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cholesterol, triglycerides, HDL and LDL cholesterol, lipoprotein (a), apolipoproteins A-I and B. Hypercoagulability tests will include fibrinogen, prothrombin fragment F1+2 and lupus anticoagulant. Annual telephone follow-up will be performed on cases and controls to ascertain mortality and stroke. Conditional logistic regression will be used to calculate the adjusted odds ratio for stroke of aortic arch atheromas in the overall study group and stratified by racial-ethnic subgroups. The study will provide important data on stroke pathophysiology and set the ground for clinical trials to assess the efficacy of therapeutic options in treating elderly patients with stroke and aortic arch atheromas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ASSEMBLY LIPOPROTEINS

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APO

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CONTAINING

Principal Investigator & Institution: Ginsberg, Henry N.; Professor; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 01-AUG-1996; Project End 31-JUL-2006 Summary: (provided by applicant): Apolipoprotein B, the major apolipoprotein on atherogenic VLDL and LDL, is essential for the assembly and secretion of these lipoproteins by human livers. Studies in cultured liver cells have provided important insights related to the unique regulation of apoB, including its inefficient translocation, its bitopic topology across the endoplasmic reticulum (ER) membrane, its degradation by the cytosolic proteasome, and some of the characteristics of its association with its lipid ligands to become a lipoprotein. However, several critical aspects of the regulation of the assembly and secretion of apoB-lipoproteins remain undefined. In the proposed studies, we will continue to use cultured hepatocyte cell-lines, particularly HepG2 and McARH7777 cells, to address unanswered questions. We will, however, extend our investigations to include studies using primary mouse hepatocytes as well as in vivo measurements of apoB-lipoprotein secretion in adenovirus-infected, transgenic, and "knockout" mouse models. Four hypotheses will be tested: Hypothesis A: The complex secondary structure of apoB, and in particular the presence of one or more densely hydrophobic b-sheet domains, is the basis for the unique aspects of its translocation across the ER and its predisposition for ubiquitination and proteasomal degradation. Hypothesis B: Newly synthesized core lipids, triglycerides (TG) and cholesteryl esters (CE) are both critical for the efficient initial translocation of apoB across the ER and its targeting for lipoprotein assembly. However, TG is the sole lipid added at the later stages of lipoprotein assembly ("the second step"). Hypothesis C: The transition of apoB from a lipid-poor lipoprotein to a TG-enriched lipoprotein that is targeted for secretion includes the completion of translation and translocation, and transport of the lipid-poor particle to either the ER Golgi Intermediate Compartment (ERGIC) or the Golgi apparatus. It is at one of these two sites that bulk lipid addition (the second step) occurs. Importantly, this trafficking can be regulated by a variety of mechanisms distinct from core-lipid synthesis. Hypothesis D: Fatty acid flux to the liver is the major determinant of the assembly and secretion of apoB-lipoproteins. The impact of fatty acid flux on apoB-lipoprotein secretion may be modulated by the status of insulin signaling in the liver, but the latter plays only a minor role in the overall regulation of apoB-lipoprotein secretion. We believe that completion of these studies will provide the basis for new and innovative approaches to the treatment of human dyslipidemias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BEHAVIORAL FACTORS AND DIETARY CHANGE IN WHTFSMP Principal Investigator & Institution: Bhargava, Alok; Professor; Economics; University of Houston 4800 Calhoun Rd Houston, Tx 77004 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): The primary purpose of the research in this project is to specify and estimate models for dietary intakes of the subjects in the Women's Health Trial: Feasibility Study in Minority Populations (WHTFSMP) taking into account the behavioral factors emphasized in the Social Learning Theory and the Health Belief Model. The comprehensive analysis will incorporate the socioeconomic factors such as education and income, and the physiological aspects such as anthropometric indicators and the current energy intakes that reflect the subjects' energy requirements. In addition, the theories of "habit persistence" in diets from the economics literature will be incorporated in the modeling framework. The subjects in the Intervention group of the WHTFSMP received counseling for adopting diets that were low in fat and high in fruits and vegetables. The research will analyze the proximate determinants of the intakes of carbohydrate, saturated, monounsaturated, and polyunsaturated fats, fiber, calcium, acarotene and ascorbic acid using the data at baseline, six and 12 months from the Control and Intervention groups of the WHTFSMP. The second objective of the research is to estimate dynamic random effects models for the subjects' risk factors for coronary disease and cancer such as plasma LDL and HDL cholesterol, triglycerides, and glucose levels. Behavioral factors, anthropometric indicators, energy derived from saturated and polyunsaturated fats, and dietary cholesterol will be explanatory variables in models for plasma LDL cholesterol. The dynamic model is suitable for plasma cholesterol since 50% of cholesterol is endogenously produced. The comprehensive analysis of the data from the WHTFSMP will be useful for refining educational programs that seek to promote healthful eating. In particular, the incorporation of the various behavioral factors in the analyses of dietary intakes will identify strategies of targeting women who are at greater risk of chronic disease but are less likely to change their behavior and would benefit from enrollment in nutrition education programs. The results from the empirical models for plasma LDL, HDL, triglycerides and glucose will be useful for identifying strategies for lowering the subjects' risks for cardiovascular disease and cancers. Overall, the results will facilitate the design of policies for improving health of especially minority women in the United States and will be useful for analyses of the Women's Health Initiative data. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOLOGY OF 12-LIPOXYGENASE ISOZYMES Principal Investigator & Institution: Funk, Colin D.; Professor of Pharmacology; Pharmacology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: Atherosclerosis, chronic inflammatory process progressing from fatty lesions to fibrous and unstable plaques, is the major underlying factor in most cases of coronary heart disease. Clinical disease as a result of atherosclerotic disease remains as the leading determinant for the extensive mortality and morbidity. and exorbitant health care costs in our society. The "LDL oxidation" hypothesis has gained general acceptance as a leading player in atherogenesis and it is recognized that oxidized LDL exhibits many pro-atherogenic properties. properties. The factors that initiate LDL, oxidating in vivo are poorly understood. However, circumstantial evidence has placed the 12/15lipoxygenase in the context of atherosclerosis. Thus, in the first specific aim, the role of

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12/15- lipoxygenase in mouse models of atherosclerosis (apoB editing catalytic polypeptide-1 (apobec-1)/LDL-receptor deficient and apoE deficient) will be assessed by quantitating lesion development throughout the aorta by the "en face" method using appropriately crossbred 12/15-lipoxygenase deficient mice. The combined effects of the anti-oxidant vitamin E with 12/15-lipooxygenase deficiency will also be examined. Total cholesterol, triglycerides, lipoprotein profiles and oxidative stress markers known as isoprostanes will be measured and correlated with lesion development. If specific 12/15-lipoxygenase inhibitors are ultimately to be used in atherosclerotic disease management they will need to be effective in limiting, or causing regression of, preexisting lesion. By using an inducible 12/15-lipoxygenase gene disruption strategy in mice with atherosclerosis at various stages this important matter will be addressed. In specific aim 2, the subset of macrophages expressing 12/15- lipoxygenase will be characterized and purified. The effects of lipid loading and factors regulating 12/15lipoxygenase gene expression will be determined. In specific aim 3, the novel 12(R)lipoxygenase will be characterized and its relevance to atherosclerosis and LDL oxidation discerned. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELL SIGNALING: MACROVASCULAR COMPLICATIONS OF DIABETES Principal Investigator & Institution: Bornfeldt, Karin E.; Pathology; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 30-NOV-2005 Summary: (provided by applicant): A majority of people with diabetes die of cardiovascular disease caused by atherosclerosis that is accelerated by diabetes. The factors that drive diabetes-accelerated atherosclerosis are still poorly understood. Our recent studies on a new porcine model show that diabetes in combination with elevated lipid intake causes increased accumulation and proliferation of arterial smooth muscle cells (SMCs) in lesions of atherosclerosis. The increased SMC proliferation occurs concomitant with hyperglycemia and elevated levels of plasma triglycerides. High glucose levels are not sufficient to induce SMC proliferation, but certain fatty acids common in triglycerides (oleate and linoleate) stimulate SMC proliferation in the presence of insulin-like growth factor I (IGF-I). We propose that diabetes leads to an increased amount of IGF-I and of lipoprotein lipase in lesion macrophages, and that lipoprotein lipase degrades triglycerides into free fatty acids that act in synergy with IGF-I to stimulate SMC proliferation. Our goal for the next five years is to address the following questions: 1. Do oleate and linoleate enhance the growth-promoting effects of IGF-I on SMCs? 2. How do oleate and linoleate synergize with the growth-promoting action of IGF-I in SMCs? 3. Does lipoprotein lipase produced by lipid loaded macrophages increase SMC proliferation by generating oleate and linoleate? 4. Does glucose or lipids associated with diabetes stimulate SMC proliferation, lipoprotein lipase and IGF-I in lesions of atherosclerosis and does lack of macrophage-derived lipoprotein lipase result in reduced SMC proliferation? We will use several animal models of diabetes-associated atherosclerosis, isolated arterial SMCs for signal transduction studies as well as a co-culture model of monocyte derived macrophages and SMCs. Increased understanding of the regulation of SMC proliferation and accumulation in diabetic lesions of atherosclerosis may provide the basis information necessary for development of highly specific drugs that can prevent lesion progression and formation of vulnerable lesions that are likely to cause the clinical symptoms of cardiovascular complications in diabetes.

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Project Title: COGNITIVE BEHAVIOR THERAPY IN ACUTE POST MYOCARDIAL INFARCTION PATIENTS Principal Investigator & Institution: Schneiderman, Neil; Professor and Director of Health Program; University of Miami Coral Gables Box 248293 Coral Gables, Fl 33134 Timing: Fiscal Year 2001; Project Start 01-JUL-1986; Project End 31-JUL-2006 Summary: (provided by applicant): Depression and inadequate social support are risk factors for medical morbidity and morality after acute myocardial infarction (AMI). The Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial is a multicenter, randomized, controlled clinical study of cognitive-behavioral treatment (CBT) for depression and inadequate social support in post-AMI patients. Because the ENRICHD trial did not focus on biological risk factors (e.g., lipoproteins, lipids, glucose tolerance, adiposity, insulin, inflammatory markers, coagulation factors), possible subclinical markers of disease (e.g., coronary calcification, elevated intima-media thickness [IMT] of carotid artery, decreased brachial artery vasodilation, increased left ventricular mass) or putative mediators (e.g., cortisol, catecholamines) of increased coronary heart disease (CHD) risk or putative subclinical markers of disease, we propose to study further some 200 Miami patients previously enrolled in ENRICHD as well as 210 (180 completors) newly-recruited post-acute MI patients. Thus, approximately 100 previously studied ENRICHD patients, who received CBT, and 100 ENRICHD patients who received usual care, would be compared in terms of posttreatment cardiovascular risk factors, possible subclinical markers of disease and other biological and psychosocial variables to determine the effects of CBT. These patients would then be compared with 210 (180 completors) newly recruited post-acute MI patients. Half of these newly recruited subjects would be randomized into the CBT condition and half into usual care. These newly recruited post-MI patients would be assessed both before and after treatment (i.e., CBT or usual care) in terms of psychosocial variables (e.g., depression and social support), putative biological mediators (e.g., elevated cortisol), risk factors (e.g., elevated triglycerides) and possible subclinical markers of disease (e.g., coronary calcification) as well as demographic and medical characteristics. The project would use all of the core units. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CONTROL OF ADIPOGENESIS AND ENERGY METABOLISM Principal Investigator & Institution: Farmer, Stephen R.; Professor; Biochemistry; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2001; Project Start 01-JUN-1997; Project End 31-MAY-2002 Summary: (Adapted from applicant's abstract): Adipose tissue plays a central role in controlling energy metabolism within the organism. Its primary function is to store triglycerides during periods of caloric excess and to mobilize these stores as free fatty acids during caloric deprivation. In modern western civilization, individuals usually consume more calories than they expend which can lead to a high incidence of obesity. In humans, obesity is one of the most common metabolic disorders and it is an independent risk factor for several pathological diseases including non-insulindependent diabetes mellitus (NIDDM), hypertension and cardiovascular disease. Recent studies suggest that some of these disorders may be linked to a breakdown in the regulatory mechanisms that control the expression of metabolic genes in mature adipocytes. Some progress towards an understanding of these processes has come from

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studies involving the identification of transcription factors which regulate adipogenesis. Most notable among these factors are members of the family of CCAAT/enhancer binding proteins (C/EBPs) and the peroxisome proliferator activated receptors (PPARs). In the case of the C/EBPs, C/EBPa is expressed in high abundance in a limited number of tissues, including fat and liver, where it plays a central role in regulating energy homeostasis. PPARg2 expression is limited to adipose tissues where it plays a central role in committing multipotential stem cells to the adipogenic lineage, as well as regulating differentiation of preadipocytes into adipocytes. The investigators have recently demonstrated that the conditional ectopic expression of C/EBPb and C/EBP( in multipotential NIH-3T3 fibroblasts induces PPARg expression which in turn stimulates adipogenesis based on the synthesis of triglycerides and their deposition into fat droplets. The specific aims are designed to define the transcriptional events that control adipogenesis. Aim 1 will determine the role of C/EBPb, C/EBP( and PPARg in inducing the early commitment phase of adipogenesis which involves the initiation of C/EBPa transcription. Aim 2 will identify and characterize the regulator elements in the C/EBPa gene and the corresponding nuclear DNA binding proteins that regulate C/EBPa transcription during the differentiation of 3T3-L1 preadipocytes. Aim 3 will determine the role of PPARg and the C/EBPs in regulating the expression of the mature, terminally differentiated adipocyte. This will involve an analysis of how these transcription factors control the expression of the insulin-dependent glucose transport system which include induction of the glucose transporter 4 (GLUT4), the insulin receptor and the insulin receptor substrate 1 (IRS1). Accordingly, mRNAs and proteins of these markers will be analyzed and the ability of NIH-3T3 cells to facilitate glucose uptake in response to insulin will be assessed. These studies should lead to insights into the molecular mechanisms regulating energy homeostasis and the defects underlying obesity and NIDDM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONTROL OF GENE TRANSCRIPTION BY ESSENTIAL FATTY ACIDS Principal Investigator & Institution: Clarke, Steven D.; Professor and Love Chair of Nutritional,; Human Ecology; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2001; Project Start 15-FEB-1999; Project End 31-DEC-2002 Summary: Dietary polyenoic (n-6) and (n-3) fatty acids (PUFA) reduces blood VLDL by coordinately: (a) inhibiting fatty acid biosynthesis; (b) reducing fatty acid flux to triglycerides; and (3) enhancing liver and skeletal muscle fatty acid oxidation. In a sense, PUFA are classic fuel partitioners (i.e. direct lipid from storage to oxidation); and in this way may protect against the development of insulin resistance and cardiovascular disease. PUFA regulation of metabolism is often viewed as a simple pleiotropic effect resulting from changes in membrane fatty acid composition. However, fatty acids may also govern gene transcription by functioning as ligand activations for members of the steroid receptor super-family (e.g. PPARs). Although PPARs per se appear not to mediate the PUFA suppression of hepatic lipogenic genes (e.g. fatty acid synthase-FA), the kinetics of the PUFA inhibition are consistent with a ligand mediated event. Thus we hypothesize that, PUFA, or a metabolite, bind to a specific PUFA response factor (RF) which interacts with the PUFA-RE and functions to silence FAS transcription by interfering with the transfactors with the PUFA-RE and functions to silence FAS transcription by interfering with the trans- factors associated with the glucocorticoid (GRE) and/or insulin (IRE) response sequences. Moreover, since PUFA

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appear to activate trans-factors of the steroid receptor super-family, we propose PUFA are dietary humoral factors when consumed t critical periods of development can "imprint" genes in a manner that alters their gene expression throughout the life cycle. The rat FAS gene including 15kbp of 5' flanking will be employed to: (a) functionally map the yet unidentified PUFA-RE and the GRE in the 5'-flanking sequences of the FAS gene; (b) characterize the interaction between the IRE and the GRE which leads to amplification pf FAS transcription; and determine how the PUFA-RE interacts to silence the GRE and IRE of FAS; and (c) identify and characterize the trans-factors responsible for the PUFA regulation of FAS transcription. These Aims will be addressed by a combination of techniques including: transfection analyses with rat liver cells in primary culture; DNAse-I hypersensitivity site mapping and in vivo footprinting of nuclei from rats fed PUFA versus 18:1 (n-9); and in vivo footprinting with hepatocytes monolayuers treated with (n-6)/(n-3) PUFA; UV cross-linking for trans-factor characterization; and yeast one-hybrid system for cloning PUFA-RE trans-factors associated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DHEA EFFECTS ON MOOD IN DEPRESSED HIV+ PATIENTS Principal Investigator & Institution: Rabkin, Judith G.; Professor; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 10-AUG-2000; Project End 31-JUL-2004 Summary: This is a double blind, placebo-controlled clinical trial of the antidepressant effect of DHEA among HIV+ individuals. Secondary goals will include determination of whether DHEA has anabolic effects or androgenic effects on enrolled subjects. The investigators will consider the basic endocrinology of adrenal steroid metabolism in the subjects, and propose to assess the effects of DHEA on immune status and viral activity with regard to the safety of the use of DHEA in HIV infected individuals. The study is an eight week double blind controlled trial of oral DHEA vs. placebo with an eight week maintenance phase for drug responders, and 16 weeks of open treatment offered to placebo non-responders (after the eight week double blind trial). They propose a 1:1 randomization and predict that 114 enrolled individuals will complete the eight week trial. If DHEA ameliorates depressive symptoms, as well as increasing libido and reducing loss of muscle mass, then the investigators will have identified an intervention with a broad spectrum of action suitable for both men and women with HIV infection, that is practical, inexpensive, and accessible. With regard to the endocrine studies, the investigators will assess precursors and metabolites of DHEA before and after oral administration of the compound, and examine effects of cortisol, triglycerides, insulin, cholesterol, growth hormone, IGF-1, and IGF-1 binding proteins. Tests will be administered at study baseline, weeks 4 and 8, including standard dose ACTH, low dose ACTH, CRF, and GNRH stimulation tests to assess the hypothalamic-pituitaryadrenal and hypothalamic-pituitary gonadal function before and after DHEA administration. This will permit the investigators to assess potential underlying mechanisms for the putative therapeutic effects of DHEA on mood, libido, and body composition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIABETIC NEUROPATHY: IMPLICATIONS FOR WOUND REPAIR Principal Investigator & Institution: Gibran, Nicole S.; Associate Professor; Surgery; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2003; Project Start 30-SEP-1999; Project End 31-AUG-2007

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Summary: (provided by applicant): This proposal explores cell signaling pathways that occur between cutaneous sensory nerve fibers and endothelial cells in response to cutaneous injury. Our previous data suggest that nerve-derived neuropeptides contribute to the normal wound repair process. In contrast, non-healing chronic ulcers associated with diabetes mellitus are characterized by microangiopathy and decreased innervations. Based on encouraging data during the past funding period we continue to explore our hypothesis that in patients with diabetes mellitus, hyperglycemia and hyperlipidemia impair microvascular endothelial cell response to nerve-derived neuropeptides and endothelial cell production of necessary inflammatory mediators. These abnormalities contribute to impaired response to cutaneous injury. We will test our hypothesis by addressing the following Aims: Aim 1: To determine the effects of hyperglycemia and matrix glycosylation on microvascular endothelial cells responses. Hyperglycemia can directly alter cellular responses and can indirectly alter cellular response by extracellular matrix molecule glycosylation. We will determine whether hyperglycemia and/or matrix molecule glycosylation alters SP-induced endothelial cell mediator synthesis, cytoskeleton organization, integrin expression and intracellular signaling. Aim 2: To determine the effect of elevated fatty acid levels on endothelial cell responses. Hyperlipidemia is strongly associated with complications in diabetes mellitus. We will determine whether elevated fatty acids alone or as Triglycerides alter SP-induced endothelial cell mediator synthesis, cytoskeleton organization, integrin expression or intracellular signaling. Aim 3: To determine the anti-oxidant regulation of microvascular endothelial cell response to hyperglycemia & hyperlipidemia. Oxidative stress due to hyperlipidemia may alter cellular response to injury. We will continue our studies of effects of antioxidants, vitamin E, vitamin C and n-acetyl cysteine on cellular responses under hyperlipidemic and hyperglycemic conditions. Aim 4: To determine whether restoration of neuropeptide activity improves wound repair in diabetic mice. We will use several approaches to evaluate the roles of neuropeptides in wound repair. Using an excisional wound repair model in hyperglycemic db/db mice, we will replace substance P and inhibit neutral endopeptidases activity. We will also test the effects of antioxidants in this murine wound model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIET THERAPY IN DIABETES MANAGEMENT OF MEXICAN AMERICANS Principal Investigator & Institution: Briones, Esperanza R.; Univ of Texas-Pan American Edinburg, Tx Timing: Fiscal Year 2002; Project Start 01-JUN-1977; Project End 31-JUL-2006 Summary: (provided by applicant): Diabetes in Hispanic Americans is a serious health problem. It affects 1.2 million or 10.6% of the Mexican American population. Approximately 24% of Mexican Americans in the U.S. between the ages of 45-74 have diabetes. In Hispanic adults, diabetes is primarily type 2, and its incidence is correlated with the occurrence of obesity. The purpose of the study is to conduct a two and half (21/2) year randomized trial of a culturally appropriate dietary and lifestyle education intervention designed for Mexican Americans with type 2 diabetes residing in Rio Grande Valley. Both males and females, with type 2 diabetes will be recruited, with two age subgroups, ages 45-59 and 60 and above. Eligible participants will be randomized into two groups. Group 1 will receive the conventional dietary counseling and group 2 will receive additional sessions and follow-up. The specific objectives of the study are: to assess the effectiveness of a culturally appropriate intervention to improve participants' adherence to dietary modifications, medication schedules, and promote sustained

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improvements in lifestyle behaviors; to assess the anthropometric measurements, health habits, and nutrient consumption of subjects at baseline and after dietary and educational sessions; to determine fasting serum glucose and glycosylated hemoglobin in assessing the level of diabetes control; and to assess the lipid profile (serum cholesterol, triglycerides, high density lipoprotein cholesterol) which are associated with the development of coronary heart disease in diabetes. Statistical calculations will be used to evaluate the differences between the two groups. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISTINCT HUMAN MACROPHAGE RECEPTOR FOR ABNORMAL VLDL Principal Investigator & Institution: Gianturco, Sandra H.; Prof/Div/Gerontology/Geriatric Medicine; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2003; Project Start 01-JAN-1991; Project End 30-JUN-2007 Summary: (provided by applicant): Elevated plasma triglycerides (TG) and TG-rich lipoproteins (TGRLP), especially postprandial (pp) TGRLP, are emerging risk factors for atherothrombotic disease. However, little is known about the molecular basis for their interaction with cells of the artery wall or in the periphery. We identified and cloned a wholly unique receptor for dietary ppTGRLP, the apoB48 receptor (apoB48R), found in human monocyte-macrophages and in foam cells in arterial lesions. Now a mouse model, deficient in this receptor, has been created, and evidence demonstrates that in an atherogenic background the loss of the apoB48R reduces atherosclerosis significantly, further implicating it in macrophage foam cell formation and reduces peripheral uptake in tissues that normally express the receptor and elevates plasma cholesterol and triglycerides (TG). Therefore, using this new mouse model, we plan to determine its role in dietary lipoprotein metabolism and ppTGRLP uptake by cells in the periphery where the receptor is highly expressed (bone marrow, spleen, skeletal muscle and adipose). Furthermore, we will identify the molecular mechanisms and the extent to which ppTGRLP are atherogenic in mouse models of atherogenesis, including the apoEand LDL R-deficient mice, crossed into the apoB48R-deficient mouse and in our newly developed apoB48R transgenic mice with enhanced tissue specific apoB48R expression in macrophages and liver (where it is not normally found) and we will evaluate the impact of the apoB48R on atherogenesis when animals are subjected to atherogenic and TG-elevating diets, thereby altering the postprandial mileau. We further plan to determine in vitro the molecular and cellular mechanisms by which the apoB48 R operates, that is, rapid, efficient accumulation of intracellular lipid. In vitro studies will identify the receptor recycling rates, endosomal/lysosomal trafficking, possible involvement of microtubules and/or microfilaments and rates of synthesis and degradation. The ligand-binding domain of the receptor will be sought as an eventual targeting site for intervention. Finally we will identify potential additional modifiers of macrophage pathobiology that may be exacerbated by the uptake of ppTGRLP via the apoB48R pathway by interfering in the normal cholesterol homeostasis, both production (HMGCoA reductase) and efflux (via ABC A1). The proposal uses the powerful techniques of mouse genetics coupled with dietary manipulations in vivo coupled with cell and molecular biology approaches in vitro aimed to answer key questions about the role of the apoB48 R and its interaction with ppTGRLP in health and disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DYSLIPIDEMIA AND RISK OF CVD IN DIABETIC MEN AND WOMEN Principal Investigator & Institution: Hu, Frank B.; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02460 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: We propose to assess biochemical markers of dyslipidemia and endothelial dysfunction, and omega-3 fatty acids in relation to risk of CVD among men and women diagnosed with type 2 diabetes in two large ongoing cohort studies, the Nurses? Health Study (NHS) and Health Professionals? Follow-up Study (HPFS). By 1998, 12,600 confirmed type 2 diabetic cases have already accumulated in the two cohorts. By the year 2002, 5,507 blood samples prospectively collected from persons with previously or newly diagnosed type 2 diabetes will be available for analyses. Using this unparalleled resource, we will specifically evaluate (1) The relationship between plasma levels of cell adhesion molecules (i.e. sICAM-1, sVCAM-1, E-selectin), diabetic dyslipidemia, and risk of CVD among diabetics; (2) the association between Lp(a) concentrations and risk of CVD among diabetics, independent of high triglycerides and low HDL; (3) the association between long-term intakes of omega-3 fatty acids and CVD risk in diabetes. The main NHS and HPFS grants will provide follow-up and documentation of CVD in addition to covariate information. Overall, the large size of these cohorts, the prospective design, the high follow-up rates, and the availability of archived blood specimens provide a unique opportunity to study the relationship between diabetic dyslipidemia and risk of CVD in an extremely cost-efficient and timely manner. In addition, these two cohorts provide an unusual opportunity to compare lipid profiles and endothelial markers of CVD between diabetic men and women. We believe that this study will provide new insight into the understanding of the atherosclerotic process in diabetes and may suggest new nutritional and pharmacological means to prevent and treat CVD complications among diabetics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECT OF CAPTOPRIL ON THE DIABETIC-HYPERTENSIVE HEART Principal Investigator & Institution: Heyliger, Clayton E.; Ponce School of Medicine G.P.O. Box 7004 Ponce, Pr 00731 Timing: Fiscal Year 2001; Project Start 30-SEP-1986; Project End 31-MAY-2005 Description (provided by applicant): Hypertension and diabetes mellitus commonly occur together. Unfortunately, very few randomized, controlled trials of antihypertensive treatment have been carried out in diabetic patients. Thus, decisions regarding the efficacy of such treatment must be based upon evidence, often controversial, extrapolated from studies in non-diabetic populations. A classic example can be seen in studies on the effect of antihypertensive therapy on lipids. Although abnormal myocardial lipid metabolism is a serious complication of diabetes mellitus and is strongly implicated in diabetes-induced primary cardiomyopathy, studies on antihypertensive therapy-induced lipid abnormality are confined to the development of atheroscelerosis and ischemic heart disease. We believe that the effect of antihypertensive agents on lipid metabolism in the cardiovascular system is not limited to the blood where they either have no effect, adversely affect or have a beneficial effect on lipid levels, but also extends to the myocardium, where they also influence lipid levels. Further, this alteration in myocardial lipid metabolism is associated with changes in cardiac contractile performance. In this regard, it is our hypothesis that the beneficial

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effect of captopril on lipid metabolism in the circulation is not confined to the blood where it decreased total cholesterol, triglycerides, and low density lipoproteins (LDL) as well as increased high density lipoproteins (HDL), but is also beneficial to the myocardium where it likewise positively influences lipid metabolism. This study will, therefore, provide evidence to support this hypothesis. It will assess the effect of captopril on myocardial lipid metabolism of the diabetic-hypertensive rat. Specifically, it will assess the effect of this agent on myocardial levels of cholesterol, triglycerides and long chain acyl carnitines and CoAs. These lipids and lipid intermediates accumulate in the diabetic heart and are strongly implicated in its depressed contractile performance. The male spontaneously hypertensive rat (SHR) will be the animal model. It will be made diabetic with a single tail vein injection of streptozotocin (60 mg/kg). Captopril will be administered in the drinking water (100 mg/kg) 3 days after diabetes induction. Rats will be sacrificed after 6 weeks of diabetes with sodium pentobarbital (75 mg/kg, i.p.). This study will present new findings about captopril therapy during diabetes plus hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXERCISE INTERVENTION IN COLORECTAL POLYP PATIENTS Principal Investigator & Institution: Mctiernan, Anne M.; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-JAN-2004 Summary: (Adapted from the Applicant's Abstract): Strong observational evidence points to a link between physical activity and reduction in risk of colon cancer. The mechanisms for this association have not been delineated, nor have the amounts and types of exercise needed for a putative protective effect been determined. We propose a randomized controlled clinical trial of a one-year moderate aerobic/strength training exercise intervention in adenomatous colon polyp patients (n=100 men, 100 women). We hypothesize that polyp patients in an exercise intervention will experience significant biological effects on colorectal epithelium, specifically Ki67 indices of proliferation, bax and bc1-2 markers of apoptosis, and prostaglandin concentrations (PGE2 and PGF2cc). Patients will be recruited on-site from gastroenterology physicians' offices and secondarily from a high-risk colorectal cancer family registry. Sedentary individuals with newly diagnosed (within the past 18 months) adenomatous colon polyp(s) will be screened for eligibility and randomized to either the exercise intervention or a stretching-control group. The exercise intervention will use existing proven methods for adopting and maintaining exercise, taken from our ongoing research program. It will consist of 3 months' facility-based exercise instruction in small groups, followed by 9 months' home-based exercise program supplemented with group behavior change meetings. The goal for exercise will be moderate-level aerobic exercise 5-6 days per week for 30-45 minutes, plus strength training 2 days per week for 15-20 minutes. Colon and rectal biopsies will be taken at baseline and 12-months, and examined for amount and patterns of epithelial cell proliferation (with Ki67 marker) and apoptosis markers (bc1-2 and bax, an inhibitor and an inducer of apoptosis, respectively). Additional potential markers of exercise effect on colon cancer risk will be measured, including rectal mucosal biopsy prostaglandin concentrations, stool frequency, insulin-like growth factor (IGF-1) and IGF binding protein (IGFBP-3), insulin, glucose, C-peptide, triglycerides, and measures of fat mass and fat distribution. Other measures at baseline and 12 months include fitness (V02max), self-reported physical activity, diet, and quality of life. Results from this unique human experimental study

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will provide important information about mechanisms of exercise effects on colon carcinogenesis and about potential Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXERCISE, DIABETES, AND CORONARY SMOOTH MUSCLE CALCIUM Principal Investigator & Institution: Sturek, Michael S.; Professor; Dalton Research Center; University of Missouri Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 31-MAR-2003 Summary: Our long-term goal is to determine if exercise training attenuates the excess coronary artery disease (CAD) in diabetes and the vascular smooth muscle (VSM) Ca (Cam) signaling mechanisms involved. In our porcine model of diabetic dyslipidemia coronary arteries show increases in contraction to prostaglandin F2alpha (PGF) and Cam responses to endothelin-1 (ET). Exercise of normal swine decreases Ca release from the sarcoplasmic reticulum (SR) and increases Ca influx, while decreasing ET-induced contraction and DNA synthesis. However, ET-induced contraction does not require Ca release that is dependent on tyrosine kinase, a signal for cell growth. Overall hypothesis: after exercise training increased ET-induced Ca influx attenuates contraction, while decreased SR Ca release attenuates growth of smooth muscle. Design: low fat control pigs (C), high fat fed (HF), and alloxan diabetic and high fat fed (D) pigs are maintained for 20 and 30 wk to study the progression of CAD and compared to D pigs exercise trained (D plus EX). Specific Aims are to test the hypotheses that in diabetes: 1) Exercise improves glycemic and lipidemic status. Diabetes will be defined by measures of blood glucose, glycated protein, insulin, etc. HDL, LDL, VLDL, triglycerides, apoproteins, glycated LDL, and ET will define features of diabetic dyslipidemia. 2) Exercise attenuates the increase in CAD. Intravascular ultrasound will assess atheroma and vasoconstrictor responses to PGF and ET in vivo. Histology and contractile tension responses of coronary rings to PGF and ET will provide in vitro measures of CAD. 3) Exercise attenuates the conversion of VSM from the contractile (cVSM) to synthetic (sVSM) phenotype. sVSM cell phenotype will be identified using digital imaging microscopy by the Cam response to UTP, perinuclear SR, DNA, smooth muscle actin, desmin, and vimentin. 4) Exercise attenuates the increased contraction of cVSM by increasing ET receptor-dependent Ca influx. Mn and Ba influx used as Ca surrogates will assess Ca influx. Subsarcolemmal Ca localization relative to ryanodine receptors will be digitally imaged. 5) Exercise attenuates the increased ET-induced Cam amplitude and nuclear Ca localization by decreasing tyrosine kinase-dependent Ca release from the SR. Imaging will assay in single cells the relative content and spatial distribution of ET, ryanodine, and IP3 receptors, tyrosine phosphorylation, DNA and Cam. Significance: the first study of Ca localization mechanisms involved in the excess CAD in diabetic dyslipidemia and the therapeutic effects of exercise on CAD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FFA METABOLISM IN DIFFERENT TYPES OF HUMAN OBESITY Principal Investigator & Institution: Jensen, Michael D.; Professor of Medicine; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001; Project Start 01-AUG-1988; Project End 31-JUL-2003 Summary: Abnormalities of fatty acid metabolisms are considered important contributors to the adverse health consequences of upper body/visceral obesity. Excess hepatic FFA delivery, perhaps originating from visceral adipose tissue lipolysis, could

20

Triglycerides

account for the reduced ability of insulin to inhibit hepatic glucose production and for the abnormal VLDL kinetics in visceral obesity. The investigators have found that overnight postabsorptive (basal) hepatic FFA delivery is increased in obesity, but that visceral lipolysis increases in proportion to visceral fat mass only in obese women. The abnormalities of hepatic glucose and lipid metabolism attributed to excess FFA would be expected to be more apparent at times of elevated plasma insulin concentrations. However, there is no information regarding the effects of insulin on splanchnic FFA metabolism in visceral obesity. Excess FFA can also impair insulin mediated glucose disposal in muscle. This could occur through direct or indirect mechanisms; increased FFA is associated with increased intramuscular triglycerides, which are independently associated with insulin resistance. The investigators propose to assess the effects of insulin on splanchnic FFA metabolism in visceral obesity and to investigate intramuscular fatty acid kinetics using a newly developed stable isotope technology. The objectives of this proposal are to determine whether: 1) insulin suppression of splanchnic FFA release is impaired in visceral obesity; 2) visceral lipolysis contributes a greater proportion of hepatic FFA delivery in viscerally obese than in non-obese individuals under hyperinsulinemic conditions; 3) intramuscular triglyceride hydrolysis is increased in visceral obesity compared with trained and sedentary lean humans; 4) insulin inhibits both intramuscular triglyceride hydrolysis and the delivery of fatty acids to pre-oxidative intramuscular pool in lean (trained and sedentary) but not viscerally obese humans; and 5) improved insulin action with respect to glucose metabolism, whether accomplished by exercise training/weight loss or via troglitazone treatment, is associated with improvements in insulin action on FFA and intramuscular fatty acid metabolism in viscerally obese humans. Completion of the studies proposed in this application will better define the role of insulin in regulating visceral lipolysis in high risk obesity and will provide novel information regarding intramuscular fatty acid metabolism in insulin resistant and insulin sensitive states. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FLAX: SAFETY & EFFICACY IN REDUCING CARDIOVASCULAR RISK Principal Investigator & Institution: Szapary, Philippe O.; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 26-SEP-2002; Project End 31-MAY-2004 Summary: (provided by applicant): Hypercholesterolemia is an important established risk factor for atherosclerotic cardiovascular disease (ASCVD). The National Cholesterol Education Program (NCEP) has recently estimated that 100 million Americans qualify for treatment of their hypercholesterolemia. Of these Americans, 65 million could be managed with diet and exercise alone, referred to as Therapeutic Lifestyle Changes (TLC) by the most recent NCEP guidelines. The NCEP has already recognized the importance of diet and Complementary Alternative Medicine (CAM) therapies in the management of dyslipidemia by incorporating soluble fiber and plant-based stanol esters as part of TLC. Flaxseed is a unique food as it contains significant amounts of soluble fiber as well as the richest source of both alpha-linolenic acid (ALA) and phytoestrogenic lignans, which have all been implicated in the prevention of ASCVD. Because flaxseed contains these constituents, it may play an important role in TLC in the future, but data is currently lacking. In addition, because lignans can bind to the estrogen receptor and elicit a hormonal response, chronic flaxseed consumption may have undesirable hormonal effects. Thus in this project, we propose to systematically evaluate the safety and efficacy of ground flaxseed ingestion in both men and women

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with hypercholesterolemia over the short term. This will be done in a single doubleblind, randomized, placebo controlled clinical trial. Because little is known about the metabolic effects of flaxseed in men, randomization will be stratified by gender. The test dose of flaxseed meal will be 40 grams administered in baked products and compared to a matching wheat bran control. The primary endpoints of this study are to evaluate the effects of flaxseed consumption on lipid metabolism and oxidative stress. The primary response variables in terms of lipid metabolism will include low density lipoprotein (LDL-C) cholesterol and post-prandial triglycerides. For the evaluation of oxidant stress, the primary response variable will be urinary isoprostane secretion, the most sensitive marker of in vivo oxidative damage. Secondary variables of interest will include markers of cholesterol metabolism, vascular inflammation, endocrine function, safety and acceptibility. The results from this study will lay the foundation for several lines of research into the clinical and biochemical effects of flaxseed supplementation in modulating cardiovascular risk. Specifically, the data generated from this project will be used as preliminary data to pursue R01 submissions to NCCAM and NHLBI to investigate the long-term effects and mechanisms of action of the various components of flaxseed on lipid metabolism and clinical endpoints in patients at risk for ASCVD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTIONAL ARTERIAL CHANGES IN ATHEROGENESIS Principal Investigator & Institution: Kullo, Iftikhar J.; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The broad long-term goal of the candidate is to develop new strategies to improve cardiovascular risk assessment. The goal of this proposal is to evaluate the association of two measures of arterial function - endothelial function and arterial compliance - with conventional and novel risk factors on one hand and with sub-clinical atherosclerosis on the other hand. The hypothesis is that these measures of arterial function mediate the deleterious effects of conventional and novel risk factors and are associated with coronary atherosclerosis in asymptomatic individuals. The novel risk factors to be studied include the 'conditional' risk factors (homocysteine, fibrinogen, lipoprotein (a), triglycerides, small dense low density lipoprotein (LDL), and C-reactive protein and polymorphisms in selected candidate genes (endothelial nitric oxide synthase and angiotensin converting enzyme). Endothelial function will be assessed by brachial artery reactivity using vascular ultrasound and arterial compliance assessed by pulse wave velocity using applanation tonometry. Because the effects of novel risk factors on arterial function may depend on the background of conventional risk factors, the measures of arterial function will be obtained in two well-characterized, community-based cohorts with different burdens of conventional risk factors. In both cohorts, coronary artery calcification measured by electron beam computed tomography, a quantitative measure of subclinical atherosclerosis, is available at no cost for the present proposal. Candidate: To obtain additional skills necessary for a career as an independently funded clinical investigator, the candidate will complete courses in research design, biostatistics and genetic epidemiology. Based on the training and experience obtained, the candidate plans to submit an R01 application in year 4 of the award building on the studies proposed in this application. Environment: The candidate is supported by an accomplished team of mentors and consultants and has access to unparalleled resources at Mayo Clinic Rochester for patient-oriented research including one of the finest General Clinical Research Centers in the country.

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Project Title: GARLIC THERAPY IN HYPERLIPIDEMIA CAUSED BY HAART Principal Investigator & Institution: Standish, Leanna J.; Professor; None; Bastyr University 14500 Juanita Dr Ne Kenmore, Wa 98028 Timing: Fiscal Year 2001; Project Start 13-SEP-2000; Project End 31-MAY-2003 Summary: This is a phase I/II randomized double-blind, placebo controlled trial to study garlic as lipid lowering therapy in hyperlipidemic HIV-infected subjects treated with highly active anti-retroviral therapy (HAART). We will utilize Garlicin/TM, an allicin-standardized dried garlic supplement in three escalating doses (700 mg, 1400 mg, and 2800 mg/day) in HIV- infected subjects (n=102, with 51/arm) who are receiving HAART. The primary aim of this study is to measure the effects of three escalating doses of Garlicin/TM on total serum cholesterol. Secondary aims include determining the tolerability and adverse events associated with three escalating doses of Garlicin/TM and gathering preliminary data on the effects on fasting serum triglycerides, basal glucose and insulin levels as well as serum transaminases (ALT and AST). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC TRIGLYCERIDES

AND

ENVIRONMENTAL

DETERMINANTS

OF

Principal Investigator & Institution: Arnett, Donna K.; Associate Professor; Epidemiology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): Hypertriglyceridemia is emerging as important predictor of atherosclerosis, and recent evidence suggests related phenotypes of triglycerides (TGs), such as TG remnant particles and small LDL particles, are particularly atherogenic. There is considerable variation in the response of TGs and related phenotypes to the environment. The aim of the proposed study is to characterize the genetic basis of the variable response of TGs to two environmental contexts, one that raises TGs (dietary fat), and one that lowers TGs (fenofibrate treatment). We will recruit 2,400 family members from 3-generational pedigrees of the ongoing NHLBI Family Heart Study (FHS) in two genetically homogeneous centers (Minneapolis and Salt Lake City). We will collect measurements before and after a dietary fat challenge to assess postprandial TGs and related atherogenic phenotypes (VLDL TGs, chylomicron TGs, TG remnant particles, HDL and LDL particle sizes, total cholesterol, LDL-C, and HDL-C). In families with 2 or more members in a sibship with TGs >= 130 mg/dl, we will conduct a short-term, placebo-controlled, randomized trial of fenofibrate in all willing and eligible family members (anticipated sample size = 1,200). A two-period crossover design will be executed with a 2-week washout between two 3-week treatment periods (placebo or micronized fenofibrate, 160 mg). About 1,000 family members have a Marshfield genome marker set available as part of NHLBI FHS; the remaining 1,400 will be typed using the same marker set. We will conduct genome-wide linkage analyses using stateof-the-art methods to localize novel genetic loci contributing to TG response in the context of fat loading and fenofibrate treatment. We will type 15 single nucleotide polymorphisms (SNPs) in ten candidate genes known to contribute to the response of TGs to dietary fat and fenofibrate, and create haplotypes for association studies. We will use combinatorial partitioning methods and neural networks to test association of the

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individual SNPs and haplotypes with response to the two environmental interventions. The identification of genetic loci that predict TG response in the presence of two disparate contexts, fat loading and fibrate therapy, may provide insights into genetic pathways (a) predisposing to hypertriglyceridemia, ultimately leading to avenues for primary prevention, and (b) predicting response to TG lowering, leading to new drug targets for hypertriglyceridemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC AND GENOMIC ANALYSIS OF APOAV Principal Investigator & Institution: Rubin, Edward M.; Director, Joint Genome Institute; Division of Life Sciences; University of Calif-Lawrenc Berkeley Lab Lawrence Berkeley National Laboratory Berkeley, Ca 94720 Timing: Fiscal Year 2003; Project Start 01-DEC-2002; Project End 30-NOV-2006 Summary: (provided by applicant): Based on human/mouse comparative sequence analysis we have identified a fourth member of the chromosome 11 apolipoprotein (apoAI, apoCIII, apoAIV) gene cluster which we have named apolipoprotein AV (apoAV). Our recent studies in humans and mice indicate that apoAV is an important determinant of plasma triglyceride levels. In mice, the overexpression of a human apoAV transgene resulted in decreased plasma triglyceride concentrations, while inactivation of the mouse apoAV gene led to increased triglyceride levels. Complementing these mouse findings, three independent human studies consistently showed that two minor apoAV haplotypes are strongly associated with increased triglycerides. These initial investigations indicate that the newly discovered apolipoprotein gene, apoAV, is an important modulator of plasma triglyceride levels in mammals. Accordingly, this grant focuses on deciphering several fundamental properties of apoAV that include: 1) determining the mechanism by which apoAV affects plasma triglycerides and its atherogenic consequences using apoAV transgenic and knockout mice, 2) investigating the factors and DNA sequences involved in the regulation of apoAV expression and 3) using a combination of human haplotype studies and defined manipulations of the mouse genome to identify apoAV single nucleotide polymorphisms (SNPs) that directly participate in determining triglyceride levels in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC DETERMINANTS: LOW HDL, HIGH TRIGLYCERIDES, OBES* Principal Investigator & Institution: Mahley, Robert W.; Director; J. David Gladstone Institutes 365 Vermont St San Francisco, Ca 94103 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): Over the past 10 years, extensive studies have been conducted in Turkey to determine the risk factors for heart disease. Studies involving approximately 10,000 Turkish men and women from six different regions of Turkey have established that this population is unique in several ways. The Turks have the lowest plasma levels of high density lipoprotein cholesterol (HDL-C) of almost any population in the world (75 percent of the men and 50 percent of the women have HDLC levels 30 kg/M2], and both men and women have a tendency toward hypertriglyceridemia. The low HDL-C, however, is independent of obesity or hypertriglyceridemia. Samples from this well-characterized population provide a unique opportunity to explore the genetic determinants associated with the high

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Triglycerides

prevalence of low HDL-C, hypertriglyceridemia, and obesity (characteristics of the metabolic syndrome). This project will analyze DNA from frozen blood samples to investigate new candidate gene targets that may provide insights into the abnormalities characterizing this population. The samples and extensive biodata are available on all 10,000 participants. In Specific Aim 1, we will identify polymorphisms in acyl CoA:diacylglycerol acyltranferase (DGAT)- I and -2 and in ATP-binding cassette A I (ABCA I) genes that are associated with differences in BMI, HDL-C, and triglyceride concentration, and other parameters such as blood pressure. These studies will focus significantly on promoter and coding sequence polymorphisms in DGAT-I and -2 and ABCAL In Specific Aim 2, we will determine whether the polymorphisms have functional significance by using a luciferase reporter system to determine expression of polymorphic forms of DGAT and ABCAI, a cholesterol efflux measurement to determine the functional significance of ABCAI coding sequence polymorphic sites, and a triglyceride synthesis assay to determine the functional significance of DGAT-I and -2 polymorphic sites. The polymorphic site association studies will be performed on DNA samples from three subgroups of Turks: (a) individuals likely to have the metabolic syndrome, (b) individuals with isolated low HDL-C (normal triglycerides), and (c) normolipidemic unaffected controls. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETICS & REGULATION OF HEPATIC LIPASE Principal Investigator & Institution: Deeb, Samir; Research Professor; Medicine; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2003 Summary: The long-term goals of this proposal are to define mechanisms of regulation of hepatic lipase (HL) levels and to determine how genetic variation at the HL gene locus modulates these levels under a variety of physiological and pathological states. HL plays a key role in lipoprotein metabolism by catalyzing the hydrolysis of triglycerides and phospholipids. A high level of HL is associated with two important metabolic risk factors for atherosclerosis: diminished concentrations of plasma high density lipoprotein cholesterol (HDL-C) and an increased prevalence of small, dense low density lipoprotein (LDL) particles. A significant proportion (20-30%) of the total variability in HL activity is explained by the common genetic variation in the regulatory sequences of the HL gene whereby, the variant form was observed to be associated with lower HL and higher HDL2 levels. Gender is another modulating factor since women have, on average, higher levels of HDL2 and lower levels of HL. The underlying hypotheses of this proposal are, first, that one or more of the observed regulatory sequence variants causes diminished HL gene expression which, in turn, results in increased HDL-C levels and expression is regulated by cholesterol and estrogens. Our preliminary in vitro studies indicate that sterols up-regulate and estrogens downregulate activity of the HL gene promoter, respectively. The specific aims are to: 1) Determine by association and linkage analysis whether the observed LIPC promoter variants underlie the observed interindividual variation in levels of hepatic lipase activity and HDL2 estrogens and sterols and assess the role of the regulatory sequence variants modulate the relationships between HL levels and gender, menopause status, estrogen replacement therapy and intra-abdominal fat deposits. The results of these studies will provide insights into the molecular genetic bases for interindividual variation in HL activity and the associated plasma lipoprotein profiles. This will open the door for novel pharmaceutical approaches that target modification of the lipoproteins.

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Project Title: GENOMIC DISSECTION OF A QTL AFFECTING THE LIPID PROFILE Principal Investigator & Institution: Olivier, Michael; Physiology; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532264801 Timing: Fiscal Year 2003; Project Start 10-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): The metabolic syndrome is a common disorder posing a significant major risk for coronary heart disease and early mortality in the Western hemisphere. Central to its cardiovascular complications is the association of the syndrome with the specific abnormalities in plasma lipid and lipoprotein profiles including increased plasma triglycerides, decreased HDL cholesterol, and predominance of dense lipoprotein particles. In search for the genetic etiology of this lipid disorder, we identified a quantitative trait locus (QTL) on human chromosome 7q36 strongly linked to variation in plasma lipid levels. We hypothesize that this QTL contains genetic variants that contribute to alterations in biologic pathways underlying the genesis of the lipid disorder. To test for this hypothesis, we propose a comprehensive approach utilizing established resources and expertise to identify the functional sequence variants within this QTL. Specifically, we will 1.) identify single nucleotide polymorphisms (SNPs) and their haplotype and linkage disequilibrium structure across the entire QTL region; 2.) Analyze association of informative SNPs with plasma triglyceride levels, LDL levels, and lipoprotein density fractions using variance component linkage/disequilibrium analyses; and 3.) Identify potentially functional sequence variants in associated genes or genomic regions using Bayesian quantitative trait nucleotide analysis. This comprehensive application of newly available genomic technologies, novel statistical approaches, the DNA and phenotypic information available, and the consortium of expertise assembled behind this project will ensure the successful elucidation of the genetic etiology of this lipid disorder and consequently the development of effective means for prevention and/or treatment of cardiovascular complications of the metabolic syndrome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GROWTH OUTCOMES IN BRONCHOPULMONARY DYSPLASIA AT 36WKS Principal Investigator & Institution: Steward, Deborah K.; None; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-MAY-2007 Summary: (provided by applicant): The prevalence of bronchopulmonary dysplasia (BPD) in very low birthweight (VLBW) infants continues to be a significant problem as more and more extremely immature preterm infants survive acute respiratory distress. Traditionally, BPD has been defined as continued requirement for supplemental oxygen at 28 days of life. Because of the extreme immaturity of the survivors, BPD is now defined as the need for mechanical ventilation and/or oxygen at 36 weeks postconceptional age (PCA). Poor growth is the most common morbidity experienced by VLBW infants with BPD. While the cause of this poor growth is multifactorial potential causative factors include inadequate nutritional intake, inefficient nutrient utilization, and inflammation associated with BPD. However, the role of these factors in the poor growth of these infants has not been examined. The purpose of this study is to prospectively characterize relationships among nutritional intake, nutrient utilization,

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Triglycerides

inflammation, and growth in VLBW infants with BPD when compared to VLBW infants at high-risk for BPD (on oxygen at 28 days of life). VLBW infants, appropriate for gestational age, will be studied at 28 days of life, 33 weeks PCA, and 36 weeks PCA. Group differences for study variables will be examined at the three time points. Study variables include growth (growth velocity, arm muscle area, and arm fat area), nutritional intake (kcal/kg/day and grams of protein/kg/day), nutrient utilization (nitrogen balance, serum prealbumin, and serum triglycerides), and inflammation (interleukin-1 ra and tumor necrosis factor). Predictors of growth velocity will also be determined by examining the interactive effects of respiratory disease with nutritional factors, nutrient utilization, and inflammatory factors. Methods to be used for data collection of the study variables include review of the medical record, computer software analyses, collection of body fluids for biochemical assays and bomb calorimetry, and anthropometric measures. Characterizing the determinants of poor growth in VLBW infants with BPD will facilitate understanding of this problem and identify promising areas for nutritional intervention. Further, nutritional intervention may also decrease the severity of BPD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HIGH ABNORMALITY

FAT

FEEDING

AND

INTRAMYOCELLULAR

LIPID

Principal Investigator & Institution: Guo, Zengkui; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: It is now known that intramyocellular triglycerides (imcTG) content in skeletal muscle of obese adults is increased and this abnormality is associated with impaired glucose metabolism in the muscle. However, the pathways responsible for the increase and the link between the increased imcTG and insulin resistance have not been studied in detail. The objective of this application is to determine the factors and pathways that are responsible for the imcTG accumulation, and to determine whether the oxidation of imcTG fatty acids is also increased and, if so, whether it directly affects glucose metabolism. It is hypothesized that elevated plasma insulin and fatty acid levels, as commonly seen in human obesity, independently stimulate imcTG synthesis and synthesis is the primary pathway leading to the increased imcTG accumulation; and that a larger imcTG pool leads to accelerated imcTG oxidation thereby interfering with muscle glucose metabolism. To test the hypotheses, three specific aims will be pursued to answer following questions: 1) Is insulin an anabolic hormone stimulating imcTG synthesis? 2) Does elevated plasma fatty acid concentration increase imcTG synthesis by providing abundant precursors? 3) Is a larger imcTG pool associated with accelerated oxidation of imcTG fatty acids, and if so, how this affects muscle glucose metabolism? A new one-pool model will be applied to determine the rates of imcTG synthesis, turnover and oxidation directly (muscle biopsy) at controlled insulin and fatty acid levels in rats made obese by high fat feeding. The oxidation of imcTG fatty acids and muscle glucose uptake, glycolysis and glycogen synthesis will be determined using multiple tracers to determine the effect of imcTG oxidation on glucose metabolism. Stable isotopic tracers (13C) and mass spectrometry (GC/MS and isotope ratio MS) will be used to quantitate the kinetics. These studies are designed to answer the questions whether an enlarged imcTG is a chemical entity that imposes a negative effect on glucose metabolism, and whether plasma insulin and fatty acids are responsible for the increased imcTG, and if so, how. Thus, the proposed research will improve the understanding of the mechanism

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of insulin resistance and imcTG abnormalities in the obese rat that will benefit investigation of human obesity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HIV PROTEASE INHIBITORS AND ATHEROSCLEROSIS Principal Investigator & Institution: Smart, Eric J.; Professor; Physiology; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant) We hypothesize that HIV protease inhibitors alter macrophage class B scavenger receptor-dependent uptake and efflux of cholesterol thereby promoting the formation of lipid-laden macrophages and atherosclerotic lesions. A major drawback to the use of HIV protease inhibitors is that they promote the development of dyslipidemia, which is an established risk factor for the development of atherosclerosis. Numerous reports have suggested a causal link between protease inhibitor therapy and atherosclerosis; however, this has not been unequivocally demonstrated in a large-scale clinical trial. The dyslipidemia, which is primarily an increase in triglycerides, is unlikely to completely account for the development of atherosclerotic lesions in HIV patients because atherosclerosis is a multifactorial disease that is not controlled by a single factor. Our preliminary data demonstrate that HIV protease inhibitors have direct effects on macrophages, which are critical cellular mediators in atherosclerotic lesion development. The generation of lipid-laden macrophages is a key event in atherogenesis and is thought to be due, in part, to unregulated uptake of modified lipoproteins. Such aberrant cholesterol accumulation is influenced by the functions of the class B scavenger receptors, SR-BI and CD36. Both receptors are found in atherosclerotic lesions and on macrophages. In addition, both receptors can mediate the uptake of lipoprotein cholesterol and the efflux of cellular cholesterol. Our preliminary data demonstrate that peritoneal macrophages isolated from LDL receptor null mice given the HIV protease inhibitors, amprenavir, indinavir, or ritonavir, contain more SR-BI and CD36 than aged-matched controls. In addition, all three protease inhibitors increased SR-BI and CD36 levels in THP-1 cells, our macrophage cell model system. The protease inhibitors also increased the cellular cholesterol content in both the in vivo and in vitro model systems, which is consistent with our hypothesis. Importantly, mice given amprenavir, indinavir, or ritonavir had significantly more atherosclerotic lesions than control mice. We will test two Specific Aims. Aim 1 : To determine the effects of HTV protease inhibitors on SR-BI and CD36 dependent cholesterol uptake and efflux. Aim 2: To determine the leukocyte (i.e., macrophages, etc.) specific effects of HIV protease inhibitors on atherosclerotic lesion formation in LDL receptor null mice that have been transplanted with bone marrow from SR-BI x LDLR and CD36 x LDLR null mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HYPOTHALAMIC DYSFUNCTION /AGED-RELATED METABOLIC DECLINE Principal Investigator & Institution: Rossetti, Luciano; Professor; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2003; Project Start 01-DEC-2002; Project End 30-NOV-2007 Summary: (provided by applicant): Chronic increases in the availability of nutrients are likely to contribute to several key metabolic features of aging. The latter include (but are not limited to) increased deposition of fat within the abdominal cavity (visceral

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Triglycerides

adiposity), increased tissue levels of triglycerides, insulin resistance, relative decrease in energy expenditure, and augmented risks for atherosclerotic disease (ASCVD) and for type 2 diabetes mellitus (DM2). Under normal circumstances, the deleterious effects of the excessive availability of nutrients are countered by the prompt activation of nutrient "counter regulatory" systems. The latter include (but are not limited to) hypothalamic neuro-circuitries partly under the control of leptin. The activation of these nutrient "counter regulatory" systems should prevent the excessive storage of energy and the onset of insulin resistance. Thus, there appears to be a functional feedback loop, which normally prevents visceral adiposity, insulin resistance, and other metabolic features of aging from developing. However, there is mounting evidence that aging is a state of leptin resistance. Consistent with these recent findings, the operation of this feedback loop is likely to be impaired and leptin may therefore fail to compensate for the deleterious effects of nutrient excess during the aging process. Our proposal will therefore focus on mechanisms responsible for hypothalamic responses to nutrient excess and how they are altered during aging. We also wish to discern impairments in hypothalamic neuro-circuitries, which are due to chronic increases in nutrient availability from those due to the aging process per se. Based on preliminary results and on this overall hypothesis we wish to pursue the following specific aims: Does aging modify the actions of leptin on energy, glucose and lipid metabolism and on insulin action? We will examine the dose-response relationship between central delivery of leptin and biological outcomes. We will particularly focus on the effect of low dose ICV leptin administration on metabolic rather than behavioral end points. Can stimulation of the melanocortin pathway overcome the leptin resistance of aging? We will test the hypothesis that activation of CNS melanocortin receptors bypasses the defect in leptin signaling in aging rats. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INNOVATIVE OBESITY PREVENTION FOR AFRICAN-AMERICAN GIRLS Principal Investigator & Institution: Robinson, Thomas N.; Assistant Professor Of; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2003; Project Start 01-AUG-1999; Project End 30-NOV-2006 Summary: (provided by applicant): We propose a 2-arm parallel group, randomized controlled trial to test the efficacy of an after school dance program and a family-based intervention to reduce television, videotape and video game use to reduce weight gain among lower socioeconomic status African-American preadolescent girls. An active placebo control group will receive an information-based community health education intervention. A total of 260 girls will be randomized to the two conditions and the interventions will last for the full 2-year period of the study. Our interventions and study design are supported by prior studies demonstrating the feasibility and potential efficacy of dance classes and reducing television viewing for reducing weight gain, formative studies, and the success of a 12-week randomized controlled pilot study of the proposed trial. Measures will be collected in girls' homes at baseline and 6, 12, 18 and 24 months. Body Mass Index (BMI) is the primary outcome measure, The primary hypothesis will be tested by comparing individual trajectories of change in the treatment and control groups over the entire two-year course of the trial, using random regression models, Specific Aims include: 1. To participate with NHLBI and the Memphis GEMS investigators to conduct a full-scale, collaborative, 2-year randomized controlled trial, including both site-specific and collaborative measures and site-specific and collaborative analyses. 2. To test the effect of the Stanford GEMS intervention on BMI

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over 2 years (the primary outcome). We hypothesize that, compared to controls, girls in the treatment-group will significantly reduce their weight gain (BMI) over the two-year study period. 3. To test the effects of the Stanford GEMS intervention on secondary outcomes over two years. We hypothesize that, compared to controls, girls in the treatment group will significantly reduce their waist circumference, triceps skinfold thickness, resting blood pressures, resting heart rate, fasting insulin, total cholesterol, LDL-cholesterol, triglycerides, television, videotape and video game use, meals eaten in front of television, total dietary calorie intake, percent of calories from fat, weight concerns, and body disatisfaction, and significantly increase their HDL-cholesterol, after school and daily physical activity, self-esteem, and school performance. 4. To conduct analyses to evaluate potential moderators and mediators of intervention effects on primary and secondary outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IS DHEA REPLACEMENT THERAPY BENEFICIAL? Principal Investigator & Institution: Holloszy, John O.; Professor; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): The major emphasis of our research on the prevention of physical frailty and loss of independence has been on the adaptations to exercise. However, because most Americans are not motivated to exercise, we have started to evaluate other approaches to maintenance of health and prevention of frailty. Of these, the most powerful appears to be DHEA replacement therapy. In this context, the overall goals of this study are to determine whether long term dehydroepiandrosterone (DHEA) replacement therapy has beneficial effects that could (a) delay the development of frailty and disability, (b) protect against development of type 2 diabetes and coronary artery disease, (c) improve quality of life, and d) obtain information on the mechanisms of DHEA action. DHEA and DHEA sulfate (DHEAS) plasma concentrations peak at about 20 yr of age and decline rapidly and markedly after age 25 yr. DHEA is a PPAR-alpha activator. PPAR-alpha plays major roles in regulating lipid metabolism and controlling inflammation. DHEA also appears to have anabolic effects on muscle and bone. The study proposed here is a randomized, double blind, placebo-controlled trial of DHEA replacement. It is designed to determine the effects of 12 mo of DHEA replacement in 65-75 yr old women and men on (a) truncal and visceral fat, (b) insulin resistance and serum triglycerides, (C) muscle mass and strength, (d) bone mineral density, (e) chronic inflammation, (f) arterial-endothelium-dependent vasodilation, and (g) sense of well being. The specific aims of this study are to test the hypotheses that 12 mo of DHEA replacement will (a) Result in significant decreases in truncal and visceral fat by shifting metabolism to fat oxidation and increasing energy wastage; (b) Decrease insulin resistance and decrease serum triglycerides; (c) Increase muscle mass and strength, by decreasing catabolic stimuli and increasing anabolic stimuli; (d) Increase bone mineral density by increasing anabolic stimuli and decreasing catabolic stimuli; (e) Reduce chronic inflammation and decrease pro-inflammatory cytokine production by peripheral blood mononuclear cells; (f) Improve arterial endothelium dependent vasodilation; and (g) Improve general sense of well being. A major emphasis of this research is on the mechanisms responsible for the biological effects of DHEA replacement. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIPID METABOLISM IN FAT CELLS Principal Investigator & Institution: Guo, Wen; Boston Medical Center Gambro Bldg, 2Nd Fl, 660 Harrison Ave, Ste a Boston, Ma 02118 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAY-2004 Summary: Medium chain fatty acid ingestion (MCFA) results in diminished fat storage in animals and humans, while similar intake of long chain fatty acids (LCFA) results in weight-gain. The goal of our project is to examine the cellular mechanisms underlying this phenomenon. Our hypothesis is that substitution of MCFA for LCFA will downregulate the expression of adipogenic proteins, lower the lipid storage capacity of adipose cells, facilitate fatty acid release from stored fat, and probably also reduce the capacity for differentiation of adipose cell precursors. The specific aims of this study focus on: 1) the metabolic fate of MCFA and how this is influenced by LCFA, glucose and insulin, 2) the effects of MCFA on fat storage and lipolysis, and on membrane lipid composition of sub-cellular components (plasma membrane, mitochondria, and endoplasmic reticulum); 3) the effects of MCFA on the expression of adipogenic proteins during the differentiation process; and 4) changes in fat cell function as a result of longterm MCFA dietary adaptation. An integrated approach will be used to characterize the metabolic end products of MCFA, to search for unidentified end products, and to explain the excess energy expenditure that results from MCFA treatment. We will identify and quantify, the major metabolic end products of fatty acids (lipids and CO2) by NMR. 13C isotope labeled substrates will be used in appropriate experiments. This greatly enhances the selectivity and sensitivity of NMR analysis. We will compare heat generation by cells adapted to MCFA or LCFA by measuring oxygen consumption and redox state; quantify the important metabolites (acetylCoA and acetylcarnitine) by HPLC, and analyze the fatty acid compositions by GLC. If significant changes in subcellular membrane composition are found as a result of MCFA treatment, subsequent effects on membrane structure and fluidity will be analyzed by solid state NMR. Other standard biochemical assays will be used for the measurement of ketone bodies, total triglycerides, cholesterol, DNA, protein, etc. The mRNA products of differentiationdependent adipogenic genes will be determined by Northern analysis. Fat cell morphology will be characterized by phase- contrast microscopy. Using this integrated approach, we anticipate developing important new information to help shed light on the molecular mechanisms of the control of obesity and obesity-related health disorders afforded through MCFA administration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIPOPROTEIN LIPASE AND PREECLAMPSIA Principal Investigator & Institution: Hubel, Carl A.; Magee-Women's Hospital of Upmc 300 Halket St Pittsburgh, Pa 15213 Timing: Fiscal Year 2001; Project Start 15-FEB-2000; Project End 31-JAN-2005 Summary: Preeclampsia is a leading cause of maternal death and increases perinatal death five-fold. There is compelling evidence that maternal endothelial dysfunction contributes to the pathogenesis of preeclampsia. Hypertriglyceridemia, decreases in high density lipoprotein (HDL) cholesterol, and abnormally small-sized low density lipoprotein (LDL) particles are characteristic features of preeclampsia. We have proposed that these lipid abnormalities promote endothelial dysfunction in preeclampsia through the generation of oxidative stress. Lipoprotein lipase (LPL) plays a vital role in the clearance of triglycerides from the circulation. The importance of LPL defects in the development of cardiovascular disease is increasingly recognized. Several

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common variations in the LPL gene promote the triad of increased triglyceride, decreased HDL cholesterol, and small-sized LDL. The dyslipidemic effects of these functional variants are accentuated by pregnancy. In our Caucasian population, a sum total of 18.8% of preeclamptics are heterozygous for either the N291S or D9N coding sequence variants of the LPL gene, compared with 4.6% of normal pregnancy controls. Accordingly, Aim 1 is to test whether these observations can be generalized to other populations. We will compare the prevalence of the four most common, functional variants in the LPL gene in Caucasians and African-Americans from western Pennsylvania, and in Icelandic women. Aim 2 is to sequence the coding and promoter regions of the LPL gene to identify other functional variants, which will then be genotyped in cases and controls. We posit that variations in the LPL gene the predispose to dyslipidemia are over-represented in women with preeclampsia. Aim 3 is to compare plasma lipids, lipid peroxidation products, and markers of endothelial dysfunction in women with preeclampsia stratified by genotype. We hypothesize that, among women with preeclampsia, those carrying LPL variants with reduced enzymatic activity will display an especially adverse blood profile. In Aim 4, we will measure plasma LPL enzyme activity in women 12 weeks postpartum to further test the hypothesis that a constitutional deficiency in LPL (hormonally and/or genetically mediated) is associated with preeclampsia. In Aim 5, we will explore the effects of heterozygous LPL deficiency on endothelial regulation of vascular function during pregnancy, using the LPL knockout mouse. This systematic approach will help to clarify the link between dyslipidemia and the pathogenesis of preeclampsia and could provide clues to prevention or treatment of the disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIPOPROTEIN LIPASE IN FATTY ACID PARTITIONING Principal Investigator & Institution: Capell, Warren H.; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005 Summary: (provided by applicant): Fatty acids are delivered to cells either circulating as free fatty acids (FFA) or esterified in triglycerides (TG) carried by lipoproteins. Lipoproteins interact with lipoprotein lipase (LPL), hydrolyzing their TG and making lipoprotein fatty acids (LPFA) available to cells. It is widely believed that once fatty acids enter cells, regardless of how they are delivered, they enter a common pool which is then partitioned to storage or oxidation based on the metabolic needs of the cell. However, there are examples in the literature that form a basis for hypothesizing that LPL may impact the uptake and metabolic partitioning of LPFA separately from FFA. In the proposed research, the following hypotheses will be tested: 1) By virtue of their interaction with LPL, LPFA are more likely to be esterified and stored as TG, while FFA are more likely to be partitioned toward oxidation. 2) Active LPL on the cell/endothelial surface is essential for this partitioning of LPFA to occur. 3) The partitioning of LPFA is less dependent on the metabolic environment than is the partitioning of FFA. 4) Overexpression of LPL leads to an intracellular TG pool that is not readily mobilized for oxidation. We plan to test these hypotheses utilizing myoblast and mouse models of LPL overexpression. Simultaneously providing separately labeled fatty acids as LPFA and FFA, we will be able to examine the partitioning toward storage or oxidation of each, and how disrupting normal LPL action affects this partitioning. We will also examine how LPL overexpression affects the mobilization of the intracellular TG pool, as stagnancy of this pool is felt to be associated with the development of insulin resistance.

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Project Title: LP(A) HOMOCYSTEINE AND CARDIOVASCULAR RISK IN ESRD Principal Investigator & Institution: Longenecker, Joseph C.; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 10-JUL-1998; Project End 30-JUN-2005 Summary: (Adapted from applicant's abstract) Dr. Longenecker, who trained in Internal Medicine (IM) at the Johns Hopkins Hospital (1990-1993), served as Associate Program Director for the IM Residency Program at Abington Memorial Hospital (1993-1996). He is seeking this MCSDA to study the epidemiology of atherosclerotic cardiovascular disease (ASCVD) in dialysis patients, complete a Ph.D. in Epidemiology and transition to an independent career in clinical research. Over the past year, he completed a Master of Public Health degree at Hopkins and joined the Welch Center for Prevention, Epidemiology and Clinical Research, one of the premiere sites for mentored clinical research in the country. Under the mentorship of Drs. Michael Klag and Josef Coresh, he received the NIDDK Renal Disease Epidemiology Training Grant, joined the CHOICE study (Choices for Healthy Outcomes in Caring for ESRD, an AHCPR-funded PORT), was appointed as a Clinical and Research Fellow in the Division of General Internal Medicine, co-authored a published paper with Dr. Klag, developed the proposed research plan, and finished writing a book on acid-base disorders to be published next year by Williams and Wilkins. Lipoprotein(a) [Lp(a)], homocysteine (tHcy) and ASCVD are markedly elevated in dialysis patients. However, there is insufficient evidence to establish Lp(a) and tHcy as independent risk factors for the increased incidence of ASCVD in this population. As an ancillary study of CHOICE, Dr. Longenecker plans to conduct a prospective study in 875 incident dialysis patients to investigate serum Lp(a) levels, Lp(a) isoforms and tHcy levels as risk factors for ASCVD. Dr. Longenecker has designed and initiated the ASCVD outcome data collection and validation procedures for the study. He will review the hospitalization records for ASCVD outcomes in the entire cohort. Lp(a) levels, Lp(a) isoforms and tHcy levels will be determined for each participant and will be analyzed as risk factors for ASCVD outcomes. Multivariate analyses will control for confounding by age, race, smoking, history of ASCVD, diabetes, hypertension, alcohol, body mass index, cholesterol, high and low density lipoproteins, triglycerides, and dialysis dose. The study will have sufficient power for a race- stratified analysis of interaction. Dr. Longenecker will later complete a metaanalysis of either Lp(a)- or tHcy-lowering therapies. Based on this quantitative review of the literature, he will conduct a clinical trial to test the efficacy of a promising Lp(a)- or tHcy-lowering therapy in dialysis patients. The combination of observational and experimental research in the supportive context of the Welch Center, CHOICE, and the Department of Epidemiology will give Dr. Longenecker the experience and tools he needs to develop into an Independent clinical scientist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MACRONUTRIENTS AND CARDIOVASCULAR RISK Principal Investigator & Institution: Appel, Lawrence J.; Associate Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 25-MAY-2002; Project End 31-MAR-2007 Summary: While there is widespread consensus that the optimal diet to reduce cardiovascular risk should be low in saturated fat, the type of macronutrient that should replace saturated fat (carbohydrate, protein or unsaturated fat) is a major, unresolved

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research question with substantial public health implications. The proposed study will evaluate these 3 dietary approaches by studying their effects on established coronary risk factors and a selected group of emerging risk factors. The study design is a randomized, three period cross-over feeding study that will compare the effects on blood pressure and plasma lipids of a carbohydrate-rich diet (the DASH diet) to two other diets, one rich in protein and another rich in unsaturated (UNSAT) fat, predominantly monounsaturated fat. The DASH diet has been shown to reduce blood pressure and LDL-cholesterol substantially, and is currently recommended by policy makers. During a 1 week run- in, all participants will be fed samples of the 3 study diets (DASH, PROTEIN and UNSAT). Using a three period cross-over design, participants will then be randomly assigned to the DASH, PROTEIN OR UNSAT diet. Each feeding period will last 6 weeks; a washout period of at least 2 weeks will separate each feeding period. Throughout feeding (run-in and the 3 intervention periods), participants will be fed sufficient calories to maintain their weight. Trial participants (n=200, approximately 50 percent female, approximately 50 percent African-American) will be 20 years of age or older, with systolic blood pressure of 120-159 mmHg and diastolic blood pressure of 80-95 mmHg. Primary outcomes variables will be blood pressure and the established plasma lipid risk factors (LDL-C, HDL-C and triglycerides). Secondary outcomes will include apolipoproteins VLDL-apoB and VLDL-apoCIII, which should be superior to triglycerides as predictors of cardiovascular events, as well as total apolipoprotein B, non-HDL cholesterol, and lipoprotein(a). In this fashion, the trial should advance our fundamental knowledge of the effects of diet on both traditional and emerging risk factors, and in the process, inform policy makers and health care providers on the relative benefits of carbohydrate, protein and unsaturated fat, predominantly monounsaturated fat, as means to reduce cardiovascular risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MAGNETIC RESONANCE OF CARDIAC C13 FLUX & METABOLIC RATE Principal Investigator & Institution: Lewandowski, E Douglas.; Professor; Physiology and Biophysics; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-AUG-1993; Project End 31-JUL-2008 Summary: (provided by applicant): This proposal exploits the opportunity for a comprehensive 13C NMR evaluation of fatty acid handling within the intact, functioning heart. The overall goal is to further develop and apply our kinetic 13C NMR methods to study the reciprocal relationship between the activity of the key regulator of fatty acid oxidation, carnitine palmitoyl transferase I (CPTI) and turnover of the myocardial triglyceride pool in normal and diabetic animal models. New and exciting findings from the previously funded period enable 13C NMR to distinguish between oxidative rates in the mitochondria and the rate of long chain fatty acid transport, via CPT1, as well as detect the incorporation rate of 13C-enriched palmitate into the myocardial triglyceride pool, all in the intact, beating heart. Therefore, this study explores the hypotheses that: 1) changes in the regulation of long chain fatty acid oxidation, via CPT1 activity, mediate the turnover rate of myocardial triglycerides and can be evaluated in whole hearts by a comprehensive examination of 13C enrichment kinetics; 2) Alterations in triglyceride content and turnover in the diabetic myocardium occur due to a combination of hyperlipidemia and changes in the expression of genes encoding enzymes for fatty acid uptake and oxidation pathways and that these can be distinguished via 13C NMR as independent mediators in the pathogenesis of diabetic cardiomyopathy. This hypothesis will be tested in both in both rat and mouse models of

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normal, diabetic, and genetically altered cardiac phenotypes. Specific aims are: 1) Determine reciprocal effects of fatty acid oxidation rates on triglyceride turnover via cardiac 13C NMR during partial inhibition of CPT1; 2) Examine long chain fatty acid oxidation rates, CPT1 activity, and triglyceride pool turnover in the hearts of rats with type-I (insulin deficient) diabetes and test for a potential link between triglyceride accumulation and turnover and the activation of protein kinase C; 3) Investigate effects of triglyceride pool size on the reciprocal nature of CPT1 activity and triglyceride turnover in a transgenic mouse model, overexpressing peroxisome proliferatoractivated receptor alpha (PPAR-alpha), that mimics the diabetic phenotype for fatty acid and glucose metabolism and allows for dietary control of myocardial triglyceride pool size; 4) Examine long chain fatty acid oxidation rates, CPT1 activity, and triglyceride turnover in a more clinically relevant animal model of type II (insulin resistant) diabetes, the db/db mouse model, versus non-diabetic, wild-type mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM & SIGNIFICANCE OF CUBILIN-MEDIATED HDL UPTAKE Principal Investigator & Institution: Argraves, W Scott.; Associate Professor; Cell Biology and Anatomy; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: We have used a unique cell culture model to study in vitro catabolism of high density lipoproteins (HDL) and to identify cubilin as a receptor that mediates endocytosis and lysosomal degradation of holoparticle HDL. The activities of cubilin are distinct from those of the other known HDL receptor, scavenger receptor SR-BI, which mediates selective lipid uptake without facilitating endocytosis and degradation of the whole particle. Cubilin is a 460-kDa peripheral membrane protein that is expressed in kidney, intestine and yolk sac edoderm. The physiological significance of cubilin activity with respect to HDL endocytosis in these tissues is unknown. The vital role served by yolk sac cubilin is indicated by the severe developmental abnormalities observed when cubilin antibodies are administered to pregnant rats or to embryos cultured ex utero. A central hypothesis of this grant application is that cubilin functions in the yolk sac endoderm to mediate uptake of maternal plasma HDL and thereby serves a role supplying the embryo with HDL-associated cholesterol, lipid-soluble vitamins, phospholipids and/or triglycerides. To test this hypothesis, and to characterize fundamental mechanistic features of cubilin function, four aims are proposed. The first aim is to define the molecular basis for ligand binding and endocytotic functions of cubilin and will include mapping binding sites for HDL apolipoproteins A-I and A-II, and establishing the basis for the association of cubilin with the plasma membrane as it lacks a membrane-spanning domain. To accomplish these goals, recombinant fragments of cubilin and monoclonal antibodies will be produced and tested using in vitro binding and cellular uptake assays. The second aim is to determine whether other cell surface proteins function in conjunction with cubilin to mediate HDL endocytosis. These studies will evaluate megalin, a receptor that binds cubilin, and several other proteins that copurify with cubilin in the process of cublilin-mediated HDL endocytosis. The third aim is to test the hypothesis that cubilin not only functions to mediate lysosomal degradation of HDL but also mediates transcytosis as a means to transport HDL or its constituents across certain epithelia. This study will involve measuring transport of radiolabeled HDL across a monolayer of cubilin-expressing cells cultured on a permeable support. The fourth aim is to determine the developmental significance of

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cubilin-mediated uptake of HDL by yolk sac endoderm. Together, these studies should provide new insights into the function of cubilin in processes such as maternalembryonic lipoprotein transport and embryonic development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MENTORED DEVELOPMENT AW

PATIENT-ORIENTED

RESEARCH

CAREER

Principal Investigator & Institution: Kosmiski, Lisa A.; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 01-AUG-2000; Project End 30-JUN-2005 Summary: PROPOSAL (Adapted from the applicant's abstract): Treatment of HIVinfected individuals with PIs is associated with changes in body fat distribution and metabolic disturbances similar to those seen in syndrome X. PI use has been variably associated with hypertriglyceridemia, insulin resistance including diabetes mellitus and the development of central obesity which is often accompanied by loss of fat from the extremities and buttocks. It is unclear how these complications relate to each other. Based on the experience of patients with syndrome X, it is highly probable that if these metabolic complications of PI therapy cluster, then they will in turn be associated with an increased risk of coronary artery disease. One hypothesis of this proposal is that patients who develop an increase in abdominal girth as well as those who develop hypertriglyceridemia without a clinically apparent change in body fat distribution will both have significantly more visceral fat and insulin resistance compared to controls. The investigators hypothesize that these changes represent one syndrome rather than several. To test this hypothesis, four groups of HIV-infected subjects will be compared: 1) PI-treated patients who have developed a "protease paunch;" 2) PI-treated patients with hypertriglyceridemia but no clinically apparent change in body fat distribution; 3) PI-treated patients free of these two complications; and 4) PI-naive patients. Body composition and visceral adiposity will be determined by dual energy X-ray absorptiometry (DEXA) and computerized tomography, respectively. Insulin sensitivity will be measured using the frequently sampled intravenous glucose test (FSIGT). A prospective study is also planned to test the hypothesis that, after the initiation of PI therapy, a decline in insulin sensitivity will predict the development of visceral fat accumulation and, therefore, may be casual in its development. This is a unique opportunity to study the development of visceral obesity and its relationship to insulin resistance. Finally, the investigators hypothesize that the decrease in peripheral adipose tissue associated with PI therapy is due to increased mobilization or decreased storage of triglycerides (TGs)in those depots. Other potential mechanisms of adipose tissue loss including apoptosis and dedifferentiation will also be studied. The loss of peripheral fat stores offer a unique opportunity to determine the genes involved in regulating adipose tissue mass and distribution in general. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METABOLIC PHENOTYPING CENTER FOR MOUSE MODELS OF DIABET* Principal Investigator & Institution: Malloy, Craig R.; Professor of Radiology and Internal Medi; Radiology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2001; Project Start 15-JUL-2001; Project End 30-JUN-2006 Summary: (Taken directly from the application) This is an application to establish a mouse phenotyping center to quantitatively evaluate liver gluconeogenesis, pyruvate

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recycling, the contribution of glycerol and Krebs cycle intermediates to glucose production, total glucose turnover, and citric acid cycle flux in live animals using a combination of 13C and 2H tracers and NMR spectroscopy. This standard metabolic assay provides the most comprehensive existing analysis of gluconeogenesis. It will be made available to on-campus and off-campus investigators having animal models of NIDDM or related disorders. In addition to the standard metabolic profile described above, a series of other phenotype specific metabolic techniques including a quantitative measure of substrate oxidation, measures of intracellular cations, and citric acid cycle flux using 13C enriched substrates will also be made available for selected animal models. A unique feature of this phenotyping center is that input will come from chemists, physicists, physiologists, computer scientists, physicians, and geneticists. All are recognized experts in 13C isotopomer analysis. A 400 MHz wide-bore NMR spectrometer will be dedicated to this project. All mice selected for phenotyping will be subjected to a standard protocol performed by high-level technicians; the data will be analyzed and interpreted by NMR spectroscopists and biochemists and made available through an interactive web site designed to allow the external investigators to test a fit of their isotopomer data to alternative metabolic models. A basic research core will focus on improving sensitivity through indirect detection of protons, develop an oral glucose tolerance test that includes 13C and 2H tracers, develop methods to measure fat oxidation in vivo, and extend measurements of extramyocellular adipose versus intramyocellular triglycerides in hind-limb mouse skeletal muscle. Finally, an administrative core will coordinate the activities of the three research cores and interface discussions between external investigators and center scientists. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METABOLISM AND GENETICS OF HYPOBETALIPOPROTEINEMIA Principal Investigator & Institution: Schonfeld, Gustav; Professor of Internal Medicine; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 01-JAN-1998; Project End 31-DEC-2007 Summary: (provided by applicant): This is a competitive renewal application to study the genetics and metabolism of familial hypobetalipoproteinemia (FHBL). Genetic studies: In addition to our families with APOB mutations on chromosome (chr) 2, we reported on seven families with linkage of FHBL to a 2cM region on chromosome 3p21. One of our aims is to find the etiologic gene in the region by positional cloning, using DHPLC (Transgenic Wave) technology and genomic DNA sequencing for mutation detection. A third group of FHBL five families manifests no linkage with either chr 2 or 3. Genomewide genotyping is being performed in these families. Our second aim is to perform linkage analyses to find susceptibility regions and ultimately the gene(s). Metabolic studies: Using magnetic resonance spectroscopy, we found 5-fold increases in liver fat in FHBL subjects bearing apoB truncation mutations compared with matched controls. We have also studied the assembly of VLDL-triglycerides (TG) in these subjects. Infusions of 2H2-palmitate, quantitation of palmitate tracer/tracee ratios in plasma and in VLDL-triglycerides by gas chromatography-mass spectrometry, and kinetic modeling of the data demonstrate that a greater proportion of VLDL-TG is derived from hepatic sources than from plasma palmitate in FHBL subjects than controls. A significant correlation was found between liver fat (by MRI) and the fractional contribution of hepatic sources (r=0.90, p=0.001). Our aim is to extend these studies in our FHBL subjects and to patients with the metabolic Syndrome X, and to evaluate the importance of metabolic "risk factors" such as body weight, insulin resistance on the extent of accumulation of liver fat in these groups.

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Project Title: MODIFIED LDL, AUTOIMMUNITY AND VASCULAR DISEASE IN DIABETES Principal Investigator & Institution: Lopes-Virella, Maria; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2001; Project Start 30-SEP-1996; Project End 31-AUG-2006 Summary: (provided by applicant) High levels of immune complexes (IC) containing oxLDL predict the development of macrovascular complications in type 1 diabetes (DM) and are associated with coronary artery disease (CAD) in type 2 DM. Data obtained during the on-going funding period shows that the levels of oxLDL-IC are significantly associated with internal carotid intima-medial thickness (pG), which results in a substitution of Ser for Gly at position 49, and at nucleic acid 1165 (G- >C, which results in a substitution of Gly for Arg and position 389. Beta1 AR polymorphisms have functional significance; whether or

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not they associate with obesity is unknown. Mutations in the 5' leader and coding regions of the human beta2 AR gene give rise to several polymorphisms, which can after receptor density and function. The working hypotheses of this submission are that polymorphisms at position 389 and haplotypes of beta2 AR polymorphisms in the 5' leader and coding regions associate with obesity. Specific Aim #1: to compare the beta1 AR allele frequencies and genotypes in healthy obese and non- obese subjects. The hypothesis driving this specific aim is that obesity associates with the Gly 389 beta1 AR allele. Specific Aims #2: to compare the distribution of beta2 AR haplotypes in healthy obese (Body Mass Indexes > 30) and non-obese (BMI < 25) subjects. Beta2 AR haplotypes will be determined by PCR and direct sequencing. The thesis driving this specific aim is that obesity associates with the Arg19-Gly16- Glu27 beta2 AR haplotype. The distribution of beta2 AR haplotypes in 118 non-obese and 118 otherwise healthy obese subjects will be compared. The results of this study will determine whether polymorphisms in beta1 and beta2 AR allels associate with obesity. The information obtained from our studies are important in designing clinical trials of interventions designed to reduce body weight. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POST ABDOMINAL FAT

MENOPAUSAL

HORMONE

THERAPY

AND

INTRA

Principal Investigator & Institution: Gower, Barbara A.; Associate Professor; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 01-DEC-2000; Project End 30-NOV-2001 Summary: Background: Hormonal and metabolic changes associated with the menopause may confer increased risk for cardiovascular disease (CVD). Data indicate that the postmenopausal period is associated with increases in total and central ("android") body fat; increases in the atherogenic components of the blood lipid profile; and deterioration of glucose tolerance - all risk factors for CVD. Changes in lipid and glucose metabolism may be secondary to accumulation of central fat, particularly intraabdominal fat (IAF), the compartment associated with dyslipidemia and insulin resistance. Hormone replacement therapy has positive effects on the lipid profile in postmenopausal women, and may affect regional fat deposition. However, the extent to which the beneficial effects of hormone therapy on disease risk factors are mediated by changes in fat distribution is not known. Few studies have examined the effects of hormone replacement therapy on body composition and fat distribution, and non have examined the effect of exogenous hormones on IAF, the adipose compartment most closely associated with disease risk. Objective: To test the hypothesis that hormone replacement therapy (HRT, combined estrogen-progestin) in postmenopausal women decreases risk by limiting IAF deposition. The proposed research will examine the effect of HRT on total, regional, and intra-abdominal fat deposition, and on the relationships between adiposity, the plasma lipid profile, and glucose metabolism. Design: Longitudinal cohort study of 140 early postmenopausal women using or not using HRT. A baseline assessment (within the first year of hormone use) and one 2-year follow-up assessment will be conducted. Total body fat will be assessed with dual-energy X-ray absorptiometry, hydrodensitometry, and deuterium dilution; and regional adiposity (thigh, abdominal, intra-abdominal) will be quantified with computed tomography. Circulating levels of total cholesterol, high- and low-density lipoprotein cholesterol, and triglycerides will be determined. Insulin sensitivity and glucose tolerance will be assessed with the tolbutaminde-modified, frequently-sampled, intravenous glucose tolerance test and minimal modeling. Significance: HRT reduces risk and incidence of

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CVD in postmenopausal women. This study will determine if HRT reduces disease risk by influencing fat distribution and decreasing IAF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTEASE INHIBITOR RELATED DYSLIPIDEMIA Principal Investigator & Institution: Wanke, Christine A.; Associate Professor; Family Medicine & Cmty Health; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2001; Project Start 12-JUL-2000; Project End 30-JUN-2005 Summary: Protease inhibitors are used as therapy in HIV patients and have been reported to cause elevations in plasma triglycerides, cholesterol, and glucose, and rarely to induce severe hypertriglyceridemia, pancreatitis, and diabetes mellitus with insulin resistance, excess fat deposition, and lipodystrophy. Our aims are to measure fasting Serum cholesterol (C), triglyceride (TG), remnant lipoprotein (RLP) C and TG, low density lipoprotein (LDL) C, high density lipoprotein C, lipoprotein(a), apolipoproteins A-I and B, apo E genotype, homocysteine, free fatty acids, glucose, insulin, and blood pressure. We will also assess smoking status, carotid artery wall thickness by ultrasound, and coronary artery calcification by computerized tomography in our prospective cohort of 400 HIV patients whose nutritional status is being evaluated and who are taking a variety of antiviral agents including protease inhibitors. Comparisons will be made on and off inhibitors and also longitudinally, and with controls. Our comparison group are participants in the Framingham Offspring Study who have had all the same parameters measured (n=3250). HIV patients who become hyperlipidemic on protease inhibitors will be treated with either gemfibrozil or atorvastatin. We will also examine the effects of protease inhibition in Hep G2 and CaCo2 cells with or without supplementation with fatty acids and cholesterol on lipoprotein assembly and secretion and apolipoprotein, LDL receptor, and microsomal transfer protein (MTP) gene expression. The effects of protease inhibition on lipoprotein metabolism and aortic foam cell formation will also be assessed in F1B hamsters on chow and on diets high in cholesterol and saturated fat. In addition, using a primed constant infusion in the constantly fed state and deuterated leucine, the secretion and catabolism of apoB-48 and apoB-100 within lipoproteins will be determined by GC/MS analysis and multicompartmental modeling in the presence or absence of protease inhibition with ritonavir in 10 males and 10 female HIV patients. We will test the following hypothesis: 1) protease inhibitors increase triglyceride and cholesterol by increasing RLP; 2) elevated RLP leads to increased carotid wall thickness and coronary calcification; 3) these increases can be ameliorated with diet, gemfibrozil and/or atorvastatin treatment; 4) in cell culture these RLP increases are elated to enhanced secretion of apo B-100 due to less intracellular degradation, and excess cellular lipid content; 5) in hamsters there are increased RLP in serum in animals on the atherogenic diet, especially with protease inhibition, and this leads to increased aortic foam cell formation; 6) in humans protease inhibition causes increased triglyceride-rich lipoprotein apo B-100 secretion. This research should define the nature of the problem, its mechanism, and methods for treatment wit regard to the hyperlipidemia induced by protease inhibitors in HIV patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REDUCTION OF TRIGLYCERIDES IN WOMEN ON HRT Principal Investigator & Institution: Kuller, Lewis H.; Professor and Chair; Epidemiology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260

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Triglycerides

Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): The risk and benefits of hormone replacement therapy (HRT) have come under increased concern in recent years because of the results of the HERS and WHI trials, the increased risk of breast cancer, new therapies, i.e., SERMs and lipid lowering drugs, bisphosphorates, and better understanding of hormone metabolism and disease. We have shown in several studies that the potential benefits of HRT are limited by lifestyle, cofactors, specifically weight gain, obesity and increased visceral abdominal fat associated metabolic changes in lipoproteins, inflammatory markers and estrogen metabolites. We are proposing a randomized trial of 500 women, on HRT for at least two years, aged 52-60 years, and three or more years postmenopausal to test whether reduction in waist circumference, triglycerides, dense LDLc, number of LDL particles, CPR, PAI-I by aggressive diet exercise, versus a health education control will decrease progression or result in regression of measures of subclinical vascular disease. The intervention is designed to reduce total fat intake to 17 percent of calories, 1300 kilo calories, and increase moderate activity to 150-240 minutes per week to obtain a 10 percent reduction in weight. The primary endpoint will be a 20 percent or at least a 20 mg decrease in triglyceride levels, a 5 cm decrease in waist circumference, and a 10 percent decrease in LDLc. This will result in changes in subclinical measurements including carotid ultrasound, electron beam computer tomography of the coronary and aorta, pulse wave velocity, endothelial function, and tonometry of the radial artery. NMR spectroscopy of lipoproteins, inflammatory markers, and estrogen metabolites will also be evaluated. Therefore, the primary goal of this trial is the modification of measures of subclinical disease among HRT users. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGIONAL ADIPOSITY AND SYNDROME X IN SPINAL CORD INJURY Principal Investigator & Institution: Braunschweig, Carol; Human Nutrition and Dietetics; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2004 Summary: (provided by applicant): Total and abdominal obesity frequently occur following SCI. Excessive total body adiposity, particularly excessive visceral abdominal adipose tissue (VAAT), and thigh skeletal muscle adiposity (TSKMAT), measured by magnetic resonance imaging (MRI), have been associated with a low-grade systemic inflammation and the metabolic syndrome (MS) (also called syndrome X) which has been defined as the presence of three or more of the following features: waist circumference (WC) greater than 40 inches, fasting triglycerides of at least 150 mg/dl, glucose equal or greater than 110 mg/dl, HDL cholesterol equal or less than 40 mg/dl and/or blood pressure of at least 130/85 mmHg. People with the MS are predisposed to developing insulin resistance and increased risks for diabetes mellitus, hypertension, and cardiovascular disease. Individuals with SCI have higher prevalence rates for these diseases than able-bodied individuals, however, measures of VAAT or TSKMAT volumes and their relation to a measure for inflammation, features of the MS or insulin resistance have not been reported for this population. This is unfortunate given that body fat distribution and inflammatory status are both modifiable risk factors. The purpose of this pilot investigation is to explore the association between measures of adiposity (total, abdominal, VAAT and TSKMAT), a sensitive marker of inflammation (CRP), features of the MS, and insulin resistance in paraplegic men compared to similar able-bodied men. The investigators propose a cross sectional investigation of community dwelling males (N = 60) recruited from urban SCI rehabilitation and trauma

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centers to determine whether the volume of VAAT, its anthropometric surrogates (WC and/or sagittal diameter), and/or the volume of TSKMAT predict concentrations of CRP, levels and numbers of features of the MS, and insulin resistance in paraplegic men and whether these variables are similar in direction, magnitude and association to those observed in able-bodied men. Four groups of men more than one year post SCI or trauma, frequency matched for age and ethnicity (15/group; 30 paraplegic SCI and 30 able-bodied men with a history of trauma resulting in a hospital stay over 5 days), will be recruited as follows: group 1 lean SCI (WC 40 inches), group 3 lean able-bodied (WC 40 inches). Correlation analysis, multiple regression, and analysis of variance will be used to determine the association between CRP, the MS, insulin sensitivity, and various measures of regional adiposity between these groups. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION AND ACTIVATION OF STATS IN ADIPOCYTES Principal Investigator & Institution: Stephens, Jacqueline M.; Associate Professor; Biological Sciences; Louisiana State Univ A&M Col Baton Rouge Office of Sponsored Programs Baton Rouge, La 70803 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 31-AUG-2003 Summary: Adipocytes are highly specialized cells which play a central role in lipid homeostasis and the maintenance of energy balance in vertebrate organisms. These cells store energy in the form of triglycerides during periods of nutritional abundance and release it in the form of free fatty acids at times of nutritional deprivation. Pathological conditions associated with altered adipocyte cell number or function include obesity and several lipodystrophy syndromes. Obesity, an excessive accumulation of adipose tissue, is a common disorder which affects over 30 percent of Americans. In humans, obesity is an independent risk factor for non-insulin dependent diabetes mellitus (NIDDM), hypertension, and coronary artery disease and is a major contributor to morbidity and mortality. Recent studies suggest that obesity and its related disorders may be linked to a breakdown in the regulatory mechanisms which control the expression of metabolic genes in adipocytes. Significant advances toward an understanding of these regulatory processes have been made by the identification of transcription factors which regulate adipocyte differentiation and gene expression. To date, members of two transcription factor families, C/EBP (C/AAAT Enhancer Binding Proteins) and PPAR (Peroxisome Proliferator Activated Receptors) have been shown to be induced during adipocyte differentiation and play a critical role in the regulation of fat-specific genes. Our recent investigations have demonstrated that an additional family of transcription factors are induced during adipocyte differentiation. The STATs (Signal Transducers and Activators of Transcription) comprise a family of transcription factors which reside in the cytoplasm of resting cells. Unlike either C/EBPs or PPARs, STATs can be rapidly activated to control gene expression. In a manner equivalent to both C/EBPalpha and PPARgamma, expression of three STAT family members correlates with lipid accumulation. Since STAT family members have unique tissue distributions and are highly expressed in adipocytes, we hypothesize that STATs play a key role in the regulation of adipocyte gene expression. To test this hypothesis, we will examine the regulation and activation of STATs in adipocytes. We have also designed a set of experiments to elucidate the function of these proteins in adipocytes. These studies may lead to insights into the molecular mechanisms regulating energy homeostasis and may have a profound impact on the defects underlying obesity and NIDDM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Triglycerides

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Project Title: REGULATION OF TRIACYLGLYCEROL METABOLISM IN OBESITY Principal Investigator & Institution: Sidossis, Labros S.; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 18-DEC-1996; Project End 30-NOV-2002 Summary: This application focuses on the hypertriglyceridemia associated with upper body obesity. The investigator hypothesizes that increased triglycerides in upper body obesity result from increased availability of free fatty acids to the liver due to resistance to insulin mediated inhibition of peripheral lipolysis. Furthermore, hyperglycemiainduced inhibiton of hepatic fatty acid oxidation results in diversion of hepatic free fatty acids into esterification for triglycerides. The investigator further proposes that the relative importance of either increased hepatic free fatty acid availability or reduced hepatic fatty acid oxidation in abnormal triglyceride production depends on feeding. To investigate these hypotheses, the investigator proposes quantification of whole body and regional (leg and splanchnic) free fatty acid kinetics and oxidation and VLDL triglycerides secretion and clearance rates in both upper body and lower body obese individuals. These measures are to be made both fasting and fed. The investigator will also manipulate free fatty acid concentrations by adjustments with nicotinic acid, lipid and, heparin infusions. The studies employ stable and radioactive isotopes for kinetic measurements and involve detailed physiologic and kinetic mathematical modeling. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RISK OF CHD IN WOMEN WITH POLYCYSTIC OVARY SYNDROME Principal Investigator & Institution: Talbott, Evelyn O.; Faculty; Epidemiology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2004 Summary: (Adapted from the Investigator's Abstract) Polycystic ovary syndrome (PCOS), characterized by chronic anovulation, hyperandrogenism, and insulin resistance, is estimated to affect four percent to eight percent of all women. In 1992, the investigators initiated the first large-scale study of cardiovascular risk factors in women with PCOS (1992-1994). They recruited 244 women with PCOS and 244 age-, race- and neighborhood-matched controls age (19-50 years of age) and determined that PCOS cases had a profile that conferred increased cardiovascular risk (increased LDLc, triglycerides, and waist/hip ratio, obesity, decreased HDLc, hyperinsulinemia, and increased diastolic and systolic blood pressure). During phase II, (1996-99) they investigated the prevalence of subclinical atherosclerosis (SCA) of the carotid arteries in women 30+ years of age from the original cohort. In preliminary analyses, PCOS cases 45+ years had significantly higher mean intima-media wall thickness (IMT) than controls (0.75mm vs. 0.70mm, p=40 years from the original cohort to determine if PCOS cases have greater initial coronary or aortic calcification and/or greater progression during years 4 and 5, 2) evaluate the progression of carotid atherosclerosis over a 5-year period of PCOS cases and controls >=40 years who participated in Phase II of the study, 3) evaluate whether CHD risk factors can be linked to the extent of coronary and aortic calcification within cases and controls, 4) evaluate vascular stiffness in PCOS cases and controls and determine CHD risk factors for aortic stiffness, and 5) evaluate endothelial function in PCOS cases and controls and changes over five years. CHD risk factors will include: HDLt, LDLc, triglycerides, glucose, insulin, Lp(a), PAI-1, blood pressure, and anthropometric measures. Information will be obtained on medical, reproductive and physical activity history. The investigators state that this study has the potential to

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identify the determinants of early SCA in this high-risk group of women and has important implications for primary as well as secondary prevention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF FREE FATTY ACIDS IN HUMAN INSULIN METABOLISM Principal Investigator & Institution: Stein, Daniel T.; Associate Professor of Medicine; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2006 Summary: Increased availability of lipid substrates, particularly plasma non-esterified free fatty acids and intracellular triglyceride stores have been linked to many aspects of the insulin resistance syndrome including obesity, dyslipidemia and Type 2 diabetes. Epidemiologic and animal data suggest that saturated fats have differential effects on the induction of insulin resistance as well as their effects (both stimulatory and inhibitory) on beta cell function compared to unsaturated fats. Current medical guidelines suggest limiting fat, particularly saturated fat intake. Surprisingly, considering the potential public health implications of dietary fat intake, little direct experimental data exists for human subjects in this area, and available data is contradictory. The goal of these studies, therefore, is to explore the effect of lipids on normal beta cell physiology and then to directly test the hypothesis that dietary saturated fatty acids time dependently stimulate insulin secretion more and then induce greater degrees of insulin secretory dysfunction with prolonged exposure as compared to unsaturated fats using the novel method of in vivo stable isotope peptide pharmacokinetics. As beta cell function deteriorates with prolonged NEFA exposure, hyperinsulinemia matching the degree of insulin resistance will be maintained by decreases in systemic and hepatic insulin clearance. We will also test the proposition that subjects at risk for Type 2 diabetes will be more sensitive to the effects of saturates compared to normal controls. Lastly we hypothesize that for the group as a whole, defects in insulin action, insulin clearance and finally beta cell secretory function will be exactly paralleled by accumulations of intracellular triglycerides in multiple tissues including within hepatocytes and skeletal myocytes as monitored non-invasively by magnetic resonance proton spectroscopy and that this provides the unifying link to systemic organ dysfunction with abnormal lipid metabolism in the insulin resistance syndromes. Preliminary data support the feasibility of our approach as well as our hypothesis. An improved understanding of beta cell - lipid interactions should provide evidence for future dietary recommendations to prevent type 2 diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF STEAROYL-COA DESATURASE IN METABOLISM Principal Investigator & Institution: Ntambi, James M.; Professor; Biochemistry; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 30-JUN-2006 Summary: (provided by applicant): Stearoyl-CoA desaturase is a central lipogenic enzyme catalyzing all reactions in the synthesis of monounsaturated fatty acids mainly oleate (C18:1) and palmitoleate (C16:1) which are the major monounsaturated fatty acids of membrane phospholipids, triglycerides, wax esters and cholesterol esters. Several SCD gene isoforms (SCD1, SCD2, SCD3) exist in the mouse. We have found that mice with a targeted disruption of the SCD1 isoform (SCD1-/-) have reduced body fat, plasma leptin and insulin levels and a reduced rate of triglyceride synthesis in liver. Compared to wild type mice, SCD1-/- mice are lean and resistant to high fat diet-

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induced obesity. The expression of lipogenic genes is reduced in the SCD1-/- mice. It is well known that fatty acid and triglyceride synthesis is regulated by the insulindependent gene expression and maturation of the sterol regulatory element binding protein-ic (SREBP-1c). What we found instead is that while the SREBP-1c gene expression was not altered in the SCD1-/- mice, the maturation of the SREBP-1 protein into its transcriptionally active form is blocked. The levels of ketone bodies and the mRNA levels of the peroxisome proliferator activated receptor alpha (PPAR-alpha) target genes are increased suggesting increased fatty acid Beta-oxidation in the SCD1-/mice. We hypothesize that SCD1 deficiency induces a signal that down regulates lipogenesis by modulating the SREBP-1 protein maturation and activates the PPARa pathway to partition fatty acids towards fatty acid Beta-oxidation. We shall design experiments to address this hypothesis using wild type (SCD1 +/+), heterozygotes (SCD1+/-) and homozygotes (SCD1-/-) mice as well as primary hepatocytes derived from these animals. The specific aims of this proposal are: 1. To determine whether SCD1 deficiency causes a blockage in the processing of the liver SREBP-1 protein to its mature form and down-regulates lipogenesis. 2. To elucidate how SCD1 deficiency upregulates fatty acid Beta-oxidation. Overall, our studies wil provide physiologically relevant information on the role of stearoyl-CoA desaturase gene expression in lipid and carbohydrate metabolism and will enhance our understanding of metabolic control of lipogenesis and dysregulation in diabetes and obesity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SLEEP METABOLISM

DISORDERED

BREATHING,

APOE

AND

LIPID

Principal Investigator & Institution: Mignot, Emmanuel J.; Director; Psychiatry and Behavioral Sci; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 21-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Recent findings suggest interrelationships between obstructive sleep apnea, lipid metabolism, and neurodegeneration. Apolipoprotein E epsilon4 (APOE e4), a genetic marker linked to increased cardiovascular disease (CVD) risk and Alzheimer's disease (AD), is associated with a two fold increased risk of sleep disordered breathing (SDB), and an increase in severity of apnea symptoms. Preliminary data suggest that this association is stronger between the ages of 50 and 65. Other experiments suggest dysregulated leptin levels in obstructive sleep apnea (OSA). Taken together, these findings suggest common pathophysiological mechanisms involving dysregulated lipid metabolism in OSA. An understanding of these mechanisms is essential for the prevention and treatment of SDB. In this project, we will: 1) extend our finding that APOE e4 increases the risk of sleep apnea in the general population using case/control and family designs; 2) examine if polymorphisms in other genes regulating lipid levels are associated with sleep apnea; 3) study the relationship between lipid regulatory gene polymorphisms, lipid profile (LDL- cholesterol, HDL-cholesterol, triglycerides), plasma leptin (and other lipid regulatory hormones), and sleep apnea levels. These studies will be critical to extend our understanding of the association between sleep apnea and the metabolic syndrome. This application will focus on one arm of this complex equation, the relationship between lipid metabolism and SDB. With lipid metabolism being critical to cardiovascular risk, this application will also trigger further studies focusing on cardiovascular impact with adequate control of SDB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SOY AND LIPOPROTEINS IN POSTMENOPASUAL WOMEN Principal Investigator & Institution: Allen, Jerilyn K.; Associate Professor; None; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant) Cardiovascular disease (CVD) remains the leading cause of mortality and disability in postmenopausal women. Menopause alters serum lipids and lipoproteins to produce a more atherogenic lipid profile that may contribute significantly to the increased risk for the development of CVD over the lifetime of women. Clinical trials have demonstrated a beneficial effect of soy protein containing isoflavones (soy) on plasma lipids and lipoproteins; however, these studies included small numbers of postmenopausal women and virtually none included sufficient African-American women. In addition, no published data exist on the impact of soy on atherogenic lipoprotein subclasses in postmenopausal women. Therefore, the primary aim of this study is to determine the effects of soy on lipids, lipoproteins and lipoprotein subclass in a sample of African-American and white postmenopausal women with lowdensity lipoprotein (LDL) cholesterol elevations that may increase their lifetime risk for CVD but would not qualify for definite pharmacotherapy under current guidelines. The secondary aims are to assess the impact of soy on menopausal quality of life, including menopausal symptoms, and to examine racial/ethnic differences in quality of life, acceptability, adherence to, and lipoprotein response to the soy supplementation. The proposed study is a double blind, parallel group, randomized clinical trial. A total of 160 healthy postmenopausal women (50 percent African-American) with LDL cholesterol between 130 mg/dL and 190 mg/dL will be enrolled. Following a pre-randomization run-in period on a NCEP Step I diet, women will be randomized to receive soy containing isoflavones or casein dietary supplements for 3 months. Major outcome variables will be assessed in both groups at baseline and again at 3 months. It is hypothesized that soy supplementation will result in significantly greater reduction in LDL cholesterol, LDL particle concentration, and prevalence of dense LDL particles and improvement in menopausal quality of life compared with placebo and that these effects will be comparable in African-Americans and whites. This will be the first study to determine whether a natural plant product can ameliorate the unfavorable changes in known and novel lipid risk factors that are a consequence of menopause in both African-American and white women. The unique transitional outcomes explored in this study will add substantially to the limited body of knowledge of the effects of soy. Evaluation of this nutritional alternative to hormone replacement therapy (HRT) that may provide a beneficial effect on lipid risk factors and menopausal symptoms but would be free of the adverse effects on triglycerides, the breast and uterus, and thrombotic events associated with HRT could have significant public health implications for postmenopausal women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRUCTURE/FUNCTION OF PROTEINS AT MOLECULAR LEVEL Principal Investigator & Institution: Stroud, Robert M.; Professor; Biochemistry and Biophysics; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 01-APR-1979; Project End 31-DEC-2002 Summary: The proposal seeks to uncover fundamental mechanisms of transmembrane processes at the level of atomic structure. Specific objectives are to understand the mechanisms of transmembrane signaling in the acetylcholine receptor superfamily of

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Triglycerides

pentameric, ion channel neuroreceptors by structural analysis of components, fragments of the AcCh Receptor alpha chain in complex with neurotoxins to which they bind tightly, the extracellular portion of a subunit, and portions of a whole receptor. These are to provide a three dimensional road map of interactions and will have broad impact on the understanding of fundamental elements in neurochemistry, and structure assisted development of selective psychoactive drugs. The structure of a bacterial, monomeric ion channel-forming protein colicin Ia (Col Ia), with similar conductance properties to neuronal receptors, is being extended in resolution from 3.0 Angstrom units to 2.3 Angstrom units. Mutations will be used to define the impact of charge and polar arrangements in regulating conductance I and selectivity of ion channels. Interpretation of the unique structural features, and their role in determining receptor binding, translocation and channel insertion will be defined by a combination of mutational, channel, forming, bacterial targeting, thermodynamic, and structural analysis. Electron microscopic analysis is to assist in defining the membrane bound channel state. The mechanism of host immunity to this bacteriocidal protein involves high affinity intra-membrane association with a three membrane-crossing immunity protein Imm Ia. The structure of this complex will be sought to uncover basic mechanisms of intramembrane interaction, with impact on the design of modulators of transmembrane receptors. The structure of a channel forming Bacillus thuringiensis toxin (CytA) at 2.3 Angstrom units is a paradigm for interpreting the many existing mutations that alter transmembrane assembly, and channel forming properties, to understand the mechanisms of channel formation, and the membrane bound form. The initial 1.6 Angstrom units structure of apo-Cholesterol esterase, an abundant, enzyme important in regulating transmembrane transport of triglycerides and cholesterol from cholesterol esters is to understand membrane active mechanisms, and to provide a template for structure assisted drug development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SUBSTRATE CYCLING IN ENERGY METABOLISM Principal Investigator & Institution: Wolfe, Robert R.; Professor; Surgery; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2001; Project Start 01-DEC-1984; Project End 31-MAY-2003 Summary: In this project we will extend our previous studies defining factors controlling hepatic triglyceride (TG) metabolism under normal conditions to the situation following severe burn injury. We will investigate the general hypothesis that hepatic fatty acid oxidation is inhibited following burn injury. Related to that general hypothesis, we propose to investigate the following specific hypotheses with regard to the response to burn injury: 1. Hepatic fatty acid oxidation is limited in burn injury by an inhibition of carnitine palmitoyltransferase-I (CPT-I). 2. CPT-I is inhibited by a high concentration of hepatic malonyl-CoA. Further, we propose that the high concentration of malonyl-CoA stems from accelerated glucose metabolism and production of pyruvate. 3. Hepatic uptake of plasma free fatty acids (FFA) is a direct function of delivery and thus not limited by an inhibition of oxidation. Rather, when oxidation is limited, plasma FFA are channeled preferentially into hepatic triglycerides. 4. Changes in FFA availability have a greater effect on hepatic TG synthesis in burn injury than normal because the low activity of CPT-I limits the extent to which fatty acid oxidation can respond to changes in availability. 5. Carbohydrate intake causes a greater hepatic uptake of glucose in burn injury than normal because of hyperglycemia. As a consequence, the de novo synthesis of fatty acids in the liver is stimulated to a greater extent than normal because of the activated state of acetyl-CoA carboxylase (ACC). 6.

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Maintenance of euglycemia during glucose intake by means of infusion will decrease the proportionate uptake of glucose by the liver, and thereby reduce the rate of fatty acid synthesis. Studies will be performed in patients with severe burns and in normal volunteers. Arterial and hepatic vein catheters will enable calculation of the splanchnic balance of substrates and metabolites labeled with a combination of stable and radioactive isotopes. Corresponding studies will be performed in normal and burned pigs in order to examine in greater depth the mechanisms responsible for the observed responses in human patients. Taken together, these results will help to explain the metabolic basis for abnormal hepatic fatty acid and triglyceride metabolism in stress and insulin-resistant states such as burn injury. This information will provide a physiological basis for the development of a practical approach to controlling increased triglyceride synthesis in insulin resistant states. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THROMBOSIS GENE POLYMORPHISMS AND EARLY CHD RISK IN HERS Principal Investigator & Institution: Herrington, David M.; Professor; Internal Medicine; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2004 Summary: (provided by applicant): The Heart and Estrogen/progestin Replacement Study (HERS) and several other clinical studies and clinical trials have observed a transient increase in risk for coronary heart disease (CHD) events after initiation of hormone replacement therapy (HRT). Some evidence suggests that this adverse effect of HRT may be limited to a subgroup of women who are uniquely at risk for a thrombotic complication of estrogen therapy. There are several well-described polymorphisms in genes whose products regulate coagulation or fibrinolysis that could augment thrombotic risk in the setting of estrogen therapy. These polymorphisms include Factor V Leiden, prothrombin 20210A, Factor VII R353Q. plasminogen activator inhibitor-1 (PAI-1) 4G/5G, fibrinogen B-beta-455A, and platelet GP IIIa P1-A1.A2. We propose a nested case-control study among HERS women with CHD (n = 361) or venous thrombotic events (VTEs) (n = 95) and two clinic-matched controls to assess the relation between the above listed polymorphisms, HRT, and risk for CHD or VTEs. We will estimate the absolute and relative risk of HRT among women with and without the six candidate thrombosis gene polymorphisms and test for evidence of a genotype * HRT interaction. In secondary analyses, we will focus on events that occurred in the first year, evaluate the effect of triglycerides on risk associated with the Factor VII and PAI-1 polymorphisms, and explore the impact of combinations of polymorphisms on risk. DNA for this project will be acquired from centrally stored Pap smears that were collected during the trial. If this project reveals a high-risk subgroup based on thrombosis gene polymorphisms, women could be screened for this condition and cautioned not to use HRT. Conversely, low-risk women might be able to use HRT more safely in pursuit of various health benefits, including a possible reduction in CHD risk. Thus, this project may lead to more effective strategies to prevent CHD in women, enhance the safety of HRT, and add to the expanding body of knowledge concerning drug/gene interactions as they relate to treatment and prevention of disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TISSUE SPECIFIC REGULATION OF LIPOPROTEIN LIPASE Principal Investigator & Institution: Eckel, Robert H.; Professor of Medicine,; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 01-DEC-1979; Project End 30-JUN-2005 Summary: Lipoprotein lipase (LPL) is a secretory glycoprotein which contributes to the delivery of lipid fuels to tissues where they are predominantly stored (adipose tissue) or oxidized (muscle). The regulation of LPL in adipose tissue and muscle is often divergent, and alterations in LPL and its regulation by hormones and nutrients are commonly seen in metabolic disorders of insulin resistance, i.e. obesity and type II diabetes mellitus. The importance of LPL in muscle to the regulation of energy balance has recently been demonstrated by the prevention of high fat diet-induced obesity in mice with targeted muscle- specific overexpression of LPL (MCKhLPL). Of interest, despite the reduction in plasma free fatty acids and triglycerides in MCKhLPL mice, muscle triglycerides were increased and insulin sensitivity decreased. This raises important questions about the contribution of LPL to fatty acid metabolism in muscle. In the current application, a series of related studies will be implemented to pursue the mechanisms by which LPL overexpression in muscle favorably alters body composition, but results in triglyceride accumulation in muscle and reductions in insulin sensitivity. In addition, a combined in vivo and in vitro approach will be used. Investigations will focus on the following hypotheses, that: 1) deprivation of energy intake, reductions in ambient temperature and exercise will modify energy expenditure and reduce adipose tissue mass more in MCKhLPL mice than controls, and that these perturbations will also affect the phenotype of female MCKhLPL mice, previously unaffected by LPL overexpression in skeletal muscle; and 2) in mice and in cultured C2C12 myoblasts stably transfected with LPL, that LPL will partition lipoprotein fatty acids preferentially to pathways of esterification prior to oxidation. Overall, these studies should provide new and important insights into the physiology of LPL in muscle, and how enhancing LPL expression in muscle affects fatty acid and triglyceride metabolism in muscle, insulin action and body composition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENZYME

TNFALPHA-LIPOPROTEIN

CONTROL

OF A

SURFACTANT

Principal Investigator & Institution: Mallampalli, Rama K.; Professor; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 31-MAY-2005 Summary: Surfactant, a surface-active mixture comprised of phosphatidylcholine (PC) and key hydrophobic proteins, is deficient in acute lung injury. The cytokine tumor necrosis factor alpha (TNFalpha),-plays a key role in the pathogenesis of sepsis-induced lung injury and decreases levels of surfactant PC. The major question addressed in this proposal is how TNFalpha decreases PC content. Previous studies have shown that TNFalpha decreases PC by increasing PC degradation. This proposal will address a complementary paradigm that TNFalpha decreases PC synthesis. The synthesis of PC is tightly regulated in cells by the rate-regulatory enzyme cytidylyltransferase (CT). CT is activated by fatty acids, but inhibited by other lipids such as ceramide and sphingosine. CT activity is also inhibited by enzyme phosphorylation induced by mitogen-activated protein (MAP) kinases. One effect of TNFalpha is the generation of ceramide derived from sphingomyelin (SM) hydrolysis. TNFalpha also activates multiple MAP kinase

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pathways, including the p42/44 MAP pathway. Ceramide rapidly deacylates to sphingosine, and sphingosine can trigger p42/44 MAP kinase activation. Further, ceramide activates cell proteases, which might degrade the CT enzyme. These observations led to the overall hypothesis that TNFalpha inhibits surfactant PC synthesis, in part, by decreasing CT activity via generation of the inhibitory lipid, ceramide. In this proposal, we will determine if the negative effects of TNFalpha on CT activity are due to induction of ceramide, and/or activation of the p42/44 MAP kinase (AIM 1), or ceramide-induced alteration of CT protein stability (AIM 2). We will also determine if fatty acids can counteract TNFalpha inhibitory effects as they stimulate CT activity and surfactant production in vitro. However, because exogenous fatty acids have mixed success and are potentially toxic in vivo, we will use a new strategy to counteract TNFalpha effects by administering very low-density lipoproteins (VLDL) with lipoprotein lipase (LPL). VLDL triglycerides are hydrolyzed to fatty acids by LPL. We will determine if activation of CT by VLDL and LPL is mediated by altering specific fatty acids or sphingolipids, and if these effects of lipoprotein pretreatment oppose inhibition of CT by TNFalpha (AIM 3). Our hypothesis will be tested by in vivo administration of TNFalpha and VLDL with analysis conducted in primary adult type II alveolar epithelial cells. These in vivo studies will be supplemented with a TNFalpha and lipoprotein-responsive type II (MLE-12) cell line. The unique contributions of this proposal impacting the field of surfactant metabolism include 1) delineation of a novel effector pathway linking TNFalpha-signaling with surfactant synthesis (AIM 1) 2) studies investigating CT protein stability which represent a new regulatory mechanism for this key surfactant enzyme (AIM 2) and 3) studies with potential clinical application by which lipoproteins modulate surfactant synthesis in the setting of cytokine-induced acute lung injury (AIM 3). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSCRIPTION FACTOR FUNCTION IN CHROMATIN Principal Investigator & Institution: Imbalzano, Anthony N.; Cell Biology; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2002; Project Start 01-AUG-1997; Project End 31-JUL-2006 Summary: (provided by applicant): To understand normal development and differentiation, it is necessary to determine the mechanisms by which cells initiate new programs of gene expression and promote formation of specific cell lineages. Typically, this involves activation of genes that are transcriptionally silent and that may be incorporated into repressive chromatin structure. Evidence supports the idea that differentiation specific transcriptional regulators and enzymes that remodel chromatin structure cooperate to render genomic DNA more accessible to the transcriptional machinery. SWI/SNF enzymes alter nucleosome structure in an ATP dependent manner and facilitate transcription factor function in vitro and in vivo. Components of these enzymes are essential for embryonic development and some act as tumor suppressors. Additionally, SWI/SNF enzymes interact with other known tumor suppressors and are implicated in cell cycle control. Thus these enzymes are broadly required for normal cell function and their misregulation is implicated in tumor formation.We recently demonstrated a requirement for SWI/SNF enzymes in the initiation of skeletal muscle and adipocyte differentiation. Skeletal muscle differentiation has long been a model for studying fundamental principles of differentiation. Understanding skeletal muscle differentiation at a molecular level will have significant implications for investigating muscle regeneration and the formation of rhabdomyosarcomas, which are tumors of myogenic derivation. Adipocytes are a central component of the energy balance system

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in mammals. They store triglycerides during periods of nutritional abundance and release free fatty acids during periods of caloric deficiency. In humans, excessive development of adipocyte tissue, or obesity, affects 30 percent of the adults in the U.S. This population is at significantly increased risk for non-insulin dependent diabetes, coronary artery disease, and hypertension. Characterization of the molecular events that initiate and regulate adipocyte differentiation is therefore also an important medical concern. The goals of Aims 1 and 2 are to understand the mechanisms by which SWI/SNF chromatin remodeling enzymes promote development and differentiation, with emphasis on how SWI/SNF enzymes and key transcriptional regulators initiate new programs of gene expression. Aim 3 will probe the generality of the requirement for SWI/SNF enzymes in different differentiation pathways and embryogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSLOCATION, ASSEMBLY, AND DEGRADATION OF APOB Principal Investigator & Institution: Chuck, Steven L.; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 31-MAR-2003 Summary: Apolipoprotein (apoB) is secreted from liver and intestine only in association with cholesterol and triglycerides as lipoprotein particles (VLDL or chylomicrons). Since the secretion of cholesterol and apo B are coupled, an understanding of the regulation of the secretion of apo B might lead to new interventions that reduce plasma cholesterol levels. The balance between assembly and degradation accounts for the primary regulation of apo B secretion. Assembly of apo B-containing lipoprotein particles in hepatic and intestinal cells appears to occur in the endoplasmic reticulum and Golgi apparatus. Intracellular degradation of newly-synthesized apo B occurs in different locations depending on the species: in HepG2 cells, apoB at the ER is degraded, whereas in rat hepatocytes, degradation of apoB occurs after it has trafficked to the golgi. The molecular mechanisms by which apo B is sorted for assembly or degradation is not known. Translocation into the endoplasmic reticulum is one step at which regulation occurs: some molecules of apoB are bound by ubiquitin while in the Sec61 complex. The sequences in apoB and the cellular proteins that mediate this early regulatory step will be identified and characterized. Other proteins that participate in the assembly or degradation of apoB also will be sought. The overall goal of these studies is to develop a molecular view of the assembly and degradation of apo B and other secretory proteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TRIGLYCERIDE SYNTHESIS AND LIPOTOXICITY Principal Investigator & Institution: Farese, Robert V.; Associate Investigator; J. David Gladstone Institutes 365 Vermont St San Francisco, Ca 94103 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): The obesity epidemic is threatening world health, largely because of its associated diseases, type 2 diabetes mellitus and atherosclerosis. Although the mechanisms underlying obesity-associated diseases are unclear, the lipotoxicity hypothesis has emerged as a plausible explanation. This hypothesis states that the deposition of excess lipids in tissues other than white adipose tissue over time leads to tissue dysfunction. For example, lipid deposition in skeletal muscle is associated with insulin resistance, in pancreatic beta cells with defective insulin secretion, and in heart muscle with cardiomyopathy. Despite these strong associations from studies in

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animals and humans, the lipotoxicity hypothesis remains unproven, and its underlying mechanisms remain unclear. Whether triglycerides themselves or precursors of triglyceride synthesis (e.g., diacylglycerol and fatty acyl CoAs) are toxic to nonadipose cells is unclear. We propose to test the lipotoxicity hypothesis by directly modulating triglyceride synthesis in specific tissues of mice. Triglyceride synthesis is catalyzed by acyl CoA:diacylglycerol (DGAT) enzymes. Aim 1 describes the generation and analysis of mice that overexpress DGAT1 in skeletal muscle, pancreatic beta cells, and cardiac muscle. Aim 2 describes the generation and analysis of mice that lack DGAT1 in skeletal muscle, beta cells, and white adipose tissue. We will use these mouse models to determine whether modulating triglyceride synthesis influences tissue lipotoxicity and to explore the mechanisms, including alterations in tissue lipids, gene expression, and signaling pathways, that contribute to lipotoxicity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VLDL AND LDL PARTICLE TYPES AS CHD RISK FACTORS Principal Investigator & Institution: Sacks, Frank M.; Associate Professor; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02460 Timing: Fiscal Year 2003; Project Start 28-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): Plasma triglyceride concentration is an independent although relatively weak risk factor for coronary heart disease (CHD). The relative weakness of plasma triglycerides to predict CHD may be due to the substantial diversity of lipoprotein particles that carry the triglycerides, some being related to atherosclerosis and CHD more than others. We have shown in patients who have had a myocardial infarction that the rather weak association between triglycerides and subsequent coronary events is secondary to a stronger relationship with specific types of VLDL remnants, those in the LDL density range that contain apoCIIl. This application seeks to extend these findings to initial coronary events in patients who do not have CHD. The Primary Specific Aim will evaluate VLDL and LDL particle types as predictors of initial coronary events in men from the Health Professional Follow-up Study (HPFS) and women from the Nurses' Health Study (NHS). A prospective nested case-control design will be used with a total of 1000 CHD cases and 1000 matched controls, with equal numbers of men and women. We will specifically investigate the role of apoCIII containing VLDL and LDL particles in diabetes by over sampling so that 50% of the patients will have type 2 diabetes mellitus. Our previous work shows that LDL apoCIII particles are independent predictors of recurrent CHD in diabetic patients who survived a myocardial infarction. We hypothesize that apoCIII may have a special role in dyslipidemia and CHD in diabetes. Secondary Aims: Besides apoCIII, other small apolipoproteins, apo C1, CII, and All are components of VLDL and LDL and modulate the metabolism of apoB lipoproteins. It is likely that these apolipoproteins have a relationship with human atherosclerosis. We will measure these apolipoproteins in VLDL and LDL and evaluate their relationship to CHD. We will also investigate the associations between these new lipoprotein risk factors and intake of foods and nutrients, physical activity, and other risk factors, including smoking, BMI, age and gender. The results will provide new means to identify nondiabetic and diabetic persons who are at high risk of developing CHD and the environmental determinants, and could form the basis for new lipoprotein targets for lipid management by diet and medicines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: WISCONSIN EPIDEMIOLOGICAL STUDY OF CARDIOVASCULAR DISEAS Principal Investigator & Institution: Klein, Ronald; Professor; Ophthalmology and Visual Sci; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2001; Project Start 01-FEB-1999; Project End 31-JAN-2003 Summary: This proposal describes a population-based cohort aimed at determining the prevalence and incidence of cardiovascular disease morbidity and mortality in people with Type 1 diabetes of long-duration. For this epidemiologic study, subjects include all insulin-taking persons who: (1) were less than 30 years of age at the time of their diagnosis, (2) had received primary medical care in an 11-county area of south-central Wisconsin, and (3) were first identified in 1979-80. Standardized protocols for examinations and interviews have been employed during the baseline, 4-, 10-, and 14year follow up examinations. Refusal rates have been low. The mean age of the cohort and the long duration of diabetes provide an opportunity to document the prevalence and incidence of coronary heart disease, myocardial infarction, angina, congestive heart failure, stroke, transient ischemic attacks, peripheral vascular disease, and cardiovascular disease mortality in a large population-based group of persons with Type 1 diabetes. Retinal photographs of each study participant were taken at the baseline examination. This will permit us to test the predictive ability of focal and generalized retinal arteriolar narrowing and arterio-venous cross changes (i.e. A/V nicking) for subsequent macrovascular events controlling for other risk factors. These factors include blood pressure, cigarette smoking, serum lipids, body mass index, duration of diabetes, and glycemia. We plan to reexamine this cohort to obtain ECGs, blood lipid fractions not previously measured, and fibrinogen, as well as upper and lower extremity blood pressures, urine specimens, and medical records. This will provide information about silent about silent infarctions and other cardiographic abnormalities as well as previously doctor-diagnosed macrovascular events in longterm survivors of Type 1 diabetes. Study examinations will be performed in a mobile van. Participants will provide two urine specimens for determination of urinary albumin excretion. Fasting blood will be obtained for determination of glycosylated hemoglobin Alc, blood sugar, serum cholesterol, triglycerides, HDL- cholesterol, LDLcholesterol, VDL-cholesterol, LDL particle size, serum creatinine, and fibrinogen. Additional study procedures include measurements of weight and height, waist and hip girth, and brachial and ankle blood pressures. Electrocardiography will also be performed. A questionnaire will be administered Participants will subsequently be interviewed yearly and clinical and hospital records and death certificates will be collected to document new cardiovascular disease events. Findings regarding the prevalence and incidence of cardiovascular disease and associated risk factors will be of great public health importance in directing further at preventing these conditions in people with Type 1 diabetes of long duration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: XALD: ROLE OF VERY LONG CHAIN FATTY ACYL-COA SYNTHETASES Principal Investigator & Institution: Watkins, Paul A.; Associate Professor; Kennedy Krieger Research Institute, Inc. Baltimore, Md 21205 Timing: Fiscal Year 2003; Project Start 01-FEB-1999; Project End 31-JAN-2007 Summary: (provided by applicant): Acyl-CoA synthetases (ACS) occupy a central position in fatty acid metabolism. For incorporation into phospholipids, triglycerides, or

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cholesterol esters, elongation, desaturation, degradation by b-oxidation, or acylation of proteins, a fatty acid must first be activated to its CoA thioester. Despite this vital function, only recently have the precise roles in metabolism of the numerous mammalian ACSs begun to be investigated. We have grouped ACSs by amino acid sequence similarity into at least six families. Two human and mouse ACS families, the very long-chain ACS (VLACS) family and a recently discovered ACS family that includes the BG gene (mutated in the fruit fly mutant "bubblegum") contain enzymes capable of activating very long-chain fatty acids (VLCFA; containing >22 carbons). VLCFA are essential components of complex lipids, particularly in the brain, and maintenance of VLCFA homeostasis is critical to normal health. Thus, enzymes that control the fate of VLCFA by any of the pathways noted above are of central importance. VLCFA accumulate in plasma and tissues of patients with X-linked adrenoleukodystrophy (XALD), a severe, often fatal neurodegenerative disorder. Defective VLCFA degradation via peroxisomal b-oxidation and decreased VLACS activity in peroxisomes have been implicated in the biochemical pathology of XALD. However, the gene defective in XALD, ABCD1, encodes ALDP, a peroxisomal protein of the ATP-binding cassette transmembrane transporter superfamily that has no VLACS activity. The VLACS and BG families contain a total of 8 enzymes. To understand overall VLCFA homeostasis, we must therefore understand the specific function of each of these enzymes. Therefore, we propose: 1) to develop a novel and generally applicable ACS assay, 2) to investigate the specific biological roles of human VLACSs, and 3) to characterize the BG1 knockout mouse and to assess the role of BG1 in XALD. Results of these studies will have a significant impact on our understanding of how fatty acids are channeled into specific metabolic pathways. Furthermore, they will facilitate elucidation of the role of enzymes belonging to the VLACS or BG families in XALD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ZEBRAFISH ASSAY FOR CHOLESTEROL AND LIPID LOWERING DRUGS Principal Investigator & Institution: Rubinstein, Amy L.; Zygogen, Llc Kell Hall 520 Atlanta, Ga 303033003 Timing: Fiscal Year 2003; Project Start 15-JUN-2003; Project End 31-MAY-2004 Summary: (provided by applicant): High levels of low density lipoprotein (LDL), cholesterol and triglycerides have been associated with an increase in cardiovascular disease. Drugs such as cholesterol-lowering statins and triglyceride-lowering fibrates have led to a reduction in coronary heart disease. Although current drugs have enjoyed some success, a need exists for improved lipid management and reduced side effects. Zygogen is developing a novel in vivo approach to identifying potential lipid-lowering drugs using Zebrafish, called Z-Lipotrack. Lipid processing is highly conserved in the Zebrafish. Because Zebrafish larvae are essentially transparent, lipid processing can be readily observed in the whole organism, with the aid of fluorescent lipid reporters. The goal of the proposed research is to develop Z-Lipotrack technology for use in high throughput compound screening, with the ultimate aim of discovering better drugs for lowering lipid levels. The proposed work will validate Z-Lipotrack as a compound screening tool. This includes testing additional control compounds, characterizing compounds identified in a small but diverse library of marketed drugs, and quantifying the fluorescent read-out in an automated fashion. Due to the high fecundity of Zebrafish, high throughput drug screening using Zebrafish larvae is feasible and could dramatically increase the chances of finding important new drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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

An Inhibitor of the Microsomal Triglyceride Transfer Protein Inhibits apoB Secretion from HepG2 Cells. by Jamil H, Gordon DA, Eustice DC, Brooks CM, Dickson JK, Chen Y, Ricci B, Chu C, Harrity TW, Ciosek CP, Biller SA, Gregg RE, Wetterau JR.; 1996 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38171

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Another hormone-sensitive triglyceride lipase in fat cells? by Saltiel AR.; 2000 Jan 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33961

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Apolipoprotein C3 SstI polymorphism and triglyceride levels in Asian Indians. by Chhabra S, Narang R, Krishnan LR, Vasisht S, Agarwal DP, Srivastava LM, Manchanda SC, Das N.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116591

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Bioconversion of Xylan to Triglycerides by Oil-Rich Yeasts. by Fall R, Phelps P, Spindler D.; 1984 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=240078

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Consistency of genetic inheritance mode and heritability patterns of triglyceride vs. high density lipoprotein cholesterol ratio in two Taiwanese family samples. by Chien KL, Hsu HC, Su TC, Yang CY, Lee YT.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155683

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Control of triglyceride synthesis by the intracellular level of long-chain acyl coenzyme A for lipid synthesis. by Kamiryo T.; 1983 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=215106

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Correlation of Propionibacterium acnes Populations with the Presence of Triglycerides on Nonhuman Skin. by Webster GF, Ruggieri MR, McGinley KJ.; 1981 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=243900

3 4

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

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

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Degradation of triglycerides by a pseudomonad isolated from milk: molecular analysis of a lipase-encoding gene and its expression in Escherichia coli. by Johnson LA, Beacham IR, MacRae IC, Free ML.; 1992 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=195672

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Direct antidiabetic effect of leptin through triglyceride depletion of tissues. by Shimabukuro M, Koyama K, Chen G, Wang MY, Trieu F, Lee Y, Newgard CB, Unger RH.; 1997 Apr 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20776

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Genetic variants in Apolipoprotein AV alter triglyceride concentrations in pregnancy. by Ward KJ, Shields B, Knight B, Salzmann MB, Hattersley AT, Frayling TM.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=280668

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Genomic interval engineering of mice identifies a novel modulator of triglyceride production. by Zhu Y, Jong MC, Frazer KA, Gong E, Krauss RM, Cheng JF, Boffelli D, Rubin EM.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15548

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Induced mutant mouse lines that express lipoprotein lipase in cardiac muscle, but not in skeletal muscle and adipose tissue, have normal plasma triglyceride and highdensity lipoprotein-cholesterol levels. by Levak-Frank S, Hofmann W, Weinstock PH, Radner H, Sattler W, Breslow JL, Zechner R.; 1999 Mar 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15913

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Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: Evidence for an antiinflammatory role for lipoprotein lipase. by Ziouzenkova O, Perrey S, Asatryan L, Hwang J, MacNaul KL, Moller DE, Rader DJ, Sevanian A, Zechner R, Hoefler G, Plutzky J.; 2003 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151409

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Managing hypertriglyceridemia. by Fung MA, Frohlich JJ.; 2003 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151985

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Managing hypertriglyceridemia. by Mercola J.; 2003 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151984

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Palmitoylation of Apolipoprotein B Is Required for Proper Intracellular Sorting and Transport of Cholesteroyl Esters and Triglycerides. by Zhao Y, McCabe JB, Vance J, Berthiaume LG.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14805

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Relationships Between the Responses of Triglyceride-Rich Lipoproteins in Blood Plasma Containing Apolipoproteins B-48 and B-100 to a Fat-Containing Meal in Normolipidemic Humans. by Schneeman BO, Kotite L, Todd KM, Havel RJ.; 1993 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46022

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Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain triglyceride. by Roe CR, Sweetman L, Roe DS, David F, Brunengraber H.; 2002 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151060

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Triglyceride accumulation protects against fatty acid-induced lipotoxicity. by Listenberger LL, Han X, Lewis SE, Cases S, Farese RV Jr, Ory DS, Schaffer JE.; 2003 Mar 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152249

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

A 52-week, multicenter, randomized, parallel-group, double-blind, double-dummy study to assess the efficacy of atorvastatin and simvastatin in reaching low-density lipoprotein cholesterol and triglyceride targets: the treat-to-target (3T) study. Author(s): Olsson AG, Eriksson M, Johnson O, Kjellstrom T, Lanke J, Larsen ML, Pedersen T, Tikkanen MJ, Wiklund O; 3T Study Investigators. Source: Clinical Therapeutics. 2003 January; 25(1): 119-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12637115&dopt=Abstract

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Accumulation of 3-hydroxy-fatty acids in the culture medium of long-chain L-3hydroxyacyl CoA dehydrogenase (LCHAD) and mitochondrial trifunctional proteindeficient skin fibroblasts: implications for medium chain triglyceride dietary treatment of LCHAD deficiency. Author(s): Jones PM, Butt Y, Bennett MJ. Source: Pediatric Research. 2003 May; 53(5): 783-7. Epub 2003 March 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12621125&dopt=Abstract

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Allergic contact dermatitis from medium-chain triglycerides in a moisturizing lotion. Author(s): Laube S, Davies MG, Prais L, Foulds IS. Source: Contact Dermatitis. 2002 September; 47(3): 171. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12492556&dopt=Abstract

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

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An enteral therapy containing medium-chain triglycerides and hydrolyzed peptides reduces postprandial pain associated with chronic pancreatitis. Author(s): Shea JC, Bishop MD, Parker EM, Gelrud A, Freedman SD. Source: Pancreatology : Official Journal of the International Association of Pancreatology (Iap). [et Al.]. 2003; 3(1): 36-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12649562&dopt=Abstract

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Angiopoietin-like protein 3 mediates hypertriglyceridemia induced by the liver X receptor. Author(s): Inaba T, Matsuda M, Shimamura M, Takei N, Terasaka N, Ando Y, Yasumo H, Koishi R, Makishima M, Shimomura I. Source: The Journal of Biological Chemistry. 2003 June 13; 278(24): 21344-51. Epub 2003 April 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12672813&dopt=Abstract

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Angiotensin-converting enzyme insertion/deletion genotype is associated with the activities of plasma coagulation factor VII and X independent of triglyceride metabolism. Author(s): Okura Y, Hayashi K, Shingu T, Kuga Y, Nomura S, Kajiyama G, Nakashima Y, Saku K. Source: Coronary Artery Disease. 2003 June; 14(4): 285-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12826927&dopt=Abstract

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Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor alpha activators. Author(s): Vu-Dac N, Gervois P, Jakel H, Nowak M, Bauge E, Dehondt H, Staels B, Pennacchio LA, Rubin EM, Fruchart-Najib J, Fruchart JC. Source: The Journal of Biological Chemistry. 2003 May 16; 278(20): 17982-5. Epub 2003 March 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12637506&dopt=Abstract

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Apolipoprotein CIII and highly active antiretroviral therapy (HAART)-induced hypertriglyceridemia. Author(s): Badiou S, Dupuy AM, Baillat V, Fabre J, Tur MD, Cristol JP, Reynes J. Source: Clin Lab. 2003; 49(1-2): 11-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12593470&dopt=Abstract

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Apolipoprotein H variant modifies plasma triglyceride phenotype in familial hypercholesterolemia: a molecular study in an eight-generation hyperlipidemic family. Author(s): Takada D, Ezura Y, Ono S, Iino Y, Katayama Y, Xin Y, Wu LL, LarringaShum S, Stephenson SH, Hunt SC, Hopkins PN, Emi M. Source: J Atheroscler Thromb. 2003; 10(2): 79-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12740481&dopt=Abstract

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Ask the doctor. At age 62 I'm a bit overweight and have diabetes. I take a statin, and my LDL cholesterol is good (84 mg/dL). But my HDL is low (30 mg/dL) and my triglycerides are above 300 mg/dL. Are high triglycerides a problem? Author(s): Lee TH. Source: Harvard Heart Letter : from Harvard Medical School. 2003 March; 13(7): 8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12654588&dopt=Abstract

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Assessment of LDL particle size by triglyceride/HDL-cholesterol ratio in nondiabetic, healthy subjects without prominent hyperlipidemia. Author(s): Maruyama C, Imamura K, Teramoto T. Source: J Atheroscler Thromb. 2003; 10(3): 186-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14564088&dopt=Abstract

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Association of prothrombin and protein S with plasma triglyceride-rich lipoproteins in humans after test meals rich in milk fat or soybean oil. Author(s): Zhou L, Xu N, Nilsson A. Source: Thrombosis Research. 2002 November 25; 108(4): 209-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617983&dopt=Abstract

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Association of the endotoxin antagonist E5564 with high-density lipoproteins in vitro: dependence on low-density and triglyceride-rich lipoprotein concentrations. Author(s): Wasan KM, Sivak O, Cote RA, MacInnes AI, Boulanger KD, Lynn M, Christ WJ, Hawkins LD, Rossignol DP. Source: Antimicrobial Agents and Chemotherapy. 2003 September; 47(9): 2796-803. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12936976&dopt=Abstract

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Atorvastatin enhances the plasma clearance of chylomicron-like emulsions in subjects with atherogenic dyslipidemia: relevance to the in vivo metabolism of triglyceride-rich lipoproteins. Author(s): Sposito AC, Santos RD, Amancio RF, Ramires JA, Chapman MJ, Maranhao RC. Source: Atherosclerosis. 2003 February; 166(2): 311-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12535744&dopt=Abstract

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Beneficial effect of icodextrin on the hypertriglyceridemia of CAPD patients. Author(s): Sisca S, Maggiore U. Source: Perit Dial Int. 2002 November-December; 22(6): 727-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12556078&dopt=Abstract

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Cholesterol lipoproteins, triglycerides, rural-urban differences and prevalence of dyslipidaemia among males in Rajasthan. Author(s): Gupta R, Prakash H, Kaul V. Source: J Assoc Physicians India. 1997 April; 45(4): 275-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12521083&dopt=Abstract

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Comparison of triglycerides and phospholipids as supplemental sources of dietary long-chain polyunsaturated fatty acids in piglets. Author(s): Mathews SA, Oliver WT, Phillips OT, Odle J, Diersen-Schade DA, Harrell RJ. Source: The Journal of Nutrition. 2002 October; 132(10): 3081-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12368399&dopt=Abstract

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Consumption of a functional oil rich in phytosterols and medium-chain triglyceride oil improves plasma lipid profiles in men. Author(s): St-Onge MP, Lamarche B, Mauger JF, Jones PJ. Source: The Journal of Nutrition. 2003 June; 133(6): 1815-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12771322&dopt=Abstract

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Contribution of APOA5 gene variants to plasma triglyceride determination and to the response to both fat and glucose tolerance challenges. Author(s): Martin S, Nicaud V, Humphries SE, Talmud PJ; EARS group. Source: Biochimica Et Biophysica Acta. 2003 April 17; 1637(3): 217-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12697303&dopt=Abstract

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Coronary artery disease risk in familial combined hyperlipidemia and familial hypertriglyceridemia: a case-control comparison from the National Heart, Lung, and Blood Institute Family Heart Study. Author(s): Hopkins PN, Heiss G, Ellison RC, Province MA, Pankow JS, Eckfeldt JH, Hunt SC. Source: Circulation. 2003 August 5; 108(5): 519-23. Epub 2003 July 07. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12847072&dopt=Abstract

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Coronary heart disease in women: triglycerides and lipoprotein biology. Author(s): Dayspring TD. Source: J Gend Specif Med. 2002 September-October; 5(5): 27-33. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12380198&dopt=Abstract

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Effect of atorvastatin on lipid parameters, LDL subtype distribution, hemorrheological parameters and adhesion molecule concentrations in patients with hypertriglyceridemia. Author(s): Empen K, Geiss HC, Lehrke M, Otto C, Schwandt P, Parhofer KG. Source: Nutr Metab Cardiovasc Dis. 2003 April; 13(2): 87-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12929621&dopt=Abstract

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Effect of desirable fasting triglycerides on the postprandial response to dietary fat. Author(s): Miller M, Zhan M, Georgopoulos A. Source: Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research. 2003 February; 51(1): 50-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12580321&dopt=Abstract

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Effect of medium-chain triglycerides on the postprandial triglyceride concentration in healthy men. Author(s): Kasai M, Maki H, Nosaka N, Aoyama T, Ooyama K, Uto H, Okazaki M, Igarashi O, Kondo K. Source: Bioscience, Biotechnology, and Biochemistry. 2003 January; 67(1): 46-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12619672&dopt=Abstract

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Effect of xuezhikang, a cholestin extract, on reflecting postprandial triglyceridemia after a high-fat meal in patients with coronary heart disease. Author(s): Zhao SP, Liu L, Cheng YC, Li YL. Source: Atherosclerosis. 2003 June; 168(2): 375-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12801622&dopt=Abstract

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Effects of a brisk walk on lipoprotein lipase activity and plasma triglyceride concentrations in the fasted and postprandial states. Author(s): Gill JM, Herd SL, Vora V, Hardman AE. Source: European Journal of Applied Physiology. 2003 April; 89(2): 184-90. Epub 2003 February 07. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12665983&dopt=Abstract

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Effects of a high-sucrose diet on body weight, plasma triglycerides, and stress tolerance. Author(s): Kanazawa M, Xue CY, Kageyama H, Suzuki E, Ito R, Namba Y, Osaka T, Kimura S, Inoue S. Source: Nutrition Reviews. 2003 May; 61(5 Pt 2): S27-33. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828189&dopt=Abstract

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Effects of atorvastatin on glucose homeostasis, postprandial triglyceride response and C-reactive protein in subjects with impaired fasting glucose. Author(s): Costa A, Casamitjana R, Casals E, Alvarez L, Morales J, Masramon X, Hernandez G, Gomis R, Conget I. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2003 September; 20(9): 743-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12925055&dopt=Abstract

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Effects of baseline level of triglycerides on changes in lipid levels from combined fluvastatin + fibrate (bezafibrate, fenofibrate, or gemfibrozil). Author(s): Farnier M, Salko T, Isaacsohn JL, Troendle AJ, Dejager S, Gonasun L. Source: The American Journal of Cardiology. 2003 October 1; 92(7): 794-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14516878&dopt=Abstract

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Effects of estrogen and medroxyprogesterone acetate on subpopulations of triglyceride-rich lipoproteins and high-density lipoproteins. Author(s): Lamon-Fava S, Posfai B, Asztalos BF, Horvath KV, Dallal GE, Schaefer EJ. Source: Metabolism: Clinical and Experimental. 2003 October; 52(10): 1330-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14564686&dopt=Abstract

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Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterols, and triglyceride. Author(s): Jurgens G, Graudal NA. Source: Cochrane Database Syst Rev. 2003; (1): Cd004022. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12535503&dopt=Abstract

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Effects of short-term detraining on postprandial metabolism, endothelial function, and inflammation in endurance-trained men: dissociation between changes in triglyceride metabolism and endothelial function. [email protected]. Author(s): Gill JM, Caslake MJ, McAllister C, Tsofliou F, Ferrell WR, Packard CJ, Malkova D. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 September; 88(9): 4328-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970306&dopt=Abstract

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Effects of simvastatin, an HMG-CoA reductase inhibitor, in patients with hypertriglyceridemia. Author(s): Isaacsohn J, Hunninghake D, Schrott H, Dujovne CA, Knopp R, Weiss SR, Bays H, Crouse JR 3rd, Davidson MH, Keilson LM, McKenney J, Korenman SG, Dobs AS, Stein E, Krauss RM, Maccubbin D, Cho M, Plotkin DJ, Mitchel YB. Source: Clin Cardiol. 2003 January; 26(1): 18-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12539808&dopt=Abstract

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Elevated triglyceride and decreased high density lipoprotein level in carbon disulfide workers in Taiwan. Author(s): Luo JC, Chang HY, Chang SJ, Chou TC, Chen CJ, Shih TS, Huang CC. Source: Journal of Occupational and Environmental Medicine / American College of Occupational and Environmental Medicine. 2003 January; 45(1): 73-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12553181&dopt=Abstract

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Elevated triglycerides and low levels of high-density lipoprotein as markers of disease activity in association with up-regulation of the tumor necrosis factor alpha/tumor necrosis factor receptor system in systemic lupus erythematosus. Author(s): Svenungsson E, Gunnarsson I, Fei GZ, Lundberg IE, Klareskog L, Frostegard J. Source: Arthritis and Rheumatism. 2003 September; 48(9): 2533-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13130473&dopt=Abstract

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Expression of human hepatic lipase in the rabbit model preferentially enhances the clearance of triglyceride-enriched versus native high-density lipoprotein apolipoprotein A-I. Author(s): Rashid S, Trinh DK, Uffelman KD, Cohn JS, Rader DJ, Lewis GF. Source: Circulation. 2003 June 24; 107(24): 3066-72. Epub 2003 Jun 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12796142&dopt=Abstract

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Fasting and daylong triglycerides in obesity with and without type 2 diabetes. Author(s): van Wijk JP, Halkes CJ, Erkelens DW, Castro Cabezas M. Source: Metabolism: Clinical and Experimental. 2003 August; 52(8): 1043-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12898471&dopt=Abstract

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Fatty acids composition of plasma phospholipids and triglycerides in children with cystic fibrosis. The effect of dietary supplementation with an olive and soybean oils mixture. Author(s): Caramia G, Cocchi M, Gagliardini R, Malavolta M, Mozzon M, Frega NG. Source: Pediatr Med Chir. 2003 January-February; 25(1): 42-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12920976&dopt=Abstract

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Fatty liver in familial hypobetalipoproteinemia: triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis. Author(s): Schonfeld G, Patterson BW, Yablonskiy DA, Tanoli TS, Averna M, Elias N, Yue P, Ackerman J. Source: Journal of Lipid Research. 2003 March; 44(3): 470-8. Epub 2002 December 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562873&dopt=Abstract

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Flow injection chemiluminescent assays for glycerol and triglycerides using a coimmobilized enzyme reactor. Author(s): Yaqoob M, Nabi A. Source: Luminescence : the Journal of Biological and Chemical Luminescence. 2003 March-April; 18(2): 67-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687625&dopt=Abstract

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Fractional esterification rate of cholesterol and ratio of triglycerides to HDLcholesterol are powerful predictors of positive findings on coronary angiography. Author(s): Frohlich J, Dobiasova M. Source: Clinical Chemistry. 2003 November; 49(11): 1873-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14578319&dopt=Abstract

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GLUT4 expression in human muscle fibres is not correlated with intracellular triglyceride (TG) content. Is TG a maker or a marker of insulin resistance? Author(s): Gaster M, Ottosen PD, Vach W, Christiansen H, Staehr P, Beck-Nielsen H, Schroder HD. Source: Apmis : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica. 2003 February; 111(2): 338-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12716391&dopt=Abstract

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Glycerol metabolism and the determination of triglycerides--clinical, biochemical and molecular findings in six subjects. Author(s): Hellerud C, Burlina A, Gabelli C, Ellis JR, Nyholm PG, Lindstedt S. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2003 January; 41(1): 46-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12636049&dopt=Abstract

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Glyceroneogenesis and the triglyceride/fatty acid cycle. Author(s): Reshef L, Olswang Y, Cassuto H, Blum B, Croniger CM, Kalhan SC, Tilghman SM, Hanson RW. Source: The Journal of Biological Chemistry. 2003 August 15; 278(33): 30413-6. Epub 2003 June 04. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12788931&dopt=Abstract

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HDL-C and triglyceride levels: relationship to coronary heart disease and treatment with statins. Author(s): Gaw A. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 2003 January; 17(1): 53-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843687&dopt=Abstract

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Hepatocyte apoB-containing lipoprotein secretion is decreased by the grapefruit flavonoid, naringenin, via inhibition of MTP-mediated microsomal triglyceride accumulation. Author(s): Borradaile NM, de Dreu LE, Barrett PH, Behrsin CD, Huff MW. Source: Biochemistry. 2003 February 11; 42(5): 1283-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12564931&dopt=Abstract

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High triglycerides/low high-density lipoprotein cholesterol, ischemic electrocardiogram changes, and risk of ischemic heart disease. Author(s): Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Source: American Heart Journal. 2003 January; 145(1): 103-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12514661&dopt=Abstract

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High versus low medium chain triglyceride content of formula for promoting short term growth of preterm infants. Author(s): Klenoff-Brumberg HL, Genen LH. Source: Cochrane Database Syst Rev. 2003; (1): Cd002777. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12535437&dopt=Abstract

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High-density lipoprotein cholesterol and triglycerides as therapeutic targets for preventing and treating coronary artery disease. Author(s): Gotto AM Jr. Source: American Heart Journal. 2002 December; 144(6 Suppl): S33-42. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12486414&dopt=Abstract

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Hypertension and triglyceride catabolism: implications for the hemodynamic model of the metabolic syndrome. Author(s): Brook RD, Glazewski L, Rajagopalan S, Bard RL. Source: Journal of the American College of Nutrition. 2003 August; 22(4): 290-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12897043&dopt=Abstract

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Hypertriglyceridemia in patients with chronic renal failure: possible mechanisms. Author(s): Prinsen BH, de Sain-van der Velden MG, de Koning EJ, Koomans HA, Berger R, Rabelink TJ. Source: Kidney International. Supplement. 2003 May; (84): S121-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12694325&dopt=Abstract

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Hypertriglyceridemia is associated with increased insulin resistance in subjects with normal glucose tolerance: evaluation in a large cohort of subjects assessed with the 1999 World Health Organization criteria for the classification of diabetes. Author(s): Moro E, Gallina P, Pais M, Cazzolato G, Alessandrini P, Bittolo-Bon G. Source: Metabolism: Clinical and Experimental. 2003 May; 52(5): 616-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12759893&dopt=Abstract

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Hypertriglyceridemia-induced acute pancreatitis--treatment with heparin and insulin. Author(s): Monga A, Arora A, Makkar RP, Gupta AK. Source: Indian J Gastroenterol. 2003 May-June; 22(3): 102-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839385&dopt=Abstract

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Hypoadiponectinemia is associated with insulin resistance, hypertriglyceridemia, and fat redistribution in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy. Author(s): Addy CL, Gavrila A, Tsiodras S, Brodovicz K, Karchmer AW, Mantzoros CS. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 February; 88(2): 627-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12574192&dopt=Abstract

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Impaired triglyceride tolerance in hemodialysis patients with different apolipoprotein E (apo E) isoforms. Author(s): Zahalkova J, Vaverkova H, Novotny D, Kosatikova Z. Source: Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2002 December; 146(2): 73-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12572901&dopt=Abstract

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Importance of high-density lipoprotein cholesterol and triglyceride levels in coronary heart disease. Author(s): Sprecher DL, Watkins TR, Behar S, Brown WV, Rubins HB, Schaefer EJ. Source: The American Journal of Cardiology. 2003 March 1; 91(5): 575-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615263&dopt=Abstract

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Improvement of glycaemic control in type 2 diabetes: favourable changes in blood pressure, total cholesterol and triglycerides, but not in HDL cholesterol, fibrinogen, Von Willebrand factor and (pro)insulin. Author(s): Becker A, van der Does FE, van Hinsbergh VW, Heine RJ, Bouter LM, Stehouwer CD. Source: The Netherlands Journal of Medicine. 2003 April; 61(4): 129-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12852722&dopt=Abstract

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In vitro and in vivo lipolysis of plasma triglycerides increases the resistance to oxidative modification of low-density lipoproteins. Author(s): Skoglund-Andersson C, Karpe F, Hellenius ML, Regnstrom J, Hamsten A, Tornvall P. Source: European Journal of Clinical Investigation. 2003 January; 33(1): 51-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12492452&dopt=Abstract

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Incidence of pain after intravenous injection of a medium-/long-chain triglyceride emulsion of propofol. An observational study in 1375 patients. Author(s): Bachmann-Mennenga B, Ohlmer A, Heesen M. Source: Arzneimittel-Forschung. 2003; 53(9): 621-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14558435&dopt=Abstract

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Increased visceral fat and serum levels of triglyceride are associated with insulin resistance in Japanese metabolically obese, normal weight subjects with normal glucose tolerance. Author(s): Katsuki A, Sumida Y, Urakawa H, Gabazza EC, Murashima S, Maruyama N, Morioka K, Nakatani K, Yano Y, Adachi Y. Source: Diabetes Care. 2003 August; 26(8): 2341-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12882859&dopt=Abstract

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Incremental area under response curve more accurately describes the triglyceride response to an oral fat load in both healthy and type 2 diabetic subjects. Author(s): Carstensen M, Thomsen C, Hermansen K. Source: Metabolism: Clinical and Experimental. 2003 August; 52(8): 1034-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12898469&dopt=Abstract

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Indinavir did not further increase mean triglyceride levels in HIV-infected patients treated with nucleoside reverse transcriptase inhibitors: an analysis of three randomized clinical trials. Author(s): Rojas C, Coplan PM, Rhodes T, Robertson MN, DiNubile MJ, Guess HA. Source: Pharmacoepidemiology and Drug Safety. 2003 July-August; 12(5): 361-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12899109&dopt=Abstract

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Influence of prolonged endurance cycling and recovery diet on intramuscular triglyceride content in trained males. Author(s): van Loon LJ, Schrauwen-Hinderling VB, Koopman R, Wagenmakers AJ, Hesselink MK, Schaart G, Kooi ME, Saris WH. Source: American Journal of Physiology. Endocrinology and Metabolism. 2003 October; 285(4): E804-11. Epub 2003 June 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783774&dopt=Abstract

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Interaction effect of Serine447Stop variant of the lipoprotein lipase gene and C-514T variant of the hepatic lipase gene on serum triglyceride levels in young adults: the Bogalusa Heart Study. Author(s): Xin X, Srinivasan SR, Chen W, Boerwinkle E, Berenson GS. Source: Metabolism: Clinical and Experimental. 2003 October; 52(10): 1337-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14564687&dopt=Abstract

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Intravenous anti TNF-alpha antibody therapy leads to elevated triglyceride and reduced HDL-cholesterol levels in patients with rheumatoid and psoriatic arthritis. Author(s): Cauza E, Cauza K, Hanusch-Enserer U, Etemad M, Dunky A, Kostner K. Source: Wiener Klinische Wochenschrift. 2002 December 30; 114(23-24): 1004-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12635469&dopt=Abstract

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Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: evidence for an antiinflammatory role for lipoprotein lipase. Author(s): Ziouzenkova O, Perrey S, Asatryan L, Hwang J, MacNaul KL, Moller DE, Rader DJ, Sevanian A, Zechner R, Hoefler G, Plutzky J. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 March 4; 100(5): 2730-5. Epub 2003 February 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12606719&dopt=Abstract

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Lipoprotein production by the heart: a novel pathway of triglyceride export from cardiomyocytes. Author(s): Nielsen LB. Source: Scand J Clin Lab Invest Suppl. 2002; 237: 35-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12570165&dopt=Abstract

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Low triglyceride, not low cholesterol concentration, independently predicts poor outcome following acute stroke. Author(s): Weir CJ, Sattar N, Walters MR, Lees KR. Source: Cerebrovascular Diseases (Basel, Switzerland). 2003; 16(1): 76-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12766366&dopt=Abstract

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Medium chain triglycerides as vehicle for palatable oral liquids. Author(s): Bahal SM, Romansky JM, Alvarez FJ. Source: Pharmaceutical Development and Technology. 2003; 8(1): 111-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12665204&dopt=Abstract

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Medium- versus long-chain triglycerides for 27 days increases fat oxidation and energy expenditure without resulting in changes in body composition in overweight women. Author(s): St-Onge MP, Bourque C, Jones PJ, Ross R, Parsons WE. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2003 January; 27(1): 95-102. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12532160&dopt=Abstract

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Medium-chain triglycerides increase energy expenditure and decrease adiposity in overweight men. Author(s): St-Onge MP, Ross R, Parsons WD, Jones PJ. Source: Obesity Research. 2003 March; 11(3): 395-402. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12634436&dopt=Abstract

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Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. Author(s): Hussain MM, Shi J, Dreizen P. Source: Journal of Lipid Research. 2003 January; 44(1): 22-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12518019&dopt=Abstract

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Myocardial triglycerides and systolic function in humans: in vivo evaluation by localized proton spectroscopy and cardiac imaging. Author(s): Szczepaniak LS, Dobbins RL, Metzger GJ, Sartoni-D'Ambrosia G, Arbique D, Vongpatanasin W, Unger R, Victor RG. Source: Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 2003 March; 49(3): 417-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12594743&dopt=Abstract

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Newly identified apolipoprotein AV gene predisposes to high plasma triglycerides in familial combined hyperlipidemia. Author(s): Ribalta J, Figuera L, Fernandez-Ballart J, Vilella E, Castro Cabezas M, Masana L, Joven J. Source: Clinical Chemistry. 2002 September; 48(9): 1597-600. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12194944&dopt=Abstract

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Octanoate inhibits triglyceride synthesis in 3T3-L1 and human adipocytes. Author(s): Guo W, Lei T, Wang T, Corkey BE, Han J. Source: The Journal of Nutrition. 2003 August; 133(8): 2512-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12888629&dopt=Abstract

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Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. Author(s): Park Y, Harris WS. Source: Journal of Lipid Research. 2003 March; 44(3): 455-63. Epub 2002 December 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562865&dopt=Abstract

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Postprandial hypertriglyceridemia-induced endothelial dysfunction in healthy subjects is independent of lipid oxidation. Author(s): Bae JH, Schwemmer M, Lee IK, Lee HJ, Park KR, Kim KY, Bassenge E. Source: International Journal of Cardiology. 2003 February; 87(2-3): 259-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559548&dopt=Abstract

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Postprandial triglyceride levels in familial combined hyperlipidemia. The role of apolipoprotein E and lipoprotein lipase polymorphisms. Author(s): Reiber I, Mezo I, Kalina A, Palos G, Romics L, Csaszar A. Source: The Journal of Nutritional Biochemistry. 2003 July; 14(7): 394-400. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915220&dopt=Abstract

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Postprandial triglycerides in response to high fat: role of dietary carbohydrate. Author(s): Kriketos AD, Sam W, Schubert T, Maclean E, Campbell LV. Source: European Journal of Clinical Investigation. 2003 May; 33(5): 383-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12713451&dopt=Abstract

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Quantitative determination of faecal fatty acids and triglycerides by Fourier transform infrared analysis with a sodium chloride transmission flow cell. Author(s): Voortman G, Gerrits J, Altavilla M, Henning M, van Bergeijk L, Hessels J. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 August; 40(8): 795-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12392307&dopt=Abstract

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R219K polymorphism of the ABCA1 gene and its modulation of the variations in serum high-density lipoprotein cholesterol and triglycerides related to age and adiposity in white versus black young adults. The Bogalusa heart study. Author(s): Srinivasan SR, Li S, Chen W, Boerwinkle E, Berenson GS. Source: Metabolism: Clinical and Experimental. 2003 July; 52(7): 930-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870173&dopt=Abstract

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Relation of triglyceride levels, fasting and nonfasting, to fatal and nonfatal coronary heart disease. Author(s): Eberly LE, Stamler J, Neaton JD; Multiple Risk Factor Intervention Trial Research Group. Source: Archives of Internal Medicine. 2003 May 12; 163(9): 1077-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12742806&dopt=Abstract

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Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia. Author(s): Attie AD, Krauss RM, Gray-Keller MP, Brownlie A, Miyazaki M, Kastelein JJ, Lusis AJ, Stalenhoef AF, Stoehr JP, Hayden MR, Ntambi JM. Source: Journal of Lipid Research. 2002 November; 43(11): 1899-907. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12401889&dopt=Abstract

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Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides. Author(s): Talmud PJ, Hawe E, Martin S, Olivier M, Miller GJ, Rubin EM, Pennacchio LA, Humphries SE. Source: Human Molecular Genetics. 2002 November 15; 11(24): 3039-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12417525&dopt=Abstract

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Safety and metabolic tolerance of a concentrated long-chain triglyceride lipid emulsion in critically ill septic and trauma patients. Author(s): Garcia-de-Lorenzo A, Lopez-Martinez J, Planas M, Chacon P, Montejo JC, Bonet A, Ortiz-Leyba C, Sanchez-Segura JM, Ordonez J, Acosta J, Grau T, Jimenez FJ. Source: Jpen. Journal of Parenteral and Enteral Nutrition. 2003 May-June; 27(3): 208-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12757115&dopt=Abstract

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Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics. Author(s): Atmaca M, Kuloglu M, Tezcan E, Ustundag B. Source: The Journal of Clinical Psychiatry. 2003 May; 64(5): 598-604. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12755665&dopt=Abstract

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Short-term triglyceride lowering with fenofibrate improves vasodilator function in subjects with hypertriglyceridemia. Author(s): Capell WH, DeSouza CA, Poirier P, Bell ML, Stauffer BL, Weil KM, Hernandez TL, Eckel RH. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 February 1; 23(2): 30713. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588776&dopt=Abstract

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Skeletal muscle triglyceride: marker or mediator of obesity-induced insulin resistance in type 2 diabetes mellitus? Author(s): Goodpaster BH, Kelley DE. Source: Curr Diab Rep. 2002 June; 2(3): 216-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12643176&dopt=Abstract

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Skeletal muscle triglycerides lowering is associated with net improvement of insulin sensitivity, TNF-alpha reduction and GLUT4 expression enhancement. Author(s): Mingrone G, Rosa G, Di Rocco P, Manco M, Capristo E, Castagneto M, Vettor R, Gasbarrini G, Greco AV. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2002 September; 26(9): 1165-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12187392&dopt=Abstract

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The effect of equicaloric medium-chain and long-chain triglycerides on pancreas enzyme secretion. Author(s): Symersky T, Vu MK, Frolich M, Biemond I, Masclee AA. Source: Clinical Physiology and Functional Imaging. 2002 September; 22(5): 307-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12487002&dopt=Abstract

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The influence of maternal triglyceride levels on infant birth weight in Peruvian women with pre-eclampsia. Author(s): Sanchez SE, Zhang C, Williams MA. Source: J Matern Fetal Neonatal Med. 2003 May;13(5):328-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12916684&dopt=Abstract

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The influence of teent (Capparis decidua) on human plasma triglycerides, total lipids and phospholipids. Author(s): Goyal R, Grewal RB. Source: Nutr Health. 2003; 17(1): 71-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12803284&dopt=Abstract

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The metabolic response to intravenous medium-chain triglycerides in infants after surgery. Author(s): Donnell SC, Lloyd DA, Eaton S, Pierro A. Source: The Journal of Pediatrics. 2002 November; 141(5): 689-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12410199&dopt=Abstract

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The TNF-alpha gene NcoI polymorphism at position -308 of the promoter influences insulin resistance, and increases serum triglycerides after postprandial lipaemia in familiar obesity. Author(s): Wybranska I, Malczewska-Malec M, Niedbal S, Naskalski JW, DembinskaKiec A. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2003 April; 41(4): 501-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12747594&dopt=Abstract

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Triglyceride, albuminuria and blood pressure are the major associations of non-fatal cardiovascular disease in Chinese type 2 diabetes. Author(s): Ko GT, Chan JC, Chow CC, Yeung VT, Chan WB, So WY, Ma RC, Ozaki R, Cockram CS. Source: Acta Diabetologica. 2003 June; 40(2): 80-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12861405&dopt=Abstract

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Triglyceride-rich lipoproteins and vascular function. Author(s): Haynes WG. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 February 1; 23(2): 1535. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12588751&dopt=Abstract

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Triglyceride-rich lipoproteins are associated with hypertension in preeclampsia. Author(s): Winkler K, Wetzka B, Hoffmann MM, Friedrich I, Kinner M, Baumstark MW, Zahradnik HP, Wieland H, Marz W. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 March; 88(3): 11626. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12629100&dopt=Abstract

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Update on the role of triglycerides as a risk factor for coronary heart disease. Author(s): Miller M, Cosgrove B, Havas S. Source: Current Atherosclerosis Reports. 2002 November; 4(6): 414-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12361487&dopt=Abstract

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VLDL-induced triglyceride accumulation in human macrophages is mediated by modulation of LPL lipolytic activity in the absence of change in LPL mass. Author(s): Milosavljevic D, Kontush A, Griglio S, Le Naour G, Thillet J, Chapman MJ. Source: Biochimica Et Biophysica Acta. 2003 February 20; 1631(1): 51-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12573449&dopt=Abstract

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Weight gain, serum leptin and triglyceride levels in patients with schizophrenia on antipsychotic treatment with quetiapine, olanzapine and haloperidol. Author(s): Atmaca M, Kuloglu M, Tezcan E, Gecici O, Ustundag B. Source: Schizophrenia Research. 2003 March 1; 60(1): 99-100. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12505146&dopt=Abstract

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

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

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

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The following is a typical result when searching for recently indexed consumer information on triglycerides: •

A year in review from A to Z: what made nutrition news in 1997. Source: Flynn, M.E. Environmental-nutrition (USA). (December 1997). volume 20(12) page 1, 4.

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Effects on blood pressure, glucose, and lipid levels of a high-monounsatured fat diet compared with a high-carbohydrate diet in NIDDM subjects. Source: Rasmussen, O.W. Thomsen, C. Hansen, K.W. Vesterlund, M. Winther, E. Hermansen, K. Diabetes-care (USA). (December 1993). volume 16(12) page 1565-1571.

Additional consumer oriented references include: •

After I had a heart attack and two bypass operations, I was put on Lipitor to lower my cholesterol. My cholesterol was never high--about 170-180 mg/dL. But my HDL was always low and triglycerides were somewhat high. Now my total cholesterol is 124 and my HDL has gone up slightly. My triglycerides are way down. My LDL cholesterol has fallen from 110 to 68. Is there any downside to such a low cholesterol level, other than the need to check my liver function tests? Source: Lee, T H Harv-Heart-Lett. 1999 January; 9(5): 7 1051-5313

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Ask the doctor. My total cholesterol level is well below 200. My LDL is low, my HDL high, and my triglycerides and homocysteine are both in the “desirable” range. The one thing out of whack is that my lipoprotein(a) level is more than double the “normal” limit. My cardiologist wants me to take niacin to bring it down. I can't find any information on how serious a problem this is, especially in the context of otherwise good cholesterol levels and a healthy lifestyle. (I exercise 5 days a week; eat a low-fat, high-fiber diet; and am not overweight.). Source: Lee, Thomas H Harv-Heart-Lett. 2002 June; 12(10): 8 1051-5313

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Differential influence of LDL cholesterol and triglycerides on lipoprotein(a) concentrations in diabetic patients. Source: Hernandez, C. Chacon, P. Garcia Pascual, L. Simo, R. Diabetes-care. Alexandria, Va. : American Diabetes Association, Inc. February 2001. volume 24 (2) page 350-355. 0149-5992

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Heart Disease Handbook. 3. Triglycerides turn troublesome. Source: Hudnall, M. Environmental-nutrition (USA). (April 1997). volume 20(4) page 1, 4. heart diseases lipoproteins triglycerides diet lipid metabolism 0893-4452

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Low-fat diets, triglycerides and coronary heart disease risk. Source: Nestle, M. BNF-nutr-bull. London : The British Nutrition Foundation. March 2000. volume 25 (1) page 49-53. 0141-9684

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My doctor has me taking Lopid (gemfibrozil) twice a day. My cholesterol level is only 187, but my HDL cholesterol is low at 25. My LDL cholesterol is”normal” at 98 and my triglycerides are 318. These pills give me stomach cramps and they are expensive. Do I need to take them? Source: Anonymous Harv-Heart-Lett. 1998 August; 8(12): 8 1051-5313

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Ratio of triglycerides to HDL cholesterol is an indicator of LDL particle size in patients with type 2 diabetes and normal HDL cholesterol levels. Author(s): Department of Endocrinology-Diabetology-Nutrition, University Hospital, Grenoble, France.

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Source: Boizel, R Benhamou, P Y Lardy, B Laporte, F Foulon, T Halimi, S Diabetes-Care. 2000 November; 23(11): 1679-85 0149-5992 •

The HDL/triglycerides trap. Source: Liebman, B. Nutr-Action-Health-Lett. Washington, D.C. : Center for Science in the Public Interest. Sept 1990. volume 17 (7) page 1, 5-7. ill. 0199-5510

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Those troubling triglycerides. Source: Rosenbaum, S. Vegetarian-times (USA). (January 1994). (no. 197) page 28, 30, 32. lipaemia triglycerides cholesterol risk 0164-8497

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Triglycerides and heart disease. Source: Anonymous Harv-Heart-Lett. 2000 September; 11(1): 1-5 1051-5313

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

By the way, doctor. As a regular reader of your newsletter, I have a pretty good idea of what a healthy person's cholesterol and triglyceride levels should be. But last year, I had a couple of tests, and the results were completely different. According to the first, my triglycerides were 285, my HDL 31, and my LDL 109. Eight months later, the same measurements came in at 175, 44, and 109. What could cause such a big swing? Is it something I should be worried about? Source: Lee, T H Harv-Health-Lett. 2002 March; 27(5): 8 1052-1577

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Combination of gemfibrozil and orlistat for treatment of combined hyperlipidemia with predominant hypertriglyceridemia. Author(s): Division of Endocrinology and Metabolism, Beth Israel Medical Center, Albert Einstein College of Medicine, New York, New York 10003, USA. Source: Tolentino, M C Ferenczi, A Ronen, L Poretsky, L Endocr-Pract. 2002 May-June; 8(3): 208-12 1530-891X

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Effect of beta-lactoglobulin on plasma retinol and triglyceride concentrations, and fatty acid composition in calves. Author(s): Department of Animal Production, Tohoku National Agricultural Experimental Station, Morioka, Iwate, Japan. [email protected] Source: Kushibiki, S Hodate, K Kurisaki, J Shingu, H Ueda, Y Watanabe, A Shinoda, M JDairy-Res. 2001 November; 68(4): 579-86 0022-0299

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Fatty acids, triglycerides, and glucose metabolism: recent insights from knockout mice. Author(s): Gladstone Institute of Cardiovascular Disease, San Francisco, California 94141-9100, USA. Source: Chen, H C Farese, R V Jr Curr-Opin-Clin-Nutr-Metab-Care. 2002 July; 5(4): 35963 1363-1950

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High triglycerides. A red flag. Source: Anonymous Mayo-Clin-Health-Lett. 2002 September; 20(9): 7 0741-6245

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High versus low medium chain triglyceride content of formula for promoting short term growth of preterm infants. Author(s): Division of Newborn Medicine, The Regional Neonatal Center, New York Medical College-Westchester Medical Center, Valhalla, NY 10595, USA. [email protected] Source: Klenoff Brumberg, H L Genen, L H Cochrane-Database-Syst-Revolume 2003; (1): CD002777 1469-493X

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Impaired triglyceride tolerance in hemodialysis patients with different apolipoprotein E (apo E) isoforms. Author(s): 3rd Clinic of Internal Medicine, University Hospital Olomouc, I.P. Pavlova 6, 775 20 Olomouc, Czech Republic. [email protected] Source: Zahalkova, J Vaverkova, H Novotny, D Kosatikova, Z Biomed-Pap-Med-FacUniv-Palacky-Olomouc-Czech-Repub. 2002 December; 146(2): 73-6 1213-8118

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Low fasting serum triglyceride and high free fatty acid levels in pulmonary fibrosis: a previously unreported finding. Author(s): Department of Medicina Interna e Patologie Sistemiche, University of Catania Medical School, Garibaldi Hospital, 95123 Catania, Italy. Source: Iannello, Silvia Cavaleri, Antonina Camuto, Massimo Pisano, Maria Grazia Milazzo, Paolina Belfiore, Francesco MedGenMed. 2002 June 14; 4(2): 5 1531-0132

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Medium chain triglycerides. Monograph. Source: Anonymous Altern-Med-Revolume 2002 October; 7(5): 418-20 1089-5159

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Plasma lipid concentrations, macronutrient digestibility and mineral absorption in dogs fed a dry food containing medium-chain triglycerides. Author(s): Department of Nutrition, Faculty of Veterinary Medicine, Utrecht University, The Netherlands. [email protected] Source: Beynen, A C Kappert, H J Lemmens, A G Van Dongen, A M J-Anim-PhysiolAnim-Nutr-(Berl). 2002 October; 86(9-10): 306-12 0931-2439

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Possible role of ginsenoside Rb1 on regulation of rat liver triglycerides. Author(s): Department of Biomedical Pharmacology, Korea Ginseng and Tobacco Research Institute, Taejon. Source: Park, K H Shin, H J Song, Y B Hyun, H C Cho, H J Ham, H S Yoo, Y B Ko, Y C June, W T Park, H J Biol-Pharm-Bull. 2002 April; 25(4): 457-60 0918-6158

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Reduction of plasma triglyceride level and enhancement of plasma albumin concentration by Oren-gedoku-to administration. Author(s): Department of Japanese Oriental Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical University. [email protected] Source: Sekiya, N Kogure, T Kita, T Kasahara, Y Sakakibara, I Goto, H Shibahara, N Shimada, Y Terasawa, K Phytomedicine. 2002 July; 9(5): 455-60 0944-7113

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The biomimetic [Cr(3)O(O(2)CCH(2)CH(3))(6)(H(2)O)(3)](+ )decreases plasma insulin, cholesterol, and triglycerides in healthy and type II diabetic rats but not type I diabetic rats. Author(s): Department of Chemistry and Coalition for Biomolecular Products, The University of Alabama, Tuscaloosa, AL 35487-0336, USA. Source: Sun, Y Clodfelder, B J Shute, A A Irvin, T Vincent, J B J-Biol-Inorg-Chem. 2002 September; 7(7-8): 852-62 0949-8257

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The history of Trilucent implants, and a chemical analysis of the triglyceride filler in 51 consecutively removed Trilucent breast prostheses. Author(s): Department of Plastic and Reconstructive Surgery, The Wellington Hospital, London, UK. Source: Kirkpatrick, W N Jones, B M Br-J-Plast-Surg. 2002 September; 55(6): 479-89 00071226

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The independence of signaling pathways mediating increased expression of plasminogen activator inhibitor type 1 in HepG2 cells exposed to free fatty acids or triglycerides. Author(s): Department of Medicine, The University of Vermont, Burlington 05405, USA.

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Source: Chen, Y Schneider, D J Int-J-Exp-Diabetes-Res. 2002 Apr-June; 3(2): 109-18 15604284

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Vitamins Ascorbic Acid Source: Integrative Medicine Communications; www.drkoop.com Niacin Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,892,00.html Pantothenic Acid Source: Healthnotes, Inc.; www.healthnotes.com Pantothenic Acid Source: Integrative Medicine Communications; www.drkoop.com Pantothenic Acid and Pantethine Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin A Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B3 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B3 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B5 (Pantothenic Acid) Source: Integrative Medicine Communications; www.drkoop.com Vitamin C (Ascorbic Acid) Source: Integrative Medicine Communications; www.drkoop.com

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Minerals Calcium Source: Healthnotes, Inc.; www.healthnotes.com Carnitine Source: Prima Communications, Inc.www.personalhealthzone.com Carnitine (l-carnitine) Source: Integrative Medicine Communications; www.drkoop.com Cerivastatin Source: Healthnotes, Inc.; www.healthnotes.com

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Chromium Source: Healthnotes, Inc.; www.healthnotes.com Chromium Source: Integrative Medicine Communications; www.drkoop.com Chromium Source: Prima Communications, Inc.www.personalhealthzone.com Chromium Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10018,00.html Creatine Source: Prima Communications, Inc.www.personalhealthzone.com Creatine Monohydrate Source: Healthnotes, Inc.; www.healthnotes.com L-carnitine Source: Healthnotes, Inc.; www.healthnotes.com L-carnitine Source: Integrative Medicine Communications; www.drkoop.com Lovastatin Source: Healthnotes, Inc.; www.healthnotes.com Pravastatin Source: Healthnotes, Inc.; www.healthnotes.com Simvastatin Source: Healthnotes, Inc.; www.healthnotes.com Vanadium Alternative names: Vanadate, Vanadyl Source: Integrative Medicine Communications; www.drkoop.com •

Food and Diet Artichoke Alternative names: Cynara scolymus Source: Healthnotes, Inc.; www.healthnotes.com Atkins Diet Source: Healthnotes, Inc.; www.healthnotes.com Coffee Source: Healthnotes, Inc.; www.healthnotes.com

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Diabetes Source: Healthnotes, Inc.; www.healthnotes.com Flaxseeds Source: Healthnotes, Inc.; www.healthnotes.com Garlic Alternative names: Allium sativum Source: Healthnotes, Inc.; www.healthnotes.com Garlic Source: Prima Communications, Inc.www.personalhealthzone.com Garlic Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,786,00.html High Cholesterol Source: Healthnotes, Inc.; www.healthnotes.com High-Fiber Diet Source: Healthnotes, Inc.; www.healthnotes.com Oats Alternative names: Avena sativa Source: Healthnotes, Inc.; www.healthnotes.com Omega-3 Fatty Acids Source: Integrative Medicine Communications; www.drkoop.com Omega-3 Fatty Acids Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,992,00.html Polyunsaturated Fats Source: Healthnotes, Inc.; www.healthnotes.com Salmon Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,102,00.html Soy Source: Prima Communications, Inc.www.personalhealthzone.com Soy Products Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,135,00.html

Nutrition

Tea Source: Healthnotes, Inc.; www.healthnotes.com The Pritikin Diet Program Source: Healthnotes, Inc.; www.healthnotes.com

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CHAPTER 3. TRIGLYCERIDES

ALTERNATIVE

MEDICINE

AND

Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to triglycerides. At the conclusion of this chapter, we will provide additional sources.

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

A risk factor for atherosclerosis: triglyceride-rich lipoproteins. Author(s): Malloy MJ, Kane JP. Source: Adv Intern Med. 2001; 47: 111-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11795072&dopt=Abstract

•

A triglyceride-rich fat emulsion and free fatty acids but not very low density lipoproteins impair endothelium-dependent vasorelaxation. Author(s): Lundman P, Tornvall P, Nilsson L, Pernow J. Source: Atherosclerosis. 2001 November; 159(1): 35-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11689204&dopt=Abstract

•

Ask the doctor. My total cholesterol level is well below 200. My LDL is low, my HDL high, and my triglycerides and homocysteine are both in the “desirable” range. The

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one thing out of whack is that my lipoprotein(a) level is more than double the “normal” limit. My cardiologist wants me to take niacin to bring it down. I can't find any information on how serious a problem this is, especially in the context of otherwise good cholesterol levels and a healthy lifestyle. (I exercise 5 days a week; eat a low-fat, high-fiber diet; and am not overweight.). Author(s): Lee TH. Source: Harvard Heart Letter : from Harvard Medical School. 2002 June; 12(10): 8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12079826&dopt=Abstract •

Association of prothrombin and protein S with plasma triglyceride-rich lipoproteins in humans after test meals rich in milk fat or soybean oil. Author(s): Zhou L, Xu N, Nilsson A. Source: Thrombosis Research. 2002 November 25; 108(4): 209-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617983&dopt=Abstract

•

Autoxidation kinetic analysis of docosahexaenoic acid ethyl ester and docosahexaenoic triglyceride with oxygen sensor. Author(s): Yoshii H, Furuta T, Siga H, Moriyama S, Baba T, Maruyama K, Misawa Y, Hata N, Linko P. Source: Bioscience, Biotechnology, and Biochemistry. 2002 April; 66(4): 749-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12036046&dopt=Abstract

•

Blood glucose- and triglyceride-lowering effect of trans-dehydrocrotonin, a diterpene from Croton cajucara Benth., in rats. Author(s): Silva RM, Santos FA, Rao VS, Maciel MA, Pinto AC. Source: Diabetes, Obesity & Metabolism. 2001 December; 3(6): 452-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11903418&dopt=Abstract

•

Comparison of triglycerides and phospholipids as supplemental sources of dietary long-chain polyunsaturated fatty acids in piglets. Author(s): Mathews SA, Oliver WT, Phillips OT, Odle J, Diersen-Schade DA, Harrell RJ. Source: The Journal of Nutrition. 2002 October; 132(10): 3081-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12368399&dopt=Abstract

•

Consumption of a functional oil rich in phytosterols and medium-chain triglyceride oil improves plasma lipid profiles in men. Author(s): St-Onge MP, Lamarche B, Mauger JF, Jones PJ. Source: The Journal of Nutrition. 2003 June; 133(6): 1815-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12771322&dopt=Abstract

•

Dietary flaxseed meal is more protective than soy protein concentrate against hypertriglyceridemia and steatosis of the liver in an animal model of obesity. Author(s): Bhathena SJ, Ali AA, Haudenschild C, Latham P, Ranich T, Mohamed AI, Hansen CT, Velasquez MT.

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Source: Journal of the American College of Nutrition. 2003 April; 22(2): 157-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12672712&dopt=Abstract •

Dietary fructans, but not cellulose, decrease triglyceride accumulation in the liver of obese Zucker fa/fa rats. Author(s): Daubioul C, Rousseau N, Demeure R, Gallez B, Taper H, Declerck B, Delzenne N. Source: The Journal of Nutrition. 2002 May; 132(5): 967-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11983823&dopt=Abstract

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Effect of xuezhikang, a cholestin extract, on reflecting postprandial triglyceridemia after a high-fat meal in patients with coronary heart disease. Author(s): Zhao SP, Liu L, Cheng YC, Li YL. Source: Atherosclerosis. 2003 June; 168(2): 375-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12801622&dopt=Abstract

•

Effects of glucagon and insulin on plasma glucose, triglyceride, and triglyceride-rich lipoprotein concentrations in laying hens fed diets containing different types of fats. Author(s): Pal L, Grossmann R, Dublecz K, Husveth F, Wagner L, Bartos A, Kovacs G. Source: Poultry Science. 2002 November; 81(11): 1694-702. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12455597&dopt=Abstract

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Effects of intravenous supplementation with alpha-tocopherol in patients receiving total parenteral nutrition containing medium- and long-chain triglycerides. Author(s): Manuel-y-Keenoy B, Nonneman L, De Bosscher H, Vertommen J, Schrans S, Klutsch K, De Leeuw I. Source: European Journal of Clinical Nutrition. 2002 February; 56(2): 121-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11857045&dopt=Abstract

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Eicosapentaenoic acid improves endothelial function in hypertriglyceridemic subjects despite increased lipid oxidizability. Author(s): Okumura T, Fujioka Y, Morimoto S, Tsuboi S, Masai M, Tsujino T, Ohyanagi M, Iwasaki T. Source: The American Journal of the Medical Sciences. 2002 November; 324(5): 247-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12449445&dopt=Abstract

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Fatty acids composition of plasma phospholipids and triglycerides in children with cystic fibrosis. The effect of dietary supplementation with an olive and soybean oils mixture. Author(s): Caramia G, Cocchi M, Gagliardini R, Malavolta M, Mozzon M, Frega NG. Source: Pediatr Med Chir. 2003 January-February; 25(1): 42-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12920976&dopt=Abstract

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•

Grape polyphenols decrease plasma triglycerides and cholesterol accumulation in the aorta of ovariectomized guinea pigs. Author(s): Zern TL, West KL, Fernandez ML. Source: The Journal of Nutrition. 2003 July; 133(7): 2268-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12840191&dopt=Abstract

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HDL-C and triglyceride levels: relationship to coronary heart disease and treatment with statins. Author(s): Gaw A. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 2003 January; 17(1): 53-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843687&dopt=Abstract

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Hepatocyte apoB-containing lipoprotein secretion is decreased by the grapefruit flavonoid, naringenin, via inhibition of MTP-mediated microsomal triglyceride accumulation. Author(s): Borradaile NM, de Dreu LE, Barrett PH, Behrsin CD, Huff MW. Source: Biochemistry. 2003 February 11; 42(5): 1283-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12564931&dopt=Abstract

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Intestinal apolipoprotein B secretion is inhibited by the flavonoid quercetin: potential role of microsomal triglyceride transfer protein and diacylglycerol acyltransferase. Author(s): Casaschi A, Wang Q, Dang K, Richards A, Theriault A. Source: Lipids. 2002 July; 37(7): 647-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12216835&dopt=Abstract

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Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. Author(s): Park Y, Harris WS. Source: Journal of Lipid Research. 2003 March; 44(3): 455-63. Epub 2002 December 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562865&dopt=Abstract

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Pharmacological management of high triglycerides and low high-density lipoprotein cholesterol. Author(s): Szapary PO, Rader DJ. Source: Current Opinion in Pharmacology. 2001 April; 1(2): 113-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11714084&dopt=Abstract

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Possible role of ginsenoside Rb1 on regulation of rat liver triglycerides. Author(s): Park KH, Shin HJ, Song YB, Hyun HC, Cho HJ, Ham HS, Yoo YB, Ko YC, Jun WT, Park HJ.


Source: Biological & Pharmaceutical Bulletin. 2002 April; 25(4): 457-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11995924&dopt=Abstract •

Propofol in a medium- and long-chain triglyceride emulsion: pharmacological characteristics and potential beneficial effects. Author(s): Theilen HJ, Adam S, Albrecht MD, Ragaller M. Source: Anesthesia and Analgesia. 2002 October; 95(4): 923-9, Table of Contents. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12351269&dopt=Abstract

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Protective effects of flax meal against hypercholesterolemia and hypertriglyceridemia in rats. Author(s): Ratnayake WM, Gilani GS. Source: Journal of the American College of Nutrition. 2003 August; 22(4): 326-7; Author Reply 327-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12897048&dopt=Abstract

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Reduction of plasma triglyceride level and enhancement of plasma albumin concentration by Oren-gedoku-to administration. Author(s): Sekiya N, Kogure T, Kita T, Kasahara Y, Sakakibara I, Goto H, Shibahara N, Shimada Y, Terasawa K. Source: Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2002 July; 9(5): 455-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12222668&dopt=Abstract

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Role of soy isoflavones in the hypotriglyceridemic effect of soy protein in the rat. Author(s): Demonty I, Lamarche B, Deshaies Y, Jacques H. Source: The Journal of Nutritional Biochemistry. 2002 November; 13(11): 671-677. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12550064&dopt=Abstract

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Short-term administration of conjugated linoleic acid reduces liver triglyceride concentration and phosphatidate phosphohydrolase activity in OLETF rats. Author(s): Rahman SM, Huda MN, Uddin MN, Akhteruzzaman S. Source: J Biochem Mol Biol. 2002 September 30; 35(5): 494-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12359092&dopt=Abstract

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The influence of teent (Capparis decidua) on human plasma triglycerides, total lipids and phospholipids. Author(s): Goyal R, Grewal RB. Source: Nutr Health. 2003; 17(1): 71-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12803284&dopt=Abstract

•

Value of VLCD supplementation with medium chain triglycerides. Author(s): Krotkiewski M.

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Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2001 September; 25(9): 1393-400. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11571605&dopt=Abstract

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

General Overview Atherosclerosis Source: Healthnotes, Inc.; www.healthnotes.com Atherosclerosis and Heart Disease Prevention Source: Prima Communications, Inc.www.personalhealthzone.com Athletic Performance Source: Healthnotes, Inc.; www.healthnotes.com Cardiovascular Disease Overview Source: Healthnotes, Inc.; www.healthnotes.com


Cystic Fibrosis Source: Healthnotes, Inc.; www.healthnotes.com Diabetes Mellitus Source: Integrative Medicine Communications; www.drkoop.com Gallstones Source: Healthnotes, Inc.; www.healthnotes.com Gout Source: Integrative Medicine Communications; www.drkoop.com Heart Attack Source: Healthnotes, Inc.; www.healthnotes.com High Cholesterol Source: Integrative Medicine Communications; www.drkoop.com High Cholesterol Source: Prima Communications, Inc.www.personalhealthzone.com High Triglycerides Source: Healthnotes, Inc.; www.healthnotes.com Hypercholesterolemia Source: Integrative Medicine Communications; www.drkoop.com Hypertension Alternative names: High Blood Pressure Source: Prima Communications, Inc.www.personalhealthzone.com Hypoglycemia Source: Healthnotes, Inc.; www.healthnotes.com Hypothyroidism Source: Healthnotes, Inc.; www.healthnotes.com Insulin Resistance Syndrome Source: Healthnotes, Inc.; www.healthnotes.com Menopause Source: Integrative Medicine Communications; www.drkoop.com Obesity Source: Integrative Medicine Communications; www.drkoop.com Pancreatic Insufficiency Source: Healthnotes, Inc.; www.healthnotes.com Pancreatitis Source: Integrative Medicine Communications; www.drkoop.com

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Peripheral Vascular Disease Source: Healthnotes, Inc.; www.healthnotes.com Psoriasis Source: Healthnotes, Inc.; www.healthnotes.com Shock Source: Integrative Medicine Communications; www.drkoop.com Tinnitus Source: Healthnotes, Inc.; www.healthnotes.com Vertigo Source: Healthnotes, Inc.; www.healthnotes.com •

Alternative Therapy Fasting Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,694,00.html

•

Herbs and Supplements Acorus Alternative names: Sweet Flag; Acorus calamus L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org ALA Source: Integrative Medicine Communications; www.drkoop.com Allium Compounds Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,1024,00.html Aloe Alternative names: Aloe vera L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Aloe Alternative names: Aloe Vera Source: Integrative Medicine Communications; www.drkoop.com Aloe Vera Alternative names: Aloe Source: Integrative Medicine Communications; www.drkoop.com Alpha-Linolenic Acid (ALA) Source: Integrative Medicine Communications; www.drkoop.com


Amino Acid K Source: Integrative Medicine Communications; www.drkoop.com Amino Acids Overview Source: Healthnotes, Inc.; www.healthnotes.com Angkak Source: Integrative Medicine Communications; www.drkoop.com Astragalus MEM Alternative names: Huang-Qi; Astragalus membranaceus Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Astragalus Sp Alternative names: Vetch, Rattlepod, Locoweed; Astragalus sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Beni-Koji Source: Integrative Medicine Communications; www.drkoop.com Bilberry Source: Prima Communications, Inc.www.personalhealthzone.com Blue-Green Algae Source: Healthnotes, Inc.; www.healthnotes.com Chinese Scullcap Alternative names: Scutellaria baicalensis Source: Healthnotes, Inc.; www.healthnotes.com Crataegus Alternative names: Hawthorn; Crataegus oxyacantha L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Curcuma Alternative names: Turmeric; Curcuma longa L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org DHA Source: Integrative Medicine Communications; www.drkoop.com Docosahexaenoic Acid Source: Healthnotes, Inc.; www.healthnotes.com Docosahexaenoic Acid (DHA) Source: Integrative Medicine Communications; www.drkoop.com Eicosapentaenoic Acid (EPA) Source: Integrative Medicine Communications; www.drkoop.com

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Equisetum Alternative names: Horsetail; Equisetum arvense L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Fenofibrate Source: Healthnotes, Inc.; www.healthnotes.com Fenugreek Alternative names: Trigonella foenum-graecum Source: Healthnotes, Inc.; www.healthnotes.com Fiber Source: Healthnotes, Inc.; www.healthnotes.com Fructo-Oligosaccharides (FOS) and Other Oligosaccharides Source: Healthnotes, Inc.; www.healthnotes.com Gemfibrozil Source: Healthnotes, Inc.; www.healthnotes.com Glipizide Source: Healthnotes, Inc.; www.healthnotes.com Glucomannan Source: Healthnotes, Inc.; www.healthnotes.com Glycyrrhiza Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Grape Seed Extract Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,793,00.html Green Tea Alternative names: Camellia sinensis Source: Healthnotes, Inc.; www.healthnotes.com Guatteria Alternative names: Guatteria gaumeri Greenman Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Guggul Alternative names: Commiphora mukul Source: Healthnotes, Inc.; www.healthnotes.com Guggul Source: Prima Communications, Inc.www.personalhealthzone.com Gugulipid Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com


Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10033,00.html Gymnema Alternative names: Gurmar; Gymnema sylvestre Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Gymnema Alternative names: Gymnema sylvestre Source: Healthnotes, Inc.; www.healthnotes.com Gymnema Sylvestre Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10034,00.html Hong Qu Source: Integrative Medicine Communications; www.drkoop.com Hung-Chu Source: Integrative Medicine Communications; www.drkoop.com Insulin Source: Healthnotes, Inc.; www.healthnotes.com Isoflavones Source: Prima Communications, Inc.www.personalhealthzone.com Lecithin Source: Prima Communications, Inc.www.personalhealthzone.com Lipase Source: Integrative Medicine Communications; www.drkoop.com L-lysine Source: Integrative Medicine Communications; www.drkoop.com Lysine Alternative names: Amino Acid K, L-Lysine Source: Integrative Medicine Communications; www.drkoop.com Maitake Alternative names: Grifola frondosa Source: Healthnotes, Inc.; www.healthnotes.com Medium Chain Triglycerides Source: Healthnotes, Inc.; www.healthnotes.com Medium-Chain Triglycerides Source: Prima Communications, Inc.www.personalhealthzone.com

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Momordica Alternative names: Bitter Gourd, Karela; Momordica charantia Linn. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Monascus Source: Integrative Medicine Communications; www.drkoop.com Ocimum Alternative names: Basil, Albahaca; Ocimum basilicum Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Panax Alternative names: Ginseng; Panax ginseng Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Plantago Psyllium Alternative names: Psyllium, Ispaghula; Plantago psyllium/ovata Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Psyllium Alternative names: Plantago ovata, Plantago ispaghula Source: Healthnotes, Inc.; www.healthnotes.com Red Koji Source: Integrative Medicine Communications; www.drkoop.com Red Leaven Source: Integrative Medicine Communications; www.drkoop.com Red Rice Source: Integrative Medicine Communications; www.drkoop.com Red Yeast Rice Alternative names: Monascus purpureus Source: Healthnotes, Inc.; www.healthnotes.com Red Yeast Rice Alternative names: Angkak, Beni-koju, Hong Qu, Hung-chu, Monascus, Red Leaven, Red Rice, Red Koji, Zhitai, Xue Zhi Kang Source: Integrative Medicine Communications; www.drkoop.com Red Yeast Rice Source: Prima Communications, Inc.www.personalhealthzone.com Red Yeast Rice Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10054,00.html Silybum Alternative names: Milk Thistle; Silybum marianum (L.) Gaertn. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org


Smilax Alternative names: Sarsaparilla; Smilax glabra Roxb. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Swertia Alternative names: Swertia sp Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Syzygium Clove Alternative names: Clove, Jamun; Syzygium sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Vacciniumb Alternative names: Bilberry; Vaccinium myrtillus L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Vanadate Source: Integrative Medicine Communications; www.drkoop.com Vanadyl Source: Integrative Medicine Communications; www.drkoop.com Zhitai Source: Integrative Medicine Communications; www.drkoop.com Zue Zhi Kang Source: Integrative Medicine Communications; www.drkoop.com

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

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

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

Development of a Laser-based Infrared Detector for High-pressure Liquid Chromatography the Analysis of Cholesterol, Cholestryl Esters and Triglycerides in Serum by Stokl, Caroline; PhD from McGill University (Canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL52227

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Effects of Exercise and a Vegetarian Diet on Carcass Composition, Organ Weights, and Serum Cholesterol and Triglycerides by Klein, Daniel Allen, PhD from Michigan State University, 1971, 65 pages http://wwwlib.umi.com/dissertations/fullcit/7208722

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Physical Properties and Crystallization Kinetics of Bulk and Emulsified Triglycerides by Campbell, Shawn Douglas; MSC from University of Guelph (Canada), 2002, 88 pages http://wwwlib.umi.com/dissertations/fullcit/MQ67342

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The Combined Effects of Aerobic Exercise and Dietary Omega-3 Fatty Acids on Plasma Lipids, Platelets and Physiological Parameters in Hyperlipidemic Subjects (Triglycerides, Eicosapentaenoic Acid, Cholesterol, Oxygen Consumption, Blood

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Pressure) by Warner, James Grant, Jr., EDD from West Virginia University, 1986, 250 pages http://wwwlib.umi.com/dissertations/fullcit/8627737 •

The Effects of Exercise Training And/or Lecithin Supplement upon Serum Cholesterol Triglycerides and Beta-lipoproteins. by Krebs, Paul Samuel, EDD from University of Arkansas, 1978, 119 pages http://wwwlib.umi.com/dissertations/fullcit/7823235

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The Effects of Triglyceride Structure on the Properties of Plant Oil-based Resins by LaScala, John Joseph; PhD from University of Delaware, 2002, 408 pages http://wwwlib.umi.com/dissertations/fullcit/3062034

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The High Performance Liquid Chromatography and Detection of Phospholipids and Triglycerides by Compton, Bruce Jon; PhD from McGill University (Canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK51915

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Triglycerides of Milk Fat by Shehata, A. Adel Y; AdvDeg from University of Guelph (Canada), 1970 http://wwwlib.umi.com/dissertations/fullcit/NK07628

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

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CHAPTER 5. CLINICAL TRIALS AND TRIGLYCERIDES Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning triglycerides.

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

Niacin for Treatment of Elevated Cholesterol and Triglycerides in HIV-Infected Patients Condition(s): HIV Infections; Hypercholesterolemia; Hypertriglyceridemia; Diabetes Mellitus Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Allergy and Infectious Diseases (NIAID) Purpose - Excerpt: The purpose of this study is to evaluate the safety, efficacy, and tolerability of extended-release niacin (Niaspan) in improving the level of fats in the blood of HIV-infected patients. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00046267

•

Reduction of Triglycerides in Women on HRT Condition(s): Cardiovascular Diseases; Atherosclerosis; Postmenopause; Heart Diseases Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI)

8

These are listed at www.ClinicalTrials.gov.

108 Triglycerides

Purpose - Excerpt: To test the effect of lifestyle intervention on subclinical cardiovascular disease measures in women taking HRT. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00023543 •

Genetic Determinants:Low HDL, High Triglycerides, Obesity Condition(s): Cardiovascular Diseases; Atherosclerosis; Hypertriglyceridemia; Obesity; Heart Diseases Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To conduct genetic studies of the metabolic syndrome which is characterized by very low levels of high density lipoprotein cholesterol (HDL-C), hypertriglyceridemia, and obesity. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00049881

•

Genetic Epidemiology of Hypertriglyceridemia Condition(s): Cardiovascular Diseases; Coronary Disease; Hyperlipidemia, Familial Combined; Hyperlipoproteinemia Type IV Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine prospectively the role of elevated plasma triglyceride (TG) as a risk factor for 20-year coronary heart disease (CHD) mortality in familial combined hyperlipidemia (FCHL) and familial hypertriglyceridemia (FHTG), the familial forms of hypertriglyceridemia. Also, to perform genetic epidemiologic studies of recently identified lipoprotein risk factors for CHD, including Atherogenic Lipoprotein Phenotypes (ALP) based on subclasses of low-density lipoproteins (LDL), Lipoprotein(a) (Lp(a)) and apolipoprotein (apo) B plasma levels, and apo E isoforms. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005368

•

Regulation of Sterol Homeostasis Condition(s): Hypertriglyceridemia Study Status: This study is no longer recruiting patients. Sponsor(s): Department of Veterans Affairs Medical Research Service Purpose - Excerpt: The purpose of this study is to determine how people with high triglycerides metabolize and absorb bile acids, compounds made in the body from cholesterol. This project has two objectives: A) To define the mechanism of impaired bile acid absorption in hypertriglyceridemia (specifically we will determine if the active or passive component of absorption is abnormal) and B) to determine the contribution of

Clinical Trials 109

an alternative pathway of bile acid synthesis which begins with 27-hydroxylation of cholesterol. Because 27-hydroxylase is present in endothelial cells as well as liver, this pathway may play a role in removal of cholesterol from incipient atherosclerotic plaque. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00018720 •

Garlic in hyperlipidemia caused by HAART Condition(s): HIV Hyperglycemia

Infections;

Hypercholesterolemia;

Hypertriglyceridemia;

Study Status: This study is not yet open for patient recruitment. Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM) Purpose - Excerpt: This is a double-blind randomized placebo controlled trial to test the use of garlic to lower cholesterol and triglycerides in hyperlipidemic HIV-infected individuals who are being treated with highly active antiretroviral therapy (HAART). The garlic will be administered as enteric-coated tablets and in two escalating dosages. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00029250 •

Re-evaluating Triglycerides in Coronary Heart Disease Condition(s): Cardiovascular Hypertriglyceridemia

Diseases;

Heart

Diseases;

Coronary

Disease;

Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To conduct a comprehensive epidemiologic investigation into the relationship between serum triglyceride (TG) levels and coronary heart disease (CHD). Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005442

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “triglycerides” (or synonyms).

110 Triglycerides

While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

111

CHAPTER 6. PATENTS ON TRIGLYCERIDES Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “triglycerides” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on triglycerides, we have not necessarily excluded nonmedical patents in this bibliography.

Patents on Triglycerides By performing a patent search focusing on triglycerides, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 9Adapted from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

112 Triglycerides

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

4-amino substituted-2-substituted-1,2,3,4-tetrahydroquinolines Inventor(s): DeNinno; Michael P. (Gales Ferry, CT), Magnus-Aryitey; George T. (Ledyard, CT), Ruggeri; Roger B. (Waterford, CT), Wester; Ronald T. (Ledyard, CT) Assignee(s): Pfizer Inc. (New York, NY) Patent Number: 6,489,478 Date filed: September 27, 2000 Abstract: Cholesteryl ester transfer protein inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDLcholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans. Excerpt(s): This invention relates to cholesteryl ester transfer protein (CETP) inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to elevate certain plasma lipid levels, including high density lipoprotein (HDL)-cholesterol and to lower certain other plasma lipid levels, such as low density lipoprotein (LDL)cholesterol and triglycerides and accordingly to treat diseases which are affected by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in certain mammals (i.e., those which have CETP in their plasma), including humans. Atherosclerosis and its associated coronary artery disease (CAD) is the leading cause of mortality in the industrialized world. Despite attempts to modify secondary risk factors (smoking, obesity, lack of exercise) and treatment of dyslipidemia with dietary modification and drug therapy, coronary heart disease (CHD) remains the most common cause of death in the U.S., where cardiovascular disease accounts for 44% of all deaths, with 53% of these associated with atherosclerotic coronary heart disease. Risk for development of this condition has been shown to be strongly correlated with certain plasma lipid levels. While elevated LDL-C may be the most recognized form of dyslipidemia, it is by no means the only significant lipid associated contributor to CHD. Low HDL-C is also a known risk factor for CHD (Gordon, D. J., et al.,: "High-density Lipoprotein Cholesterol and Cardiovascular Disease", Circulation, (1989), 79: 8-15). Web site: http://www.delphion.com/details?pn=US06489478__

•

Blends for barrier layers for food products Inventor(s): Cain; Frederick William (Wormerveer, NL), Dekker; Willem (Wormerveer, NL), Smith; Kevin Warren (Sharnbrook, GB), Talbot; Geoffrey (Purfleet, GB) Assignee(s): Unilever Patent Holdings BV (NL) Patent Number: 6,461,654 Date filed: August 31, 2000

Patents 113

Abstract: Blends of a natural wax, such as sunflower wax and glyceride materials, substantially being triglycerides and having an N20>20 display excellent properties when applied in barrier layers for compound food products. Excerpt(s): it should have a low water permeability. it should stick well to the surfaces of the layers that it is supposed to protect against the water migration. it should not be too brittle, so that the formation of cracks in this layer is avoided as much as possible. Web site: http://www.delphion.com/details?pn=US06461654__ •

Blood-pool selective carrier for lipophilic imaging agents Inventor(s): Counsell; Raymond E. (Ann Arbor, MI), Longino; Marc A. (Ann Arbor, MI), Weichert; Jamey P. (Ann Arbor, MI) Assignee(s): The Board of Regents of the University of Michigan (Ann Arbor, MI) Patent Number: 6,645,463 Date filed: April 10, 1998 Abstract: A surface-modified lipoprotein-like oil-in-water emulsion useful as a bloodpool selective delivery vehicle for lipophilic imaging agents or lipophilic derivatives of water-soluble imaging agents. The blood-pool selective delivery vehicle remains in the blood for several hours, shows very little early hepatic sequestration, and is cleared from the blood within 24 hours. The mean diameter of the oil phase is less than 150 nm which minimizes sequestration by the reticuloendothelial system. The surface of the oil phase is modified with a polyethyl glycol-modified phospholipid to prevent normal interactions with the receptor sites of the hepatocytes. In radiographic imaging, radioactive or stable, synthetic or semi-synthetic polyhalogenated triglycerides, such as 2-oleoylglycerol-1,3-bis[7-(3-amino-2,4,6-triiodophenyl)heptanoate], or lipid soluble derivatives of traditional water-soluble contrast agents, such as aliphatic esters of iopanoic, diatrizoic, and acetrizoic acid, may be incorporated into the lipophilic core of a lipoprotein-like emulsion particle. Excerpt(s): This invention relates generally to an oil-in-water emulsion, and more particularly, to an oil-in-water emulsion that functions as a blood-pool selective carrier or delivery vehicle for lipophilic imaging agents, or lipid-soluble derivatives of watersoluble, imaging agents incorporated therein. Conventional water-soluble contrast media for x-ray computed tomography (CT) and magnetic resonance imaging (MRI) rapidly diffuse out of the blood following injection. Vascular imaging, for example, therefore depends on invasive intra-arterial infusion of large amounts of contrast media at or near the suspected site of disease. Despite administration of a bolus dose of contrast media, enhancement lasts for only a few seconds. In CT angiography, as a specific example, a large amount (

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